Article:Altered Redox Homeostasis in Branched-Chain Amino Acid Disorders, Organic Acidurias, and Homocystinuria. (5884027)

From ScienceSource
Jump to: navigation, search

This page is the ScienceSource HTML version of the scholarly article described at Its title is Altered Redox Homeostasis in Branched-Chain Amino Acid Disorders, Organic Acidurias, and Homocystinuria. and the publication date was 2018-03-20. The initial author is Eva Richard.

Fuller metadata can be found in the Wikidata link, which lists all authors, and may have detailed items for some or all of them. There is further information on the article in the footer below. This page is a reference version, and is protected against editing.

Converted JATS paper:

Journal Information

Title: Oxidative Medicine and Cellular Longevity

Altered Redox Homeostasis in Branched-Chain Amino Acid Disorders, Organic Acidurias, and Homocystinuria

  • Eva Richard
  • Lorena Gallego-Villar
  • Ana Rivera-Barahona
  • Alfonso Oyarzábal
  • Belén Pérez
  • Pilar Rodríguez-Pombo
  • Lourdes R. Desviat

Centro de Biología Molecular Severo Ochoa UAM-CSIC, Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), CIBERER, IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain

Publication date (collection): /2018

Publication date (epub): 3/2018


Inborn errors of metabolism (IEMs) are a group of monogenic disorders characterized by dysregulation of the metabolic networks that underlie development and homeostasis. Emerging evidence points to oxidative stress and mitochondrial dysfunction as major contributors to the multiorgan alterations observed in several IEMs. The accumulation of toxic metabolites in organic acidurias, respiratory chain, and fatty acid oxidation disorders inhibits mitochondrial enzymes and processes resulting in elevated levels of reactive oxygen species (ROS). In other IEMs, as in homocystinuria, different sources of ROS have been proposed. In patients' samples, as well as in cellular and animal models, several studies have identified significant increases in ROS levels along with decreases in antioxidant defences, correlating with oxidative damage to proteins, lipids, and DNA. Elevated ROS disturb redox-signaling pathways regulating biological processes such as cell growth, differentiation, or cell death; however, there are few studies investigating these processes in IEMs. In this review, we describe the published data on mitochondrial dysfunction, oxidative stress, and impaired redox signaling in branched-chain amino acid disorders, other organic acidurias, and homocystinuria, along with recent studies exploring the efficiency of antioxidants and mitochondria-targeted therapies as therapeutic compounds in these diseases.


1. Introduction

A growing body of evidence indicates that disruption of redox homeostasis is involved in the pathophysiology of several inborn errors of metabolism (IEMs), including organic acidurias, respiratory chain disorders, fatty acid oxidation disorders, and aminoacidopathies [[1][7]]. IEMs are defined as genetic defects that affect a metabolic pathway or cellular process and are commonly characterized by a specifically altered biochemical profile that guides the diagnosis [[8]]. They belong to the category of rare diseases (defined by the EU as those with an incidence lower than 1 in 2000), and most of them are inherited in autosomal recessive fashion. In the classic IEMs, pathology results from accumulation of toxic metabolites and/or from the deficiency or absence of substrates necessary to perform normal cellular functions. Many of them are systemic, and in most cases, they affect the central nervous system [[8]].

Several IEMs share common pathomechanisms as a consequence of the accumulation of toxic metabolites; these inhibit specific mitochondrial enzymes and processes, resulting in mitochondrial dysfunction, impaired energy metabolism, increased reactive oxygen species (ROS) levels, altered antioxidant response capability, and increased oxidative stress, resulting in damage to DNA, proteins, and lipids [[2], [3], [9], [10]]. The brain and heart, frequently affected in IEMs, are energy-demanding organs highly sensitive to oxidative stress due to their high rate of oxygen consumption, substantial iron and polyunsaturated lipid contents, and relatively low activity of their antioxidant defences and repair enzymes [[11]]. Metabolic profiling of oxidative stress in IEM patients' samples has documented the correlation between oxidative stress markers and biochemical and clinical parameters [[12], [13]].

Mitochondria, which are the major energy producers in the cell, and where many important metabolic pathways take place, are the major ROS producers [[14]]. Mitochondrial ROS is generated, in the form of superoxide anion (O2−), at complexes I and III of the electron transport chain and are rapidly converted to hydrogen peroxide (H2O2) by the enzyme superoxide dismutase (MnSOD). Mitochondrial matrix complexes such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, or branched-chain alpha-ketoacid dehydrogenase (BCKDH) can also generate O2−. Other cellular sources of ROS exist, and an active interplay between all of them has been documented [[15]]. To avoid the noxious consequences of ROS, mitochondria express a variety of antioxidant enzymes, including MnSOD, peroxiredoxins, and glutathione peroxidase (GPX) [[16]]. Among the nonprotein antioxidants, glutathione (L-γ-glutamyl-L-cysteinylglycine) represents the main antioxidant defence present in the cell. An increase in ROS levels correlates with a decrease in reduced glutathione (GSH). Thus, the ratio of oxidized (GSSG) to reduced (GSH) is indicative of cellular redox balance and has been used as a biomarker of oxidative stress in different diseases including IEMs [[17][20]].

At physiological concentrations, ROS are recognized to act as signaling molecules modifying specific proteins that will transmit a message modulating specific cellular pathways, in what is known as redox signaling [[15]]. Well-known examples include redox-sensitive changes in conformation and function of receptors, transcription factors, kinases, and phosphatases, which lead to a specific cellular response [[15]]. At high concentrations, ROS may cause extensive damage to cells, by peroxidation of lipids, carbonylation of proteins, or DNA base oxidation. These toxic effects can disrupt mitochondrial function causing a further increase in ROS production, thus forming a vicious cycle. In cases of chronic, high levels of ROS production, apoptosis or autophagy/mitophagy processes are triggered [[16]]. All this has led to redefine the concept of oxidative stress, initially conceived as an alteration in the balance between oxidant and antioxidant molecules, to a disturbance in redox signaling with possible molecular and/or cellular damage [[15]].

In the mitochondria, H2O2 is the most likely signal involved in redox signaling and in transcription regulation, through thiol/disulfide exchange reactions [[21]]. Signal transduction by H2O2 may occur via peroxiredoxin-2 and transcription factor STAT3 [[22]]. H2O2 acts on redox-sensitive targets such as transcription factor NRF2 involved in antioxidant response, NFκΒ protein complex involved in inflammation, stress kinase JNK, and insulin-like growth factor IGF1, linking energy metabolism and inflammatory responses [[23]]. Oxidative stress and bioenergetics deficits trigger signaling through mitophagy receptors such as ATG32, BCL2-L-13, and FUNDC1, leading to the elimination of damaged mitochondria [[24]].

In IEMs, as in cardiovascular and neurodegenerative diseases, the production of pathological amounts of ROS resulting in oxidative damage may indeed disturb redox signaling and induce cell stress responses, which may in some cases lead to cell death [[1], [25]]. However, the exact molecular mechanisms and cellular pathways involved in this progression are scarcely characterized. In some IEMs, specific activation of stress kinases p38 and JNK and of autophagy/mitophagy and apoptotic pathways has been documented [[6], [7], [26], [27]].

A recent review provided insight into the adaptive stress responses that operate in IEMs, linking mitochondrial biogenesis to cellular antioxidant, anti-inflammatory, protein quality control, and autophagy functions [[1]]. As a first line of cellular responses to oxidative stress, the expression of antioxidant enzymes and heat-shock proteins increases, along with an upregulation of glycolysis and activation of mitochondrial biogenesis, as occurs in multiple acyl-CoA dehydrogenation deficiency [[28]]. ROS-mediated activation of AMP-activated protein kinase (AMPK) could be the link between metabolic reprogramming, mitochondrial biogenesis, and activation of cellular stress repair pathways, followed by the progression to proinflammatory responses controlled by signaling pathways mTOR/HIF-1α/NFκΒ [[1]].

The presence of interconnected redox-signaling pathways and their alterations in disease contributing to the pathogenesis suggests that specific compounds targeting excessive ROS or mitochondrial dysfunction may show therapeutic potential. This has been explored in some IEMs, in which several antioxidants or mitochondrial biogenesis activators have proven effective in cellular and/or animal models of disease [[29][32]]. However, clinical efficacy of these approaches remains unproven. In addition, the possible interference of these therapies with cellular redox signaling should be taken into account for careful design and appropriate clinical testing.

In this study, we describe sources of ROS in specific IEMs; we summarize the available data on altered redox homeostasis and oxidative damage in patients' samples and in animal models of disease; we discuss potential implications for redox signaling and describe the recent advances in antioxidant- and mitochondria-targeted therapies for these pathologies. To this aim, we have focused in selected branched-chain amino acid disorders, organic acidurias, and defects leading to the accumulation of homocysteine (homocystinuria) (Figure 1). For other IEMs, namely inherited mitochondrial diseases and fatty acid oxidation disorders, the readers are referred to recent reviews [[9], [33]].

2. Branched-Chain Amino Acid Disorders and Organic Acidurias

Branched-chain amino acids (BCAAs: Val, Ile, Leu) are essential amino acids not only necessary for protein synthesis but also key nitrogen donors involved in interorgan and intercellular nitrogen shuttling [[34]] and key nutrient signals involved in important functions including food intake regulation. Leu has long been known as an anabolic nutrient-signaling molecule that stimulates protein synthesis by activation of the mTORC1 pathway in selected tissues [[35]]. Recently, mitochondrial sirtuin 4 (SIRT4), acting as a lysine deacylase, has been reported to control Leu catabolism and insulin secretion, reinforcing the hypothesis of a possible link between BCAA metabolism and insulin secretion [[36]]. All these data underscore the critical role of BCAAs metabolism in humans' health and disease, as was evidenced with the characterization of maple syrup urine disease (MSUD) [[37]] and, more recently, with the description of branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency [[38], [39]].

Organic acidurias/acidemias are described as IEMs affecting enzymes, receptors, or transport proteins in the catabolic pathway of amino acids and odd-chain fatty acids and characterized by the abnormal accumulation of organic acids in body fluids [[40]]. More than 65 organic acidurias have been described, with MSUD, propionic acidemia (PA), and methylmalonic acidurias (MMA) among the most prevalent. A secondary mitochondrial dysfunction induced by accumulating toxic metabolites is an important pathomechanism in these disorders [[10]]. Patients with organic acidurias show elevated plasma protein carbonyls and lower GSH levels in leukocytes [[20]]. Here we briefly summarize the published data on branched-chain amino acid disorders and specific organic acidurias with a profile of altered redox homeostasis.

2.1. Disorders Involving Branched-Chain α-Ketoacid Dehydrogenase

MSUD (MIM #248600), caused by the deficiency of branched-chain α-ketoacid dehydrogenase complex (BCKDHc) activity, is characterized by elevated levels of BCAAs and their corresponding α-keto-acids (BCKAs) in body fluids and tissues, resulting in complex neurological phenotypes [[37]]. As the important gatekeeping enzyme that it is, BCKDHc is regulated by reversible phosphorylation catalyzed by a specific BCKD kinase (BCKDK) that inhibits BCKDHc function, halting the catabolic pathway of BCAAs [[41]], and a dephosphorylation catalyzed by the mitochondrial protein phosphatase PP2Cm (encoded by the PPM1K gene) that stimulates BCKDHc activity [[42]]. Optimal BCKDHc activity necessary to maintain BCAA homeostasis is achieved by the coordinated response of BCKDK and PP2Cm activities. Blockage or unrestrained BCAA metabolism through BCKDHc leads to a dysmetabolism of BCAAs resulting in MSUD or BCKDK deficiency (MIM #614923) (Figure 1), two different clinical conditions with a hallmark of neurological perturbation.

