Methylmalonic acid — an endogenous toxin?

Kölker, Stefan; Okun, Jürgen G.

doi:10.1007/s00018-005-4463-2

Cited by 47 publications

(38 citation statements)

References 74 publications

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“…We observed a dramatic regression of cardiomyopathy in one patient with PA after liver transplantation. However, neither liver nor renal transplantation (33-37) seem to prevent neurologic complications in many MMA and PA, a complication most likely related to the blood-brain barrier (38). Thus, the potential of anaplerotic substrates to sustain the TCA cycle flux in patients with MMA and PA could represent another therapeutic option to prevent long-term energetic complications.…”

Section: Discussionmentioning

confidence: 99%

Multiple OXPHOS Deficiency in the Liver, Kidney, Heart, and Skeletal Muscle of Patients With Methylmalonic Aciduria and Propionic Aciduria

et al. 2009

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ABSTRACT:We investigated respiratory chain (RC), tricarboxylic acid cycle (TCA) enzyme activities, and oxidative stress in the tissues of six patients with organic aciduria (OA) presenting various severe complications to further document the role of mitochondrial OXPHOS dysfunction in the development of complications. Two children with propionic acidemia (PA), presenting a severe cardiomyopathy, and four with methylmalonic aciduria (MMA), who developed a neurologic disease (3/4) and renal failure (2/4), were followed. We measured RC and TCA cycle enzyme activity in patient tissues and assessed oxidative metabolism in fibroblasts in vitro. Various RC deficiencies were found in tissues of patients with PA and MMA. TCA cycle enzyme activities were normal when investigated and reactive oxygen species were decreased as well as detoxifying systems activities in the two patients tested. In conclusion, mitochondrial dysfunction was found in all investigated tissues of six patients with organic acidemia presenting with severe complications. Reactive oxygen species production and detoxification were decreased in fibroblast primary cultures. Our results bring further support for a role of secondary respiratory deficiency in the development of late multiorgan complications of these diseases. (Pediatr Res 66: 91-95, 2009) P ropionic aciduria (PA) and methylmalonic aciduria (MMA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids. PA results from mutations in the PCCA or PCCB genes, encoding the ␣ and ␤ subunits of propionyl-CoA carboxylase, respectively, which converts propionyl-CoA into methylmalonyl-CoA. MMA is caused by mutations in the MUT gene, encoding the methylmalonyl-CoA mutase (MCM), or more rarely in genes encoding the coenzyme adenosylcobalamin of MCM. MCM converts methylmalonyl-CoA into succinylCoA, an intermediate of the tricarboxylic acid cycle (TCA) cycle, which generates NADH used by the mitochondrial respiratory chain (RC).Organic acidurias (OA) usually present as an acute metabolic distress at birth, when the enzymatic deficiency is complete, or later in life, when the deficiency is less severe. As propionate is produced by the catabolism of branched-chain amino acids, fatty acids with a carbon odd-chain and the intestinal flora, the treatment is based on a strict low-protein diet associated with a sufficient caloric intake, carnitine, and antibiotics. However, despite the therapeutic improvements of the last 20 y (1), the overall outcome of patients with OA remains unsatisfying: reports are increasing of long-term complications, such as neurologic disorders by degeneration of the basal ganglia (2), progressive renal failure (3), acute pancreatitis (4,5), and cardiomyopathy (6). It is commonly believed that 2-methylcitrate, methylmalonic acid (MA), and other accumulated metabolites derived from propionate inhibit some mitochondrial enzymes and are toxic on multiple tissues. However, current treatments designed to limit the accumulation of toxins rema...

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Section: Discussionmentioning

confidence: 99%

Multiple OXPHOS Deficiency in the Liver, Kidney, Heart, and Skeletal Muscle of Patients With Methylmalonic Aciduria and Propionic Aciduria

et al. 2009

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“…Thus, how MMA contributes to the neuropathogenesis of methylmalonic acidurias is open to discussion. This has been discussed in detail in a recently published review article (Kö lker and Okun 2005).…”

Section: Brainmentioning

confidence: 90%

“…Since little or even no mitochondrial de novo synthesis of GSH occurs, the mitochondrial GSH pool is highly dependent on transport of cytosolic GSH via DCC (Smith et al 1996). It is known that several DCAs inhibit GSH uptake via DCC (Chen and Lash 1998) and thus it has been speculated that accumulating DCAs, such as MMA, cause intramitochondrial GSH depletion (Kö lker and Okun 2005). As suggested for the neuropathogenesis, it is reasonable to assume that CRF in methylmalonic aciduria is induced by a synergism of DCA-induced mechanisms, resulting in mitochondrial dysfunction and subsequently cell death (Fig.…”

Section: Kidneymentioning

confidence: 99%

“…MMA, the biochemical key metabolite of methylmalonic acidurias, was first considered to act as the main neurotoxic metabolite in this condition, whereas other studies have highlighted toxic effects by propionyl-CoA and 2-methylcitrate (Kö lker et al 2003;Okun et al 2002). The role of MMA and the concept of synergistic inhibition by alternative accumulating metabolites in neuropathogenesis of methylmalonic acidurias has been described in detail in a review article from our laboratory (Kö lker and Okun 2005). This review includes significant further insights into underlying pathomechanisms of organic acidurias which have been published in the last year (Kö lker et al 2006a,b;Sauer et al 2006;Schwab et al 2006).…”