MSUD results from mutations in the genes E1α-BCKDHA (MIM #608348), E1β-BCKDHB (MIM #24861), and E2-DBT (MIM #248610) [[37]]. The disease affects 1 : 185,000 newborns worldwide and is manifested by diverse clinical phenotypes, ranging from the most severe form—seen in 70% of patients with MSUD and associated with a profound neurological impact and high mortality if not treated early—to mild forms that present during early development. The mechanisms underlying brain injury are not completely understood. Different studies have been carried out using chemical induction of the disease by BCAAs or BCKAs in cultured cells [[43], [44]] and animal models [[45][48]]. All converge in the identification of oxidative stress, brain energy deficit, and/or alterations in the brain's neurotransmission balance, mostly affecting glutamate [[46]], as important neurodegenerative determinants. Recent studies in human peripheral blood mononuclear cells have shown that 10 mM of BCAAs can directly trigger a mechanism that involves the two major ROS sources, NADPH oxidase and mitochondria. BCAAs stimulate the activation of the redox-sensitive transcription factor NFκΒ resulting in the release of proinflammatory molecules [[49]].

Increases in lipid and protein oxidation are detected in plasma of MSUD patients [[50], [51]]. The two branched-chain aminotransferases (BCATs) involved in the conversion of BCAAs in BCKAs contain redox-active cysteine residues and could be affected by an oxidative environment. Their inhibition would provoke a further increase in the BCAA levels that could exacerbate the effect of the blockage [[34]]. An increased inflammatory profile has also been observed in plasma samples from MSUD patients maintained at low BCAA levels indicating the presence of sustained inflammation and activation of the immune system probably as a result of unbalanced ROS production [[52]].

On the other hand, mutations in the PPM1K gene in human result in a mild increase of BCAA and BCKA levels compatible with a mild variant form of MSUD (Figure 1), which nevertheless results in ROS increases along with the activation of the JNK and p38 MAP kinases [[42]]. This could be related to its critical role for mitochondrial function and cell survival previously described in animal models [[53]].

In the reverse of the MSUD metabolic problem, BCKDK patients (MIM #614923) manifest an unrestrained BCAA metabolism with decreased BCAA and BCKA levels, accompanied by neurocognitive phenotypes [[38], [39]]. However, also in this case, the mitochondrial response to BCKDK deficiency seems to be the increase in O2−, alterations in the expression of MnSOD and GPX, and alterations in the bioenergetics' profile with reductions in ATP-linked respiration and intracellular levels. All these data support the hyperfusion response of BCKDK-deficient mitochondria to stress and the altered cell fate observed in patients' fibroblasts [[54]]. Apart from the canonical ROS-producing sites in mitochondrial electron transfer chain, several reports pointed towards the important role of mitochondrial 2-oxoacid dehydrogenase complexes (2-oxoglutarate dehydrogenase, pyruvate dehydrogenase, and BCKDH) that share the E3 dihydrolipoamide dehydrogenase, as major O2−/H2O2 producers under conditions of maximum activities of substrate oxidation [[55], [56]]. Therefore, the most likely result from the uninhibited activity of BCKDHc could be a misbalance in redox equilibrium and an increase in the production of O2−/H2O2 [[54][56]].

2.2. Propionic Acidemia

Propionic acidemia (PA, MIM #606054) is one of the most frequent life-threatening organic acidurias, affecting 1 in 100,000 live births worldwide. PA results from mutations in the PCCA or PCCB gene that encode the α and β subunits of propionyl-CoA carboxylase (PCC), respectively. PCC is a biotin-dependent mitochondrial enzyme that catalyzes the reaction of propionyl-CoA to D-methylmalonyl-CoA, the first step of the propionate oxidation pathway (Figure 1). Propionyl-CoA derives from the catabolism of certain amino acids including BCAAs (Ile, Val, Thr, and Met), of cholesterol, and from the beta-oxidation of odd chain fatty acids and bacteria gut production [[57]]. PCC deficiency results in the accumulation and excretion of propionate, 3-hydroxypropionate, methylcitrate, and propionylglycine, which are the biochemical hallmarks for diagnosis [[57]]. PA leads to a multisystemic disorder that affects the cardiovascular, gastrointestinal, renal, nervous, and immune systems [[58], [59]]. The clinical outcome varies from a severe neonatal form characterized by ketoacidosis, feeding refusal, lethargy, failure to thrive, seizures, and encephalopathy to a milder-late onset form with metabolic decompensations, failure to thrive, and diverse neurological deficiencies [[60][62]]. Cardiomyopathy and neurological features are associated with a high morbidity and mortality and have been attributed to bioenergetic failure and intracellular accumulation of toxic metabolites [[63], [64]].

A number of in vitro and in vivo studies of propionyl-CoA metabolites have shown inhibition of enzymes involved in energy production pathways, such as respiratory chain complex III [[65]] and pyruvate dehydrogenase complex [[66]]. Furthermore, propionyl-CoA reacts with oxaloacetate to produce methylcitrate that inhibits enzymes such as phosphofructokinase aconitase and citrate synthase [[67]]. In addition, propionate, at concentrations similar to those found in the plasma of PA patients, strongly inhibits oxygen consumption as well as oxidation of pyruvate and alpha-ketoglutarate in rat liver mitochondria [[66], [68]]. Moreover, the lack of PCC that blocks the anaplerotic biosynthesis of succinyl-CoA from propionyl-CoA may result in diminished TCA cycle activity [[69]]. This could be especially relevant for the heart and skeletal muscle, for which propionate is a major anaplerotic substrate. Propionic acid was shown to stimulate the production of O2− in the presence of Ca2+ influx activators in human neutrophils [[70]], to increase protein carbonylation in rats [[71]] and to stimulate lipid peroxidation in rat cerebral tissues [[72]].

The secondary mitochondrial dysfunction in PA is manifested as a decrease in ATP and phospho-creatine production, a decrease in the activity of respiratory chain complexes, mtDNA depletion, and abnormal mitochondrial structures present in PA patients' biopsies. This is evident particularly in high-energy-demanding organs such as the brain and heart [[73][75]]. In addition, evidence of oxidative stress and cellular damage has been shown in PA patients' fibroblasts through detection of elevated intracellular H2O2 levels correlating with the activation of the JNK and p38 pathways [[26]]. Urinary samples from PA patients show high levels of oxidative stress markers [[12]].

Alterations in redox homeostasis and mitochondrial function were observed in a hypomorphic mouse model of PA (Pcca−/− (A138T)) [[5]]. These include increased O2− production and in vivo mitochondrial H2O2 levels, mtDNA depletion, lipid oxidative damage, and tissue-specific alterations in the activities of OXPHOS complexes and in antioxidant defences. An increase in the DNA repair enzyme 8-guanine DNA glycosylase 1 (OGG1) induced by oxidative stress was also found in the liver of PA mice [[32]]. These alterations show a good correlation with the altered mitochondrial function and oxidative damage detected in PA patients' samples [[12], [73][77]].

2.3. Methylmalonic Acidurias

Methylmalonic acidurias (MMA) include a heterogeneous group of autosomal recessive genetic disorders caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MCM) or by defects in cobalamin (cbl) absorption, intracellular cbl trafficking, or synthesis of adenosylcobalamin (Adocbl) and methylcobalamin (Mecbl), which serve as cofactors for MCM and for the cytosolic enzyme methionine synthase, respectively (Figure 1). Two clinical entities have been described: (i) isolated MMA, characterized by methylmalonic acid accumulation and caused by MCM deficiency, defects in Adocbl synthesis, and methylmalonyl-CoA epimerase deficiency and (ii) combined MMA and homocystinuria, characterized by methylmalonic acid and homocysteine accumulation and caused by defects in intracellular cbl metabolism (Figure 1).

2.3.1. Isolated MMA

MCM (MIM #251000; mut0 or mut− enzymatic subtypes), encoded by the mut gene, is a mitochondrial matrix enzyme that catalyzes the conversion of L-methylmalonyl-CoA to succinyl-CoA [[57]]. Biochemically, the disease is characterized by accumulation of methylmalonic acid and by accumulation of propionate, 3-hydroxypropionate, and 2-methylcitrate, due to activation of alternative pathways of propionate oxidation. Clinical presentation varies from a severe, early onset form of the disease, with neonatal ketoacidosis, lethargy, failure to thrive, encephalopathy, and hepatomegaly, to a milder late-onset presentation usually diagnosed during infancy that has a less serious neurological outcome [[57]]. Neurological symptoms, including psychomotor delay, irritability, lethargy, hypotonia, convulsions, and coma, have been related to a failure in mitochondrial oxidative metabolism. Mitochondrial dysfunction could be due to a combination of the inhibition of specific enzymes and transporters, limitation in the availability of substrates for mitochondrial metabolic pathways, and oxidative damage [[78]].

Mitochondrial toxicity of methylmalonic acid has been examined in vitro using a variety of normal tissues and extracts, including rat brain, mouse muscle, and bovine heart, suggesting an impairment of mitochondrial function, ROS generation, and other secondary metabolic perturbations [[72], [79][81]]. In addition, 2-methylcitric acid, malonic acid, and propionyl-CoA inhibit respiratory chain and tricarboxylic cycle [[82]]. In cultured neurons, methylmalonic acid decreases ATP/ADP ratio, collapses ion gradients, causes membrane depolarization, and increases intracellular calcium levels, leading to necrotic and apoptotic cell death [[78]].

Experimental evidence using patients' samples and a mut-knockout mouse identified multiple oxidative phosphorylation (OXPHOS) defects in MMA perturbations in antioxidant defences and resulting oxidative damage, indicating deficient energy metabolism caused by methylmalonyl-CoA accumulation and reduced succinyl-CoA levels [[73], [83][86]]. Proteomic analysis of patient liver samples by two-dimensional differential in-gel electrophoresis (2D–DIGE) and mass spectrometry (MALDI-MS and LC-MSMS) showed alterations of enzymes involved in free radical scavenging [[87]]. In patient's fibroblasts, proteomic analysis (2-D DIGE/MALDI-TOF) identified several differentially expressed proteins related to oxidative stress and apoptosis (cytochrome c, MnSOD, and mitochondrial glycerophosphate dehydrogenase) [[88]]. In a study using high-dimensional flow cytometry, patients with MMA showed lower GSH levels in T lymphocytes, monocytes, and neutrophils, compared to healthy controls [[20]]. Oxidative damage markers (F-2 isoprostanes and dityrosine) were found increased in urinary samples from MMA patients [[12], [89]]. Plasma from patients showed significantly higher levels of protein carbonyls as compared to healthy controls [[20]].

In addition, various parameters of oxidative stress and apoptosis were evaluated in cultured fibroblasts from a spectrum of patients with MMA showing a significant increase in intracellular ROS content, MnSOD protein and apoptosis rate compared to controls [[6]]. Furthermore, cytochrome c oxidase deficiency was observed in renal tubular megamitochondria from a MMA patient [[90]], and mitochondrial ultrastructural abnormalities were found in renal samples from MMA mice [[89]] and in liver samples from MMA mut0 patients undergoing transplantation [[91]].

2.3.2. MMA Combined with Homocystinuria

Cobalamin deficiency type C with methylmalonic aciduria and homocystinuria (cblC; MMACHC; MIM #277400 and #609831) (Figure 1) is the most frequent genetic disorder of vitamin B12 metabolism. MMACHC protein is a processing enzyme involved in an early cytoplasmic step in the cofactor-trafficking pathway. It exhibits unusual chemical versatility with demonstrated gluthatione transferase, reductive decyanase, and aquocobalamin reductase activities and converts incoming cobalamin derivatives to an intermediate that can be partitioned into Mecbl and Adocbl synthesis to support cellular needs [[92][94]]. MMACHC catalyzes the glutathione- (GSH-) dependent dealkylation of alkylcobalamins and the reductive deacyanation of cyanocobalamin [[95]].

Early-onset patients with cblC disease present multisystem failure while there are late-onset patients exhibiting a milder form, with progressive neurological symptoms and behavioural disturbances [[96]]. Maculopathy and abnormal vision are extremely common in early-onset patients [[97]].

Increasing evidence provides support that oxidative stress is closely associated with the physiopathology of this disorder. In this disease, there is a combined contribution of mitochondrial ROS due to accumulation of methylmalonic acid, as well as of homocysteine-derived ROS (see below, the Homocystinuria section). Patient-derived fibroblasts showed elevated ROS, apoptosis, and active phosphorylated forms of p38 and JNK stress-kinase levels [[98], [99]]. High levels of oxidative damage biomarkers have been found in urinary samples [[12]]. Decreased levels of proteins involved in cellular detoxification (members of the peroxiredoxin family and isoforms of glutathione-S-transferases) were detected in patient-derived fibroblasts by proteomics techniques [[100], [101]]. Another proteomic study in patients' lymphocytes revealed the deregulation in the expression of proteins involved in oxidative stress and cellular detoxification, especially those related to glutathione metabolism [[102]]. In relation to this, an imbalance of glutathione metabolism was observed in cblC blood samples with a significant decrease in total and reduced glutathione, along with an increase in different oxidized glutathione forms [[19]]. GSH depletion could be the consequence of a reduced synthesis since total glutathione and its rate-limiting precursor (cysteine) is decreased in cblC patients [[19]]. In addition, increased levels of protein-bound glutathione were detected, providing evidence of the impact of changes in glutathione pools in the pathogenesis of cblC disease through redox regulation of protein function [[19]]. Furthermore, two mutant MMACHC proteins exhibited impaired glutathione binding, and stabilization of the cob(II)alamin derivative has been observed in presence of physiologically relevant glutathione concentrations. The preferential stabilization of cob(II)alamin by the mutants with a concomitant increase in GSSG production offers insights into ROS production [[103]].

2.4. Glutaric Aciduria Type I

Glutaric aciduria type I (GAI, OMIM #231670) is caused by the deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), responsible for the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA, in the catabolic pathways of lysine and tryptophan [[104]]. The deficiency causes accumulation of glutarate and 3-hydroxyglutarate, and patients are at risk of acute striatal injury during encephalopathic crises before 4 years of age, frequently precipitated by nonspecific illnesses [[105]]. These episodes lead to the appearance of neurological symptoms including dystonia, dyskinesia, seizures, and coma [[106]]. Current treatment for GAI includes dietary lysine restriction and carnitine supplementation, although this does not prevent striatal degeneration in about one-third of the patients. Excitotoxicity, oxidative stress, and mitochondrial dysfunction induced by accumulating metabolites have been associated with brain pathogenesis, although the exact underlying mechanisms remain unclear [[4], [107], [108]].

Glutaric acid administration induces lipid peroxidation and alterations in antioxidant defences in rats [[109]]. GCDH-deficient knockout mice (Gcdh−/−) show a biochemical phenotype comparable to GAI patients but do not develop striatal degeneration [[110]]. These mice exhibit protein oxidative damage and reduction of antioxidant defences in the brain when subjected to an acute lysine overload [[111]]. Indeed, GCDH knockout mice fed on a high-lysine chow represent an animal model of GAI encephalopathy g [[112]]. In these mice, high concentrations of glutaric acid within neurons were correlated with mitochodrial swelling and biochemical changes (depletion of alpha-ketoglutarate and accumulation of acetyl-CoA) consistent with Krebs cycle disruption [[113]].

2.5. Other Organic Acidurias

There are several other organic acidurias in which there is an inhibition of energy metabolism attributed to accumulation of toxic metabolites in mitochondria. These include 3-methylcrotonyl-CoA carboxylase deficiency (MCC, MIM #210200 and #210210), 2-methyl-3-hydroxybutyric aciduria (MOHBA, MIM #203750), 3-methylglutaconic aciduria (MHGA, MIM #250950), D-2-hydroxyglutaric aciduria (D-2-OHGA, MIM #600721), L-2-hydroxyglutaric aciduria (L-2-OHGA, MIM #236792), 3-hydroxy-3-methylglutaric aciduria (3-HMGA, MIM #246450), and ethylmalonic encephalopathy (EE, MIM #602473). Deficiencies in several respiratory chain complexes have been reported in some of these pathologies, such as MOHBA (I and IV) [[114]], MGA (I and V) [[115]], D-2-OHGA (V and IV) [[116]], and EE (IV and II) [[117]]. Abnormal structure of mitochondria was also found in patients' samples with MHGA [[118]].

A growing body of experimental evidence indicates that impairment of redox homeostasis induced by the major organic acids accumulating in 3-HMGA contributes to the brain and liver pathophysiology [[3]]. Lipid and protein damage, along with a decrease of antioxidant defences, have been observed in patients' plasma and urine [[3]].

A recent transcriptome study in MCC-deficient patient-derived fibroblasts revealed an altered gene expression profile indicative of mitochondrial dysfunction, decreased antioxidant response, and disruption of energy homeostasis [[119]]. This correlates with previous in vitro studies in the cerebral cortex of young rats in which the accumulated metabolites have been shown to disrupt energy homeostasis and cause lipid peroxidation [[120]].

3. Homocystinuria

In several IEMs, increased ROS causes pathophysiological oxidative damage that is not originated in the mitochondria. This is the case of homocystinuria in which excess homocysteine (Hcy) directly promotes ROS formation. Hcy is a sulphur-containing amino acid derived from the demethylation of the essential amino acid methionine. Autoxidation of two Hcy molecules yields the oxidized disulphide homocystine, two protons and two electrons, generating ROS in the form of O2−, hydrogen radical, or H2O2 [[121]]. Formation of mixed disulphides also contributes to the additional formation of ROS [[121]]. In addition to its inherent reactivity, specific mechanisms such as reduction in bioavailable nitric oxide and decreased glutathione peroxidase activity may play a role in Hcy-induced oxidative stress [[122], [123]]. Plasma Hcy has been known for decades as a risk marker for cardiovascular disease, which is explained by Hcy-induced oxidative damage in endothelial cells [[124]]. Induction of NADPH oxidase or downregulation of thioredoxin expression have been postulated as underlying mechanisms [[125]]. Elevated homocysteine concentration has also been proposed as a risk factor for neurodegenerative diseases inducing neurological dysfunction via oxidative stress [[126]].

Hcy metabolism stands at the intersection of two pathways: remethylation to methionine and transsulfuration to cystathionine [[127]]. Inherited homocystinurias have in common accumulation of homocysteine with subsequent neurotoxicity. This group of diseases encompasses two distinctive clinical entities: classical homocystinuria due to cystathionine β-synthase (CBS) deficiency (transsulfuration pathway) and the rare inborn errors of cobalamin and folate metabolism (remethylation pathway) [[128]] (Figure 1).

3.1. Homocystinuria due to Cystathionine β-Synthase Deficiency

Deficiency of cystathionine β-synthase (CBS, MIM #236200) is a disorder of methionine metabolism leading to elevated methionine and an abnormal accumulation of Hcy and its metabolites (homocystine, homocysteine-cysteine complex, and others) in the blood and urine. In the case of excess cellular methionine levels, the transsulfuration pathway plays an important role in Hcy metabolism and converts Hcy into cystathionine with the help of the enzyme CBS (Figure 1). The cystathionine formed is then converted into cysteine by cystathionine γ-lyase. Although the pathophysiology of CBS deficiency is not yet well established, Hcy excess or cysteine deficiency rather than the accumulation of methionine is more likely to cause the pathogenesis of this disease [[127]]. CBS deficiency is clinically characterized by heterogeneous clinical manifestations in various organs and tissues, such as thinning and lengthening of the long bones, osteoporosis, dislocation of the ocular lens, thromboembolism, and mental retardation [[127]].

Oxidative stress may play an important role in the pathophysiology of homocystinuria, as deduced from studies carried out in patients and animal models [[129]]. Protein, lipid, and DNA oxidative damage and decreased antioxidant defences have been found in patients [[130][132]]. Increases in lipid, protein, and DNA oxidative damage biomarkers have been reported in CBS-deficient mice [[133]] and in samples from animal models subjected to Hcy administration [[134], [135]].

3.2. Homocystinuria due to Remethylation Defects

Remethylation disorders are due to deficiencies of enzymes involved in the remethylation of Hcy to methionine causing homocystinuria. They include defects in methionine synthase (MTR, MIM #156570), methionine synthase reductase (MTRR, MIM #602568), MMADHC 5(MIM #611935), and 5,10-methylene tetrahydrofolate reductase enzyme (MTHFR, MIM #236250) (Figure 1) [[136]]. Biochemically, these disorders are characterized by Hcy elevation and low-to-normal methionine levels, without urinary methylmalonic acid excretion. Patients present severe clinical symptoms, which are mainly neurological for MTHFR deficiency and neurohematological for MTR and MTRR defects [[136]]. Two major mechanisms have been proposed to explain the pathogenesis of these diseases: (i) defective methionine synthesis (with a consequent drop in S-adenosylmethionine production and deficiencies of numerous methylation reactions leading to hypomyelination in the central nervous system) [[137]] and (ii) Hcy excess [[127]].

Patient-derived fibroblasts with defects in MTR, MTRR, or MTHFR show a significant increase in ROS content, in MnSOD levels, in the rate of apoptosis, and in the levels of the active phosphorylated forms of p38 and JNK stress kinases [[7]]. Increased mRNA and protein levels of Herp, Grp78, IP3R1, pPERK, ATF4, CHOP, asparagine synthase, GADD45, and MAM-associated proteins were also found in these cells indicating an increase in endoplasmic reticulum stress and subsequent mitochondrial calcium overload. In addition, an activation of autophagy process and a substantial degradation of altered mitochondria by mitophagy were detected in patient-derived fibroblasts [[138]].

4. Challenges in ROS Detection

ROS production plays an important role in physiological and pathological processes. In order to understand how they contribute to these cellular processes, it is essential to identify the specific reactive species produced, levels, and subcellular localization. ROS lifetime ranges from nanoseconds to seconds due to their high reactivity and depends on numerous clearance mechanisms such as the intracellular antioxidant levels [[139]]. Steady state concentration of mitochondrial O2− and H2O2 have been estimated to be in the picomolar and low nanomolar ranges, respectively. ROS detection thereby requires specific molecular probes that promptly interact with ROS to compete with antioxidants and generate stable products, which can be accurately quantified. However, their very short life span and extremely low concentration and instability, as well as the large diversity of possible chemical reactions, make ROS assessment challenging. Excellent reviews by different authors cover the limitations, progress, and perspectives of the most widely used tools and new approaches described for monitoring ROS detection [[139][142]]. In this section, we focus on some of the most common detection strategies used to asses oxidative stress in vitro and in vivo in organic acidurias, pointing out some of their methodological constrains and concerns.