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confidence: 94%

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Neurodegeneration and chronic renal failure in methylmalonic aciduria—A pathophysiological approach

Morath

Okun

Müller

et al. 2007

J of Inher Metab Disea

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121

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In the last decades the survival of patients with methylmalonic aciduria has been improved. However, the overall outcome of affected patients remains disappointing. The disease course is often complicated by acute life-threatening metabolic crises, which can result in multiple organ failure or even death, resembling primary defects of mitochondrial energy metabolism. Biochemical abnormalities during metabolic derangement, such as metabolic acidosis, ketonaemia/ketonuria, lactic acidosis, hypoglycaemia and hyperammonaemia, suggest mitochondrial dysfunction. In addition, long-term complications such as chronic renal failure and neurological disease are frequently found. Neuropathophysiological studies have focused on various effects caused by accumulation of putatively toxic organic acids, the so-called 'toxic metabolite' hypothesis. In previous studies, methylmalonate (MMA) has been considered as the major neurotoxin in methylmalonic aciduria, whereas more recent studies have highlighted a synergistic inhibition of mitochondrial energy metabolism (pyruvate dehydrogenase complex, tricarboxylic acid cycle, respiratory chain, mitochondrial salvage pathway of deoxyribonucleoside triphosphate (dNTP)) induced by propionyl-CoA, 2-methylcitrate and MMA as the key pathomechanism of inherited disorders of propionate metabolism. Intracerebral accumulation of toxic metabolites ('trapping' hypothesis') is considered a biochemical risk factor for neurodegeneration. Secondary effects of mitochondrial dysfunction, such as oxidative stress and impaired mtDNA homeostasis, contribute to pathogenesis of these disorders. The underlying pathomechanisms of chronic renal insufficiency in methylmalonic acidurias are not yet understood. We hypothesize that renal and cerebral pathomechanisms share some similarities, such as an involvement of dicarboxylic acid transport. This review aims to give a comprehensive overview on recent pathomechanistic concepts for methylmalonic acidurias.

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“…Formation of the toxic metabolites may in fact occur within the brain [12]. This is particularly true for OAs related to propionate metabolism in which neither diet, vitamin therapy, nor liver transplantation appears to prevent neurological complications [12]. …”

Section: Introductionmentioning

confidence: 99%

Integration of Proteomics and Metabolomics in Exploring Genetic and Rare Metabolic Diseases

et al. 2017

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Background: Inherited metabolic disorders or inborn errors of metabolism are caused by deficiency of enzymatic activities in the catabolism of amino acids, carbohydrates, or lipids. These disorders include aminoacidopathies, urea cycle defects, organic acidemias, defects of oxidation of fatty acids, and lysosomal storage diseases. Inborn errors of metabolism constitute a significant proportion of genetic diseases, particularly in children; however, they are individually rare. Clinical phenotypes are very variable, some of them remain asymptomatic, others manifest metabolic decompensation in neonatal age, and others encompass mental retardation at later age. The clinical manifestation of these disorders can involve different organs and/or systems. Some disorders are easily managed if promptly diagnosed and treated, whereas in other cases neither diet, vitamin therapy, nor transplantation appears to prevent multi-organ impairment. Summary: Here, we discuss the principal challenges of metabolomics and proteomics in inherited metabolic disorders. We review the recent developments in mass spectrometry-based proteomic and metabolomic strategies. Mass spectrometry has become the most widely used platform in proteomics and metabolomics because of its ability to analyze a wide range of molecules, its optimal dynamic range, and great sensitivity. The fast measurement of a broad spectrum of metabolites in various body fluids, also collected in small samples like dried blood spots, have been facilitated by the use of mass spectrometry-based techniques. These approaches have enabled the timely diagnosis of inherited metabolic disorders, thereby facilitating early therapeutic intervention. Due to its analytical features, proteomics is suited for the basic investigation of inborn errors of metabolism. Modern approaches enable detailed functional characterization of the pathogenic biochemical processes, as achieved by quantification of proteins and identification of their regulatory chemical modifications. Key Message: Mass spectrometry-based “omics” approaches most frequently used to study the molecular mechanisms underlying inherited metabolic disorders pathophysiology are described.

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Methylmalonic acid — an endogenous toxin?

Cited by 47 publications

References 74 publications

Multiple OXPHOS Deficiency in the Liver, Kidney, Heart, and Skeletal Muscle of Patients With Methylmalonic Aciduria and Propionic Aciduria

Multiple OXPHOS Deficiency in the Liver, Kidney, Heart, and Skeletal Muscle of Patients With Methylmalonic Aciduria and Propionic Aciduria

Neurodegeneration and chronic renal failure in methylmalonic aciduria—A pathophysiological approach

Integration of Proteomics and Metabolomics in Exploring Genetic and Rare Metabolic Diseases

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