Assessment of ROS levels has largely relied on the detection of end products [[143]]. The small cell-permeable probes 2′,7′-dichlorodihydrofluorescein (H2DCF) and dihydroethidium (DHE) are the most commonly used molecules for intracellular ROS detection of H2O2 and O2−, respectively. Despite the fact that H2DCF is one of the most commonly used probes, many concerns have been raised regarding its mechanism of action and specificity [[144]]. For instance, it is known that a host of ROS species such as nitric oxide, peroxynitrite anions (ONOO−), and even organic hydroperoxides can oxidize H2DCF. In addition, redox reactions with DCF and DCFH may lead to generation of the DCF-free radical anion [[145]], which produces O2− and reacts with antioxidants such as thiols and ascorbate [[146]]. Intracellular ROS generation throughout oxidation of H2DCF has been detected in PA, cobalamin disorders (cblB, cblC, cblE, and cblG), MTHFR deficiency, and MSUD patient-derived fibroblasts [[26], [42], [98]]. Recently, mitochondrial ROS generation has been measured in the cortex of a mouse model of MMA (induced by MMA and ammonia) [[147]]. DCF measurements should be carefully considered, and extra controls for the assessment of ROS production are required. Thus, DCF has been suggested as a general oxidative stress indicator instead of serving as a specific proof of H2O2 production.

DHE has been extensively used for intracellular O2− measurements together with its mitochondrial-targeted analog (MitoSOX). The specificity of DHE and its oxidative products has been a matter of debate for decades [[144]]. DHE can form two fluorescent products. One is ethidium, which is formed by nonspecific redox reactions, while the other is 2-hydroxyethidium (2-OH-E+), a specific adduct of O2− [[148]]. The fluorescent spectra of ethidium and 2-OH-E+ overlap, and it is therefore difficult to accurately measure only 2-OH-E+ by simple fluorescent detection methods. However, careful use of specific wavelengths of excitation allows separation of these to signals [[149]]. DHE staining has been used to measure O2− production in brain and heart cryosections of Pcca−/− (A138T) mice [[5]]. MitoSOX has been used to measure the basal production of mitochondrial O2− in cobalamin disorders (cblB and cblE) and in BCKDK-deficient patient-derived fibroblasts [[6], [7], [54]]. However, the combination of DHE and analytical methods such as high-pressure liquid chromatography and mass spectrometry is essential to validate DHE as a technique to quantify O2− [[150]].

In order to have a better understanding of ROS mitochondrial regulation and its role in oxidative damage and redox signaling, new approaches to measure mitochondrial ROS levels within living organisms are essential. Logan et al. developed a radiometric mass spectrometry probe approach. This method is based on the use of the MitoB probe, which comprises a triphenylphosphonium (TPP) cation driving its accumulation inside the mitochondria, conjugated to an arylboronic acid that reacts with H2O2 to form a phenol MitoP. Once MitoB is administrated to the animal, the probe is modified in vivo by ROS to generate an exomarker product (MitoP). The MitoB/MitoP ratio allows assessment of the levels of ROS in vivo [[151], [152]]. This technique has been applied to the mouse model of PA, to measure relative levels of H2O2 in the liver and heart [[5]]. The main advantages of this approach are its high selectivity, in vivo localization, and the use of analytical techniques such as LC-MS/MS to identify and quantify exomarkers. However, some significant weaknesses are also observed such as its inherently invasive methodology and the time-consuming nature of sample preparation.

Despite the progress achieved in the field of ROS detection, there is a clear need to develop noninvasive, in vivo, and more selective methods to address many important questions related to the role of altered redox homeostasis in the pathology of IEMs.

5. Redox-Based Therapeutic Approaches

Most IEMs in which altered redox homeostasis and oxidative damage have been documented as described in this work do not have an effective treatment. Therapy mainly consists on protein restriction and supplementation with special formulas that provide the necessary nutrients for adequate growth and development, as well as the administration of specific compounds aiming to detoxify the accumulated metabolites or to enhance residual enzymatic activities [[10], [153]]. However, the clinical outcome overall remains unsatisfactory, as multiorgan complications (neurological, cardiac, renal, hematological, and gastrointestinal, among others) persist. In this scenario, antioxidants and mitochondrial activators/protectors may be beneficial to prevent or ameliorate oxidative damage contributing to organ pathophysiology.

Chemically, antioxidants are reduced compounds that directly react with ROS avoiding the oxidation of a third molecule. The in vitro mode of action of nutraceutical and synthetic antioxidants is mainly based on their capacity to act as free radical scavengers. However, in vivo antioxidant response depends on distribution, absorption, metabolism, and excretion of the compound, hampering a direct action on ROS. In fact, it is now clear that in vivo antioxidants provide indirect cellular and tissue protection against oxidative damage by targeting NRF2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) [[154], [155]], modulating the antioxidant response (Figure 2).

NRF2 transcription factor regulates cellular homeostasis by binding to regulatory DNA regions known as electrophile response elements or EpRE (previously named antioxidant regulatory elements (AREs)). Under oxidative stress, NRF2 translocates to the nucleus, binds to EpRE sequences, and promotes the transcription of antioxidant enzymes, genes of GSH metabolism, and NADPH regeneration (Figure 2) [[156]].

Antioxidant response can also be driven by SIRT1, a class I histone deacetylase that mediates deacetylation in a NAD+-dependent manner. SIRT1 is mainly localized in the nucleus where, apart from histones, it can interact with and deacetylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and Forkhead box protein O3 (FOXOa3) [[157], [158]]. Deacetylated PGC1α and FOXOa3 have an increased transcriptional activity and promote mitochondrial biogenesis and expression of antioxidant genes (Figure 2). Therefore, NRF2 and SIRT1 activation by polyphenolic compounds represent the main targets for antioxidant therapy to reduce oxidative damage.

Several studies have evaluated different antioxidant compounds as adjuvant therapy in a number of IEMs. The brain is highly sensitive to free radicals due to its high energetic demands, its high lipid content, and its low regeneration capacity. In this context, oxidative damage has been proposed as one of the mechanisms involved in the development of the characteristic neurological symptoms of PA, MMA, MSUD, GAI, and homocystinuria patients. Even though the transport rate of antioxidants through the blood brain barrier is low, different studies have reported a reversion of brain damage after antioxidant treatments in these diseases [[159][162]].

In organic acidurias, a beneficial effect of L-carnitine supplementation with in vitro antioxidant properties has been described [[13], [163]]. L-carnitine shows antioxidant capacities as it can act as ROS scavenger and reduce lipid peroxidation to an extent comparable to that seen with α-tocopherol [[164]]. It also protects endogenous antioxidant enzymes from peroxidative damage and induces elevated cellular GSH [[31]]. L-carnitine supplementation is routinely included in the treatment of PA and MMA, to prevent a secondary carnitine deficiency and to promote detoxification of propionic and methylmalonic acids, which are excreted in the form of carnitine esters. Evaluation of oxidative stress parameters in urine from PA and MMA patients during treatment with L-carnitine- and protein-restricted diet showed a significant reduction of urinary and plasma biomarkers of oxidative damage to lipids and proteins [[13], [163]]. L-carnitine treatment was also shown to reduce plasma malondialdehyde concentrations and urine dityrosine and isoprostanes in patients with MSUD [[51], [165]].

In a MMA patient with optic neuropathy, CoQ10 treatment in conjunction with vitamin E resulted in improved visual acuity [[166]]. Interestingly, treatment of MMA mice with CoQ10 and vitamin E showed a significant amelioration in the loss of glomerular filtration rate and a normalization of plasma lipocalin-2 levels [[89]], indicating that the therapeutic effects are not restricted to the nervous system.

Recently, in vitro and in vivo studies in PA have also shown the positive effect of antioxidant treatment. Using patients' fibroblasts, different antioxidants (tiron, trolox, resveratrol, and MitoQ) significantly reduced H2O2 levels and regulated the expression of antioxidant enzymes [[30]]. In the hypomorphic mouse model of PA [[167]], oral treatment with resveratrol and MitoQ protected against lipid and DNA oxidative damage and induced the expression of antioxidant enzymes [[32]]. In addition to its antioxidant properties, resveratrol exerts different effects on mitochondrial function and dynamics [[168]], which clearly contributes to its beneficial effect in IEMs with mitochondrial ROS production, such as organic acidemias and respiratory chain defects [[169]].

A clinical trial (NCT01793090) is ongoing in patients with MMA cblC-type defect to investigate the safety and efficacy of the EPI-743 compound in relation to visual and neurological impairment. This molecule targets NADPH quinone oxidoreductase 1, thus providing beneficial effects in diseases characterized by oxidative stress and alterations in glutathione redox balance, as is the case of mitochondrial diseases [[170]].

Taurine, a compound potentially reducing oxidative damage, is being tested in a clinical trial with homocystinuria (CBS-deficient) patients (NCT01192828). Taurine treatment in a mouse model of CBS deficiency reversed GSH depletion with potential beneficial effects [[171]].

Although the use of antioxidants as potential therapies holds great interest for many diseases (including IEMs) in which oxidative stress plays a pathophysiological role, there is to date limited clinical evidence of their efficacy, which may be related to pharmacokinetic and/or pharmacodynamics reasons [[172]]. The intracellular levels of the specific antioxidant, its distribution throughout the body, together with the subcellular location are factors that influence the in vivo effects. Moreover, antioxidants react with free radicals with the same rate constant as other natural molecules, and their intracellular concentrations cannot overcome this kinetic limitation. Therefore, antioxidant effectiveness in vivo could be limited [[154]].

Throughout the years, different studies have shown both beneficial and adverse effects of antioxidant compounds. In vitro β-carotene shows antioxidant and anti-inflammatory effects when administered at low doses whereas prooxidant and proinflammatory responses have been reported at higher concentrations [[173], [174]]. Similar contradictory results have been obtained in in vivo studies. While in a randomized trial dietary consumption of β-carotene and vitamins C and E did not affect cancer incidence and mortality [[175]], higher doses of these compounds did not show any health beneficial effect. In fact, they could significantly increase the risk of mortality (reviewed in [[176], [177]]). ROS are required at physiological concentrations for optimal cellular homeostasis [[178]]. Therefore, free radical scavenging by antioxidants could be undesirable as disruption of redox balance would lead to cellular dysfunction and originate different side effects.

New indirect antioxidant approaches targeting redox enzymes or NRF2 agonists that upregulate cellular antioxidant defences are promising alternatives that warrant further investigation [[155]].

6. Conclusions and Future Perspectives

The pathophysiological role of ROS in IEMs has been firmly established in many studies revealing oxidative damage to proteins, lipids, and DNA in patients' samples and animal models, correlating with clinical and biochemical parameters (Figure 3). Consequently, different antioxidants have been successfully used in cellular and animal models of IEMs [[30][32], [89], [98]]. Despite these positive results, for other diseases, there is no clear conclusion on the efficacy of antioxidant treatments in human clinical trials, which limits the expectations also for IEMs.

In the past years, we have gained deeper insights into the complex and dynamic roles of ROS signals in normal and pathological processes, yet the field of redox signaling in IEMs is still in its infancy. Novel technologies such as redox proteomics [[179]] or transgenic animals expressing redox reporters [[180]] are revolutionising the field and represent excellent tools to investigate redox regulatory networks in disease. They may also provide insight to explain the poor performance of antioxidant therapies in clinical trials. In many IEMs, mitochondrial ROS-targeting agents that accumulate in the mitochondria and compounds activating or improving mitochondrial function may constitute a valid approach. Further preclinical research is warranted to investigate basic mechanisms of redox signaling and their implications for IEM disease progression, as well as exploring the benefits of targeted antioxidant therapies.



This work was supported by the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (Grant nos. SAF2016-76004-R and PI16/00573) and by Fundación Isabel Gemio. Centro de Biología Molecular Severo Ochoa receives an institutional grant from Fundación Ramón Areces.


  1. R. K. J. OlsenN. CorneliusN. GregersenRedox signalling and mitochondrial stress responses; lessons from inborn errors of metabolismJournal of Inherited Metabolic Disease201538470371910.1007/s10545-015-9861-52-s2.0-8493725064526025548
  2. M. WajnerA. LatiniA. T. S. WyseC. S. Dutra-FilhoThe role of oxidative damage in the neuropathology of organic acidurias: insights from animal studiesJournal of Inherited Metabolic Disease200427442744810.1023/B:BOLI.0000037353.13085.e22-s2.0-434463082815303000
  3. G. LeipnitzC. R. VargasM. WajnerDisturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3-hydroxy-3-methylglutaryl-CoA lyase deficiencyJournal of Inherited Metabolic Disease20153861021102810.1007/s10545-015-9863-32-s2.0-8494548539126041581
  4. M. WajnerS. I. GoodmanDisruption of mitochondrial homeostasis in organic acidurias: insights from human and animal studiesJournal of Inherited Metabolic Disease2011431313810.1007/s10863-011-9324-02-s2.0-7995231039921249436
  5. L. Gallego-VillarA. Rivera-BarahonaC. Cuevas-MartinIn vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: implications for the pathophysiology of this disorderFree Radical Biology and Medicine20169611210.1016/j.freeradbiomed.2016.04.0072-s2.0-8496381941827083476
  6. E. RichardA. Alvarez-BarrientosB. PerezL. R. DesviatM. UgarteMethylmalonic acidaemia leads to increased production of reactive oxygen species and induction of apoptosis through the mitochondrial/caspase pathwayThe Journal of Pathology2007213445346110.1002/path.22482-s2.0-3674901252717948227
  7. E. RichardL. R. DesviatM. UgarteB. PerezOxidative stress and apoptosis in homocystinuria patients with genetic remethylation defectsJournal of Cellular Biochemistry2013114118319110.1002/jcb.243162-s2.0-8486941314622887477
  8. E. MoravaS. RahmanV. PetersM. R. BaumgartnerM. PattersonJ. ZschockeQuo vadis: the re-definition of “inborn metabolic diseases”Journal of Inherited Metabolic Disease20153861003610.1007/s10545-015-9893-x2-s2.0-8494546750926420281
  9. R. K. J. OlsenN. CorneliusN. GregersenGenetic and cellular modifiers of oxidative stress: what can we learn from fatty acid oxidation defects?Molecular Genetics and Metabolism2013110S31S3910.1016/j.ymgme.2013.10.0072-s2.0-8488958037924206932
  10. E. RichardP. Rodriguez-PomboL. R. DesviatF. PalauS. CadenasMitochondrial organic acidurias. Part II: mitochondrial dysfunctionMitochondrial Pathophysiology2011Kerala, IndiaResearch Signpost173191
  11. E. L. StreckG. A. CzapskiC. Goncalves da SilvaNeurodegeneration, mitochondrial dysfunction, and oxidative stressOxidative Medicine and Cellular Longevity20132013282604610.1155/2013/8260462-s2.0-84886691367
  12. P. J. Mc GuireA. ParikhG. A. DiazProfiling of oxidative stress in patients with inborn errors of metabolismMolecular Genetics and Metabolism2009981-217318010.1016/j.ymgme.2009.06.0072-s2.0-6774911778819604711
  13. G. S. RibasG. B. BianciniC. MesckaOxidative stress parameters in urine from patients with disorders of propionate metabolism: a beneficial effect of L-carnitine supplementationCellular and Molecular Neurobiology2012321778210.1007/s10571-011-9736-82-s2.0-8485655355221833551
  14. R. J. MaillouxS. L. McBrideM. E. HarperUnearthing the secrets of mitochondrial ROS and glutathione in bioenergeticsTrends in Biochemical Sciences2013381259260210.1016/j.tibs.2013.09.0012-s2.0-8488813359824120033
  15. A. BindoliM. P. RigobelloPrinciples in redox signaling: from chemistry to functional significanceAntioxidants & Redox Signaling201318131557159310.1089/ars.2012.46552-s2.0-8487571655423244515
  16. T. FinkelSignal transduction by mitochondrial oxidantsJournal of Biological Chemistry201228774434444010.1074/jbc.R111.2719992-s2.0-8485682100621832045
  17. N. BallatoriS. M. KranceS. NotenboomS. ShiK. TieuC. L. HammondGlutathione dysregulation and the etiology and progression of human diseasesBiological Chemistry2009390319121410.1515/BC.2009.0332-s2.0-6224909697519166318
  18. H. SalmiJ. V. LeonardR. LapattoPatients with organic acidaemias have an altered thiol statusActa Paediatrica201210111e505e50810.1111/j.1651-2227.2012.02799.x2-s2.0-8486709760622849335
  19. A. PastoreD. MartinelliF. PiemonteGlutathione metabolism in cobalamin deficiency type C (cblC)Journal of Inherited Metabolic Disease201437112512910.1007/s10545-013-9605-32-s2.0-8489183715623568438
  20. K. R. AtkuriT. M. CowanT. KwanInherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemiaProceedings of the National Academy of Sciences2009106103941394510.1073/pnas.08134091062-s2.0-6264910779519223582
  21. M. P. MurphyMitochondrial thiols in antioxidant protection and redox signaling: distinct roles for glutathionylation and other thiol modificationsAntioxidants & Redox Signaling201216647649510.1089/ars.2011.42892-s2.0-8485672919221954972
  22. M. C. SobottaW. LiouS. StöckerPeroxiredoxin-2 and STAT3 form a redox relay for H2O2 signalingNature Chemical Biology2015111647010.1038/nchembio.16952-s2.0-8492492167325402766
  23. F. YinH. SanchetiZ. LiuE. CadenasMitochondrial function in ageing: coordination with signalling and transcriptional pathwaysThe Journal of Physiology201659482025204210.1113/JP2705412-s2.0-8494176793626293414
  24. H. WuH. WeiS. A. SehgalL. LiuQ. ChenMitophagy receptors sense stress signals and couple mitochondrial dynamic machinery for mitochondrial quality controlFree Radical Biology and Medicine201610019920910.1016/j.freeradbiomed.2016.03.0302-s2.0-8496273418327036363
  25. A. BonehSignal transduction in inherited metabolic disorders: a model for a possible pathogenetic mechanismJournal of Inherited Metabolic Disease201538472974010.1007/s10545-015-9820-12-s2.0-8493725066225735935
  26. L. Gallego-VillarC. Perez-CerdaB. PerezFunctional characterization of novel genotypes and cellular oxidative stress studies in propionic acidemiaJournal of Inherited Metabolic Disease201336573174010.1007/s10545-012-9545-32-s2.0-8488434993923053474
  27. P. AlcaideB. MerineroP. Ruiz-SalaDefining the pathogenicity of creatine deficiency syndromeHuman Mutation201132328229110.1002/humu.214212-s2.0-7995178237921140503
  28. H. RochaR. FerreiraJ. CarvalhoCharacterization of mitochondrial proteome in a severe case of ETF-QO deficiencyJournal of Proteomics201175122122810.1016/j.jprot.2011.04.0252-s2.0-8485871203721596162
  29. J. Lopez-ErauskinS. FourcadeJ. GalinoAntioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophyAnnals of Neurology2011701849210.1002/ana.223632-s2.0-7996074801421786300
  30. L. Gallego-VillarB. PerezM. UgarteL. R. DesviatE. RichardAntioxidants successfully reduce ROS production in propionic acidemia fibroblastsBiochemical and Biophysical Research Communications2014452345746110.1016/j.bbrc.2014.08.0912-s2.0-8490753345325159844
  31. G. S. RibasC. R. VargasM. WajnerL-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disordersGene2014533246947610.1016/j.gene.2013.10.0172-s2.0-8488761519524148561
  32. A. Rivera-BarahonaE. Alonso-BarrosoB. PerezM. P. MurphyE. RichardL. R. DesviatTreatment with antioxidants ameliorates oxidative damage in a mouse model of propionic acidemiaMolecular Genetics and Metabolism20171221-2435010.1016/j.ymgme.2017.07.0092-s2.0-8502636524528774709
  33. G. HayashiG. CortopassiOxidative stress in inherited mitochondrial diseasesFree Radical Biology and Medicine201588Part A101710.1016/j.freeradbiomed.2015.05.0392-s2.0-8494298591526073122
  34. J. E. SperringerA. AddingtonS. M. HutsonBranched-chain amino acids and brain metabolismNeurochemical Research20174261697170910.1007/s11064-017-2261-52-s2.0-8501752044528417264
  35. J. M. HanS. J. JeongM. C. ParkLeucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathwayCell2012149241042410.1016/j.cell.2012.02.0442-s2.0-8486277740722424946
  36. K. A. AndersonF. K. HuynhK. Fisher-WellmanSIRT4 is a lysine deacylase that controls leucine metabolism and insulin secretionCell Metabolism2017254838855.e1510.1016/j.cmet.2017.03.0032-s2.0-8501693610028380376
  37. D. T. ChuangV. E. ShiC. R. ScriverA. L. BeaudetW. SlyD. ValleMaple syrup urine diesease (branched chain ketoaciduria)The Metabolic and Molecular Basis of Inherited Disease2001New YorkMcGraw-Hill19712005
  38. G. NovarinoP. El-FishawyH. KayseriliMutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsyScience2012338610539439710.1126/science.12246312-s2.0-8486768783022956686
  39. A. Garcia-CazorlaA. OyarzabalJ. FortTwo novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patientsHuman Mutation201435447047710.1002/humu.225132-s2.0-8489613718424449431
  40. G. R. D. VillaniG. GalloE. ScolamieroF. SalvatoreM. Ruoppolo“Classical organic acidurias”: diagnosis and pathogenesisClinical and Experimental Medicine201717330532310.1007/s10238-016-0435-02-s2.0-8498625290027613073
  41. R. A. HarrisM. JoshiN. H. JeoungMechanisms responsible for regulation of branched-chain amino acid catabolismBiochemical and Biophysical Research Communications2004313239139610.1016/j.bbrc.2003.11.0072-s2.0-034573529714684174
  42. A. OyarzabalM. Martinez-PardoB. MerineroA novel regulatory defect in the branched-chain α-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine diseaseHuman Mutation201334235536210.1002/humu.222422-s2.0-8487308388023086801
  43. A. SittaG. S. RibasC. P. MesckaA. G. BarschakM. WajnerC. R. VargasNeurological damage in MSUD: the role of oxidative stressCellular and Molecular Neurobiology201434215716510.1007/s10571-013-0002-02-s2.0-8490337218224220995
  44. P. de Lima PelaezC. FunchalS. O. LoureiroBranched-chain amino acids accumulating in maple syrup urine disease induce morphological alterations in C6 glioma cells probably through reactive speciesInternational Journal of Developmental Neuroscience200725318118910.1016/j.ijdevneu.2007.01.0012-s2.0-3424739073917317075
  45. W. J. ZinnantiJ. LazovicK. GriffinDual mechanism of brain injury and novel treatment strategy in maple syrup urine diseaseBrain2009132, Part 490391810.1093/brain/awp0242-s2.0-6444908625819293241
  46. T. FriedrichA. M. LambertM. A. MasinoG. B. DownesMutation of zebrafish dihydrolipoamide branched-chain transacylase E2 results in motor dysfunction and models maple syrup urine diseaseDisease Models & Mechanisms20125224825810.1242/dmm.0083832-s2.0-8485801088422046030
  47. R. BridiJ. AraldiM. B. SgarbiInduction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine diseaseInternational Journal of Developmental Neuroscience200321632733210.1016/S0736-5748(03)00074-12-s2.0-004212235412927581
  48. R. BridiC. A. BraunG. K. Zorziα-Keto acids accumulating in maple syrup urine disease stimulate lipid peroxidation and reduce antioxidant defences in cerebral cortex from young ratsMetabolic Brain Disease200520215516710.1007/s11011-005-4152-82-s2.0-2004439095515938133
  49. O. ZhenyukhE. CivantosM. Ruiz-OrtegaHigh concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activationFree Radical Biology and Medicine201710416517710.1016/j.freeradbiomed.2017.01.0092-s2.0-8500943133428089725
  50. A. G. BarschakA. SittaM. DeonOxidative stress in plasma from maple syrup urine disease patients during treatmentMetabolic Brain Disease2008231718010.1007/s11011-007-9077-y2-s2.0-3914910646418026828
  51. C. P. MesckaC. A. Y. WayhsC. S. VanzinProtein and lipid damage in maple syrup urine disease patients: L-carnitine effectInternational Journal of Developmental Neuroscience2013311212410.1016/j.ijdevneu.2012.10.1092-s2.0-8487052501523137711
  52. C. P. MesckaG. GuerreiroB. DonidaInvestigation of inflammatory profile in MSUD patients: benefit of L-carnitine supplementationMetabolic Brain Disease20153051167117410.1007/s11011-015-9686-92-s2.0-8494118958426002427
  53. G. LuS. RenP. KorgeA novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and developmentGenes & Development200721778479610.1101/gad.14991072-s2.0-3414712953417374715
  54. A. OyarzabalI. Bravo-AlonsoM. Sanchez-AragoMitochondrial response to the BCKDK-deficiency: some clues to understand the positive dietary response in this form of autismBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease20161862459260010.1016/j.bbadis.2016.01.0162-s2.0-8495828110026809120
  55. J. KaplonL. ZhengK. MeisslA key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescenceNature2013498745210911210.1038/nature121542-s2.0-8487867919923685455
  56. C. L. QuinlanR. L. S. GoncalvesM. Hey-MogensenN. YadavaV. I. BunikM. D. BrandThe 2-oxoacid dehydrogenase complexes in mitochondria can produce superoxide/hydrogen peroxide at much higher rates than complex IJournal of Biological Chemistry2014289128312832510.1074/jbc.M113.5453012-s2.0-8489693558324515115
  57. W. A. FentonR. A. GravelL. E. RosenbergC. R. ScriverA. L. BeaudetW. SlyD. ValleDisorders of propionate and methylmalonate metabolismThe Metabolic and Molecular Bases of Inherited Disease2001New YorkMcGraw-Hill2165219010.1007/978-94-009-5778-7_11
  58. L. PenaB. K. BurtonSurvey of health status and complications among propionic acidemia patientsAmerican Journal of Medical Genetics Part A2012158A71641164610.1002/ajmg.a.353872-s2.0-8486270390422678880
  59. L. PenaJ. FranksK. A. ChapmanNatural history of propionic acidemiaMolecular Genetics and Metabolism201210515910.1016/j.ymgme.2011.09.0222-s2.0-8485534418121986446
  60. S. KölkerA. G. CazorlaV. ValayannopoulosThe phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentationJournal of Inherited Metabolic Disease20153861041105710.1007/s10545-015-9839-32-s2.0-8494544674525875215
  61. S. KölkerV. ValayannopoulosA. B. BurlinaThe phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotypeJournal of Inherited Metabolic Disease20153861059107410.1007/s10545-015-9840-x2-s2.0-8494544027425875216
  62. S. C. GrünertS. MüllerleileL. De SilvaPropionic acidemia: clinical course and outcome in 55 pediatric and adolescent patientsOrphanet Journal of Rare Diseases201381p. 610.1186/1750-1172-8-62-s2.0-8487211460223305374
  63. J. BaruteauI. HargreavesS. KrywawychSuccessful reversal of propionic acidaemia associated cardiomyopathy: evidence for low myocardial coenzyme Q10 status and secondary mitochondrial dysfunction as an underlying pathophysiological mechanismMitochondrion20141715015610.1016/j.mito.2014.07.0012-s2.0-8490743493125010387
  64. M. NizonC. OttolenghiV. ValayannopoulosLong-term neurological outcome of a cohort of 80 patients with classical organic aciduriasOrphanet Journal of Rare Diseases201381p. 14810.1186/1750-1172-8-1482-s2.0-8488438534124059531
  65. S. W. SauerJ. G. OkunG. F. HoffmannS. KoelkerM. A. MorathImpact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on mitochondrial energy metabolismBiochimica et Biophysica Acta (BBA) - Bioenergetics20081777101276128210.1016/j.bbabio.2008.05.4472-s2.0-5294908467318582432
  66. N. GregersenThe specific inhibition of the pyruvate dehydrogenase complex from pig kidney by propionyl-CoA and isovaleryl-Co-ABiochemical Medicine1981261202710.1016/0006-2944(81)90026-02-s2.0-00194412447295301
  67. S. Cheema-DhadliC. C. LeznoffM. L. HalperinEffect of 2-methylcitrate on citrate metabolism: implications for the management of patients with propionic acidemia and methylmalonic aciduriaPediatric Research197591290590810.1203/00006450-197512000-000082-s2.0-0016717991127973
  68. D. A. StumpfJ. McafeeJ. K. ParksL. EgurenPropionate inhibition of succinate:CoA ligase (GDP) and the citric acid cycle in mitochondriaPediatric Research198014101127113110.1203/00006450-198010000-000082-s2.0-00189610276780967
  69. H. BrunengraberC. R. RoeAnaplerotic molecules: current and futureJournal of Inherited Metabolic Disease2006292-332733110.1007/s10545-006-0320-12-s2.0-3374510511816763895
  70. S. NakaoY. MoriyaS. FuruyamaR. NiedermanH. SugiyaPropionic acid stimulates superoxide generation in human neutrophilsCell Biology International199822533133710.1006/cbir.1998.02632-s2.0-003246864210198152
  71. F. K. RigoL. PasquettiC. R. M. MalfattiPropionic acid induces convulsions and protein carbonylation in ratsNeuroscience Letters2006408215115410.1016/j.neulet.2006.08.0752-s2.0-3374933330016997462
  72. F. U. FontellaV. PulrolnikE. GassenPropionic and L-methylmalonic acids induce oxidative stress in brain of young ratsNeuroreport200011354154410.1097/00001756-200002280-000232-s2.0-003400471710718311
  73. Y. de KeyzerV. ValayannopoulosJ. F. BenoistMultiple OXPHOS deficiency in the liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduriaPediatric Research2009661919510.1203/PDR.0b013e3181a7c2702-s2.0-7014909536219342984
  74. R. MardachM. A. VerityS. D. CederbaumClinical, pathological, and biochemical studies in a patient with propionic acidemia and fatal cardiomyopathyMolecular Genetics and Metabolism200585428629010.1016/j.ymgme.2005.04.0042-s2.0-2304447528315939644
  75. M. A. SchwabS. W. SauerJ. G. OkunSecondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxinsBiochemical Journal2006398110711210.1042/BJ200602212-s2.0-3374716713316686602
  76. K. FragakiA. CanoJ. F. BenoistFatal heart failure associated with CoQ10 and multiple OXPHOS deficiency in a child with propionic acidemiaMitochondrion201111353353610.1016/j.mito.2011.02.0022-s2.0-7995375867621329767
  77. S. YanoS. YanoL. LiInfantile mitochondrial DNA depletion syndrome associated with methylmalonic aciduria and 3-methylcrotonyl-CoA and propionyl-CoA carboxylase deficiencies in two unrelated patients: a new phenotype of mtDNA depletion syndromeJournal of Inherited Metabolic Disease200326548148810.1023/A:10251254278682-s2.0-004182817514518828
  78. D. R. MeloA. J. KowaltowskiM. WajnerR. F. CastilhoMitochondrial energy metabolism in neurodegeneration associated with methylmalonic acidemiaJournal of Bioenergetics and Biomembranes2011431394610.1007/s10863-011-9330-22-s2.0-7995231785521271280
  79. L. F. PettenuzzoC. Ferreira GdaA. L. SchmidtC. S. Dutra-FilhoA. T. WyseM. WajnerDifferential inhibitory effects of methylmalonic acid on respiratory chain complex activities in rat tissuesInternational Journal of Developmental Neuroscience2006241455210.1016/j.ijdevneu.2005.10.0052-s2.0-3334447402916324816
  80. S. R. MirandolaD. R. MeloP. F. SchuckG. C. FerreiraM. WajnerR. F. CastilhoMethylmalonate inhibits succinate-supported oxygen consumption by interfering with mitochondrial succinate uptakeJournal of Inherited Metabolic Disease2008311445410.1007/s10545-007-0798-12-s2.0-4084909752918213522
  81. M. A. MorathJ. G. OkunI. B. MullerNeurodegeneration and chronic renal failure in methylmalonic aciduria—a pathophysiological approachJournal of Inherited Metabolic Disease2008311354310.1007/s10545-007-0571-52-s2.0-4074908685017846917
  82. S. KolkerJ. G. OkunMethylmalonic acid—an endogenous toxin?Cellular and Molecular Life Sciences200562662162410.1007/s00018-005-4463-22-s2.0-1704438624515770414
  83. V. ValayannopoulosL. HubertJ. F. BenoistMultiple OXPHOS deficiency in the liver of a patient with CblA methylmalonic aciduria sensitive to vitamin B(12)Journal of Inherited Metabolic Disease200932215916210.1007/s10545-009-1023-12-s2.0-6444908444219277894
  84. R. J. ChandlerP. M. ZerfasS. ShanskeMitochondrial dysfunction in mut methylmalonic acidemiaThe FASEB Journal20092341252126110.1096/fj.08-1218482-s2.0-6534912755019088183
  85. K. HayasakaK. MetokiT. SatohComparison of cytosolic and mitochondrial enzyme alterations in the livers of propionic or methylmalonic acidemia: a reduction of cytochrome oxidase activityThe Tohoku Journal of Experimental Medicine1982137332933410.1620/tjem.137.3292-s2.0-00203243636287671
  86. M. A. CossonG. TouatiF. LacailleLiver hepatoblastoma and multiple OXPHOS deficiency in the follow-up of a patient with methylmalonic aciduriaMolecular Genetics and Metabolism2008951-210710910.1016/j.ymgme.2008.06.0072-s2.0-5164910017318676166
  87. M. CaterinoR. J. ChandlerJ. L. SloanThe proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient liversMolecular BioSystems201612256657410.1039/C5MB00736D2-s2.0-8495649541026672496
  88. E. RichardL. MonteolivaS. JuarezQuantitative analysis of mitochondrial protein expression in methylmalonic acidemia by two-dimensional difference gel electrophoresisJournal of Proteome Research2006571602161010.1021/pr050481r2-s2.0-3374583640816823967
  89. I. ManoliJ. R. SysolL. LiTargeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemiaProceedings of the National Academy of Sciences201311033135521355710.1073/pnas.13027641102-s2.0-8488241575623898205
  90. Z. K. ZsengellerN. AljinovicL. A. TeotMethylmalonic acidemia: a megamitochondrial disorder affecting the kidneyPediatric Nephrology201429112139214610.1007/s00467-014-2847-y2-s2.0-8493071444324865477
  91. Y. WilnaiG. M. EnnsA. K. NiemiJ. HigginsH. VogelAbnormal hepatocellular mitochondria in methylmalonic acidemiaUltrastructural Pathology201438530931410.3109/01913123.2014.9216572-s2.0-8490758356924933007
  92. J. KimC. GherasimR. BanerjeeDecyanation of vitamin B12 by a trafficking chaperoneProceedings of the National Academy of Sciences200810538145511455410.1073/pnas.08059891052-s2.0-5574910194018779575
  93. J. KimL. HannibalC. GherasimD. W. JacobsenR. BanerjeeA human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalaminsJournal of Biological Chemistry200928448334183342410.1074/jbc.M109.0578772-s2.0-7045024268119801555
  94. Z. LiC. GherasimN. A. LesniakR. BanerjeeGlutathione-dependent one-electron transfer reactions catalyzed by a B12 trafficking proteinJournal of Biological Chemistry201428923164871649710.1074/jbc.M114.5673392-s2.0-8490212266524742678
  95. Z. LiA. ShanmuganathanM. RuetzCoordination chemistry controls the thiol oxidase activity of the B12-trafficking protein CblCJournal of Biological Chemistry2017292239733974410.1074/jbc.M117.7885542-s2.0-8502074537028442570
  96. J. P. Lerner-EllisJ. C. TironeP. D. PawelekIdentification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC typeNature Genetics20053819310010.1038/ng16832-s2.0-2944445109416311595
  97. J. D. Weisfeld-AdamsE. A. McCourtG. A. DiazS. C. OliverOcular disease in the cobalamin C defect: a review of the literature and a suggested framework for clinical surveillanceMolecular Genetics and Metabolism2015114453754610.1016/j.ymgme.2015.01.0122-s2.0-8492642049225742969
  98. E. RichardA. Jorge-FinniganJ. Garcia-VilloriaGenetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC)Human Mutation200930111558156610.1002/humu.211072-s2.0-7035074136719760748
  99. A. Jorge-FinniganA. GamezB. PerezM. UgarteE. RichardDifferent altered pattern expression of genes related to apoptosis in isolated methylmalonic aciduria cblB type and combined with homocystinuria cblC typeBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease201018021195996710.1016/j.bbadis.2010.08.0022-s2.0-7795665239220696242
  100. L. HannibalP. M. DiBelloM. YuThe MMACHC proteome: hallmarks of functional cobalamin deficiency in humansMolecular Genetics and Metabolism2011103322623910.1016/j.ymgme.2011.03.0082-s2.0-7995803979621497120
  101. L. HannibalP. M. DiBelloD. W. JacobsenProteomics of vitamin B12 processingClinical Chemistry and Laboratory Medicine201351347748810.1515/cclm-2012-05682-s2.0-8488237517923241609
  102. M. CaterinoA. PastoreM. G. StrozzieroThe proteome of cblC defect: in vivo elucidation of altered cellular pathways in humansJournal of Inherited Metabolic Disease201538596997910.1007/s10545-014-9806-42-s2.0-8494046282425585586
  103. C. GherasimM. RuetzZ. LiS. HudolinR. BanerjeePathogenic mutations differentially affect the catalytic activities of the human B12-processing chaperone CblC and increase futile redox cyclingJournal of Biological Chemistry201529018113931140210.1074/jbc.M115.6371322-s2.0-8492948390025809485
  104. S. GoodmanF. FrermanC. R. ScriverA. L. BeaudetW. S. SlyD. ValleOrganic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric acidemiaThe Metabolic and Molecular Basis of Inherited Disease2001New YorkMcGraw-Hill Inc21952204
  105. S. KölkerS. F. GarbadeC. R. GreenbergNatural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiencyPediatric Research200659684084710.1203/01.pdr.0000219387.79887.862-s2.0-3374510632416641220
  106. K. A. StraussE. G. PuffenbergerD. L. RobinsonD. H. MortonType I glutaric aciduria, part 1: natural history of 77 patientsAmerican Journal of Medical Genetics2003121C1385210.1002/ajmg.c.2000712888985
  107. A. U. AmaralC. CecattoB. SeminottiExperimental evidence that bioenergetics disruption is not mainly involved in the brain injury of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overloadBrain Research2015162011612910.1016/j.brainres.2015.05.0132-s2.0-8494089994025998543
  108. S. KolkerS. W. SauerG. F. HoffmannI. MullerM. A. MorathJ. G. OkunPathogenesis of CNS involvement in disorders of amino and organic acid metabolismJournal of Inherited Metabolic Disease200831219420410.1007/s10545-008-0823-z2-s2.0-4314909050118392748
  109. A. LatiniG. C. FerreiraK. ScussiatoInduction of oxidative stress by chronic and acute glutaric acid administration to ratsCellular and Molecular Neurobiology200727442343810.1007/s10571-006-9134-92-s2.0-3424854546417235690
  110. D. M. KoellerM. WoontnerL. S. CrnicBiochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type IHuman Molecular Genetics200211434735710.1093/hmg/11.4.34711854167
  111. B. SeminottiR. T. RibeiroA. U. AmaralAcute lysine overload provokes protein oxidative damage and reduction of antioxidant defenses in the brain of infant glutaryl-CoA dehydrogenase deficient mice: a role for oxidative stress in GA I neuropathologyJournal of the Neurological Sciences20143441-210511310.1016/j.jns.2014.06.0342-s2.0-8490679385424996493
  112. W. J. ZinnantiJ. LazovicE. B. WolpertA diet-induced mouse model for glutaric aciduria type IBrain2006129489991010.1093/brain/awl0092-s2.0-3364508791816446282
  113. W. J. ZinnantiJ. LazovicC. HousmanMechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type IJournal of Clinical Investigation2007117113258327010.1172/JCI316172-s2.0-3604895913917932566
  114. C. Perez-CerdaJ. García-VilloriaR. Ofman2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: an X-linked inborn error of isoleucine metabolism that may mimic a mitochondrial diseasePediatric Research200558348849110.1203/01.pdr.0000176916.94328.cd2-s2.0-2434449737416148061
  115. W. SperlP. JešinaJ. ZemanDeficiency of mitochondrial ATP synthase of nuclear genetic originNeuromuscular Disorders2006161282182910.1016/j.nmd.2006.08.0082-s2.0-3384519830517052906
  116. C. G. da SilvaC. A. J. RibeiroG. LeipnitzInhibition of cytochrome c oxidase activity in rat cerebral cortex and human skeletal muscle by D-2-hydroxyglutaric acid in vitroBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease200215861819110.1016/S0925-4439(01)00088-62-s2.0-003700582311781152
  117. D. ZafeiriouP. Augoustides-SavvopoulouD. HaasEthylmalonic encephalopathy: clinical and biochemical observationsNeuropediatrics2007382788210.1055/s-2007-9844472-s2.0-3454874293517712735
  118. S. B. WortmannR. J. T. RodenburgA. JonckheereBiochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategyBrain2009132113614610.1093/brain/awn2962-s2.0-5884910210819015156
  119. L. ZandbergH. C. van DykF. H. van der WesthuizenA. A. van DijkA 3-methylcrotonyl-CoA carboxylase deficient human skin fibroblast transcriptome reveals underlying mitochondrial dysfunction and oxidative stressThe International Journal of Biochemistry & Cell Biology20167811612910.1016/j.biocel.2016.07.0102-s2.0-8497887249827417235
  120. Â. ZanattaA. P. MouraA. M. ToninNeurochemical evidence that the metabolites accumulating in 3-methylcrotonyl-CoA carboxylase deficiency induce oxidative damage in cerebral cortex of young ratsCellular and Molecular Neurobiology201333113714610.1007/s10571-012-9879-22-s2.0-8487178515123053545
  121. M. R. HaydenS. C. TyagiHomocysteine and reactive oxygen species in metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: the pleiotropic effects of folate supplementationNutrition Journal20043110.1186/1475-2891-3-42-s2.0-2942558869
  122. C. G. ZouR. BanerjeeHomocysteine and redox signalingAntioxidants & Redox Signaling200575-654755910.1089/ars.2005.7.5472-s2.0-1764440932615890000
  123. D. W. JacobsenHyperhomocysteinemia and oxidative stress: time for a reality check?Arteriosclerosis, Thrombosis, and Vascular Biology20002051182118410.1161/01.ATV.20.5.11822-s2.0-0034022607
  124. H. J. BlomConsequences of homocysteine export and oxidation in the vascular systemSeminars in Thrombosis and Hemostasis2000Volume 26Number 0322723210.1055/s-2000-8467
  125. N. TyagiK. C. SedorisM. SteedA. V. OvechkinK. S. MoshalS. C. TyagiMechanisms of homocysteine-induced oxidative stressAmerican Journal of Physiology-Heart and Circulatory Physiology20052896H2649H265610.1152/ajpheart.00548.20052-s2.0-2824449286216085680
  126. F. BonettiG. BromboG. ZulianiThe relationship between hyperhomocysteinemia and neurodegenerationNeurodegenerative Disease Management20166213314510.2217/nmt-2015-000827033101
  127. S. H. MuddH. L. LevyJ. P. KrausK. KinzlerA. BallabioS. E. AntonarakisA. L. BeaudetB. VogelsteinD. ValleDisorders of transsulfurationThe Online Metabolic and Molecular Bases of Inherited Diseases2011New YorkMcGrall-Hill
  128. M. SchiffH. J. BlomTreatment of inherited homocystinuriasNeuropediatrics201243629530410.1055/s-0032-13298832-s2.0-8487023611323124942
  129. J. L. FaverzaniT. G. HammerschmidtA. SittaM. DeonM. WajnerC. R. VargasOxidative stress in homocystinuria due to cystathionine β-synthase deficiency: findings in patients and in animal modelsCellular and Molecular Neurobiology20173781477148510.1007/s10571-017-0478-02-s2.0-8501413050928258516
  130. C. S. VanzinG. B. BianciniA. SittaExperimental evidence of oxidative stress in plasma of homocystinuric patients: a possible role for homocysteineMolecular Genetics and Metabolism20111041-211211710.1016/j.ymgme.2011.06.0132-s2.0-8005254616721742526
  131. C. S. VanzinV. ManfrediniA. E. MarinhoHomocysteine contribution to DNA damage in cystathionine β-synthase-deficient patientsGene2014539227027410.1016/j.gene.2014.02.0152-s2.0-8489674022624534463
  132. C. S. VanzinC. P. MesckaB. DonidaLipid, oxidative and inflammatory profile and alterations in the enzymes paraoxonase and butyrylcholinesterase in plasma of patients with homocystinuria due CBS deficiency: the vitamin B12 and folic acid importanceCellular and Molecular Neurobiology201535689991110.1007/s10571-015-0185-72-s2.0-8493751335425805165
  133. K. RobertJ. NehmeE. BourdonCystathionine β synthase deficiency promotes oxidative stress, fibrosis, and steatosis in mice liverGastroenterology200512851405141510.1053/j.gastro.2005.02.0342-s2.0-1904438559515887121
  134. E. L. StreckP. S. VieiraC. M. WannmacherC. S. Dutra-FilhoM. WajnerA. T. WyseIn vitro effect of homocysteine on some parameters of oxidative stress in rat hippocampusMetabolic Brain Disease200318214715412822833
  135. C. MattéF. M. StefanelloV. MackedanzHomocysteine induces oxidative stress, inflammatory infiltration, fibrosis and reduces glycogen/glycoprotein content in liver of ratsInternational Journal of Developmental Neuroscience200927433734410.1016/j.ijdevneu.2009.03.0052-s2.0-6734918770519460627
  136. D. WatkinsD. S. RosenblattC. R. ScriverA. L. BeaudetW. SlyD. ValleInherited disorders of folate and cobalamin transport amd metabolismThe Metabolic and Molecular Bases of Inherited Diseases2011New YorkMcGrall-Hill38973933
  137. R. SurteesDemyelination and inborn errors of the single carbon transfer pathwayEuropean Journal of Pediatrics1998157S2S118S12110.1007/PL000142969587038
  138. A. Martinez-PizarroL. R. DesviatM. UgarteB. PerezE. RichardEndoplasmic reticulum stress and autophagy in homocystinuria patients with remethylation defectsPLoS One2016113, article e015035710.1371/journal.pone.01503572-s2.0-8496250872826959487
  139. S. I. DikalovD. G. HarrisonMethods for detection of mitochondrial and cellular reactive oxygen speciesAntioxidants & Redox Signaling201420237238210.1089/ars.2012.48862-s2.0-8489177853222978713
  140. X. ZhangF. GaoImaging mitochondrial reactive oxygen species with fluorescent probes: current applications and challengesFree Radical Research201549437438210.3109/10715762.2015.10148132-s2.0-8492762608625789762
  141. B. KalyanaramanM. HardyR. PodsiadlyG. ChengJ. ZielonkaRecent developments in detection of superoxide radical anion and hydrogen peroxide: opportunities, challenges, and implications in redox signalingArchives of Biochemistry and Biophysics2017617384710.1016/
  142. K. DebowskaD. DebskiM. HardyToward selective detection of reactive oxygen and nitrogen species with the use of fluorogenic probes – limitations, progress, and perspectivesPharmacological Reports201567475676410.1016/j.pharep.2015.03.0162-s2.0-8494046219126321278
  143. W. A. PryorS. S. GodberNoninvasive measures of oxidative stress status in humansFree Radical Biology and Medicine1991103-417718410.1016/0891-5849(91)90073-C2-s2.0-00259727931650736
  144. A. C. RibouSynthetic sensors for reactive oxygen species detection and quantification: a critical review of current methodsAntioxidants & Redox Signaling201625952053310.1089/ars.2016.67412-s2.0-8498794786127225539
  145. M. WronaP. WardmanProperties of the radical intermediate obtained on oxidation of 2′,7′-dichlorodihydrofluorescein, a probe for oxidative stressFree Radical Biology and Medicine200641465766710.1016/j.freeradbiomed.2006.05.0062-s2.0-3374609928816863999
  146. C. RotaC. F. ChignellR. P. MasonEvidence for free radical formation during the oxidation of 2′-7′-dichlorofluorescin to the fluorescent dye 2′-7′-dichlorofluorescein by horseradish peroxidase:possible implications for oxidative stress measurementsFree Radical Biology and Medicine1999277-887388110.1016/S0891-5849(99)00137-92-s2.0-003283013210515592
  147. L. F. F. RoyesP. GabbiL. R. RibeiroA neuronal disruption in redox homeostasis elicited by ammonia alters the glycine/glutamate (GABA) cycle and contributes to MMA-induced excitabilityAmino Acids20164861373138910.1007/s00726-015-2164-12-s2.0-8496011725926940724
  148. H. ZhaoJ. JosephH. M. FalesDetection and characterization of the product of hydroethidine and intracellular superoxide by HPLC and limitations of fluorescenceProceedings of the National Academy of Sciences2005102165727573210.1073/pnas.05017191022-s2.0-1764439460015824309
  149. K. M. RobinsonM. S. JanesM. PeharSelective fluorescent imaging of superoxide in vivo using ethidium-based probesProceedings of the National Academy of Sciences200610341150381504310.1073/pnas.06019451032-s2.0-3375006395517015830
  150. J. ZielonkaM. HardyB. KalyanaramanHPLC study of oxidation products of hydroethidine in chemical and biological systems: ramifications in superoxide measurementsFree Radical Biology and Medicine200946332933810.1016/j.freeradbiomed.2008.10.0312-s2.0-5814916884219026738
  151. A. LoganH. M. CocheméP. B. L. PunUsing exomarkers to assess mitochondrial reactive species in vivoBiochimica et Biophysica Acta (BBA) - General Subjects20141840292393010.1016/j.bbagen.2013.05.0262-s2.0-8489012955223726990
  152. A. LoganI. G. ShabalinaT. A. PrimeIn vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator miceAging Cell201413476576810.1111/acel.122122-s2.0-8490498897224621297
  153. B. MerineroC. Perez-CerdaL. R. DesviatF. PalauS. CadenasMitochondrial organic acidurias. Part I: biochemical and molecular basisMitochondrial Pathophysiology2011Kerala (India)Research Signpost145171
  154. H. J. FormanK. J. A. DaviesF. UrsiniHow do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivoFree Radical Biology and Medicine201466243510.1016/j.freeradbiomed.2013.05.0452-s2.0-8489236938223747930
  155. H. H. H. W. SchmidtR. StockerC. VollbrachtAntioxidants in translational medicineAntioxidants & Redox Signaling201523141130114310.1089/ars.2015.63932-s2.0-8493888318226154592
  156. J. D. HayesA. T. Dinkova-KostovaThe Nrf2 regulatory network provides an interface between redox and intermediary metabolismTrends in Biochemical Sciences201439419921810.1016/j.tibs.2014.02.0022-s2.0-8489742197024647116
  157. A. BrunetL. B. SweeneyJ. F. SturgillStress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylaseScience200430356662011201510.1126/science.10946372-s2.0-1214429056314976264
  158. S. NemotoM. M. FergussonT. FinkelSIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1αJournal of Biological Chemistry200528016164561646010.1074/jbc.M5014852002-s2.0-1814441131315716268
  159. L. F. PettenuzzoPatrícia F. SchuckA. T. S. WyseAscorbic acid prevents water maze behavioral deficits caused by early postnatal methylmalonic acid administration in the ratBrain Research2003976223424210.1016/S0006-8993(03)02722-72-s2.0-003870649012763258
  160. L. PettenuzzoP. F. SchuckF. FontellaAscorbic acid prevents cognitive deficits caused by chronic administration of propionic acid to rats in the water mazePharmacology Biochemistry and Behavior200273362362910.1016/S0091-3057(02)00856-02-s2.0-0036342519
  161. C. A. RibeiroÂ. M. SgaravattiR. B. RosaInhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine diseaseNeurochemical Research200833111412410.1007/s11064-007-9423-92-s2.0-3694903232217680360
  162. F. S. RodriguesM. A. SouzaD. V. MagniN-Acetylcysteine prevents spatial memory impairment induced by chronic early postnatal glutaric acid and lipopolysaccharide in rat pupsPLoS One2013810, article e7833210.1371/journal.pone.00783322-s2.0-8488625764524205200
  163. G. S. RibasV. ManfrediniJ. F. de MariReduction of lipid and protein damage in patients with disorders of propionate metabolism under treatment: a possible protective role of L-carnitine supplementationInternational Journal of Developmental Neuroscience201028212713210.1016/j.ijdevneu.2010.01.0022-s2.0-7764919301420100562
  164. I. GulcinAntioxidant and antiradical activities of L-carnitineLife Sciences200678880381110.1016/j.lfs.2005.05.1032-s2.0-3054445531816253281
  165. G. GuerreiroC. P. MesckaA. SittaUrinary biomarkers of oxidative damage in maple syrup urine disease: the L-carnitine roleInternational Journal of Developmental Neuroscience201542101410.1016/j.ijdevneu.2015.02.0032-s2.0-8492334917125680940
  166. S. Pinar-SueiroR. Martinez-FernandezS. Lage-MedinaL. Aldamiz-EchevarriaE. VecinoOptic neuropathy in methylmalonic acidemia: the role of neuroprotectionJournal of Inherited Metabolic Disease201033S319920310.1007/s10545-010-9084-82-s2.0-84897928136
  167. A. J. GuenzelS. E. HofherrM. HillestadGeneration of a hypomorphic model of propionic acidemia amenable to gene therapy testingMolecular Therapy20132171316132310.1038/mt.2013.682-s2.0-8487969279723648696
  168. M. R. de OliveiraS. F. NabaviA. ManayiM. DagliaZ. HajheydariS. M. NabaviResveratrol and the mitochondria: from triggering the intrinsic apoptotic pathway to inducing mitochondrial biogenesis, a mechanistic viewBiochimica et Biophysica Acta (BBA) - General Subjects20161860472774510.1016/j.bbagen.2016.01.0172-s2.0-8495671890626802309
  169. A. Lopes CostaC. Le BachelierL. MathieuBeneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signalingHuman Molecular Genetics20142382106211910.1093/hmg/ddt6032-s2.0-8489787807424365713
  170. A. W. El-HattabA. M. ZaranteM. AlmannaiF. ScagliaTherapies for mitochondrial diseases and current clinical trialsMolecular Genetics and Metabolism201712231910.1016/j.ymgme.2017.09.0092-s2.0-8502970490028943110
  171. K. N. MacleanH. JiangS. AivazidisTaurine treatment prevents derangement of the hepatic γ-glutamyl cycle and methylglyoxal metabolism in a mouse model of classical homocystinuria: regulatory crosstalk between thiol and sulfinic acid metabolismThe FASEB Journal2018article fj.201700586R10.1096/fj.201700586r
  172. O. FiruziR. MiriM. TavakkoliL. SasoAntioxidant therapy: current status and future prospectsCurrent Medicinal Chemistry201118253871388810.2174/0929867118034143682-s2.0-8005224434621824100
  173. P. PalozzaS. SeriniA. TorselloRegulation of cell cycle progression and apoptosis by beta-carotene in undifferentiated and differentiated HL-60 leukemia cells: possible involvement of a redox mechanismInternational Journal of Cancer200297559360010.1002/ijc.100942-s2.0-003705072511807783
  174. S. L. YehH. M. WangP. Y. ChenT. C. WuInteractions of β-carotene and flavonoids on the secretion of pro-inflammatory mediators in an in vitro systemChemico-Biological Interactions20091792-338639310.1016/j.cbi.2008.12.0062-s2.0-6254916469919135038
  175. J. LinN. R. CookC. AlbertVitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trialJournal of the National Cancer Institute20091011142310.1093/jnci/djn4382-s2.0-5854909492019116389
  176. G. BjelakovicD. NikolovaL. L. GluudR. G. SimonettiC. GluudMortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysisJAMA2007297884285710.1001/jama.297.8.8422-s2.0-3384737845117327526
  177. G. BjelakovicD. NikolovaL. L. GluudR. G. SimonettiC. GluudAntioxidant supplements for prevention of mortality in healthy participants and patients with various diseasesCochrane Database of Systematic Reviews20123, article CD00717610.1002/14651858.CD007176.pub2
  178. K. R. MartinJ. C. BarrettReactive oxygen species as double-edged swords in cellular processes: low-dose cell signaling versus high-dose toxicityHuman & Experimental Toxicology2002212717510.1191/0960327102ht213oa2-s2.0-003601552112102499
  179. L. I. LeichertT. P. DickIncidence and physiological relevance of protein thiol switchesBiological Chemistry2015396538939910.1515/hsz-2014-03142-s2.0-8492794105825719318
  180. Y. FujikawaL. P. RomaM. C. SobottaMouse redox histology using genetically encoded probesScience Signaling20169419p. rs110.1126/scisignal.aad38952-s2.0-8496249031926980443
The underlying source XML for this text is taken from The license for the article is Creative Commons Attribution 4.0 International. The main subject has been identified as homocystinuria.