Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins

Schwab, Marina A.; Sauer, Sven W.; Okun, Jürgen G.; Nijtmans, Leo; Rodenburg, Richard J.; Heuvel, Lambert P. van den; Dröse, Stefan; Brandt, Ulrich; Hoffmann, Georg F.; Laak, Henk ter; Kölker, Stefan; Smeitink, Jan A.M.

doi:10.1042/bj20060221

Cited by 170 publications

(149 citation statements)

References 22 publications

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“…However, current treatments designed to limit the accumulation of toxins remain insufficient. Recently, a secondary RC deficiency was suggested to be the cause of these complications, as elevated levels of lactate were found in globi pallidi of patients (7), and mitochondrial dysfunction was confirmed in a few patients (6,8,9). Here, we report on six patients, with OA, two PA, and four MMA, in whom we found multiple RC deficiencies in several tissues, including skeletal muscle, liver, heart, and kidney.…”

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confidence: 83%

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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confidence: 83%

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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“…3-MGA-uria was also found frequently in patients presenting with a metabolic crisis due to an organic aciduria. Propionyl-CoA has been shown to noncompetitively inhib-it pyruvate dehydrogenase complex (PDHc, (Schwab et al 2006)), also multiple OXPHOS deficiency in different tis-sues was detected in organic aciduria patients (de Keyzer et al 2009).…”

Section: -Mga-uria Is Mostly Correlated With Mitochondrial Dysfunctionmentioning

confidence: 99%

3‐Methylglutaconic aciduria—lessons from 50 genes and 977 patients

Wortmann

Kluijtmans

Rodenburg

et al. 2013

J of Inher Metab Disea

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Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven,

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“…Defects in propionate metabolism have been associated with a broad range of secondary effects arising from the accumulation of propionyl-CoA and/or propionate-derived metabolites. These secondary effects include the inhibition of enzymes involved in branched chain amino acid turnover, and those of the pyruvate dehydrogenase complex and electron transport chain and, ultimately, result in a cellular acidosis (9)(10)(11)(12). Membrane potential and cytosolic pH homeostasis are essential for the survival of all cells and potentially more so for those residing in acidic niches, including the phagosomes of immune-activated macrophages (13,14).…”

Section: -F)mentioning

confidence: 99%

Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids

Eoh

Rhee

2014

Proc. Natl. Acad. Sci. U.S.A.

149

177

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Few mutations attenuate Mycobacterium tuberculosis (Mtb) more profoundly than deletion of its isocitrate lyases (ICLs). However, the basis for this attenuation remains incompletely defined. Mtb's ICLs are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids. Here, we report that Mtb's ICLs are essential for survival on both acetate and propionate because of its methylisocitrate lyase (MCL) activity. Lack of MCL activity converts Mtb's methylcitrate cycle into a "dead end" pathway that sequesters tricarboxylic acid (TCA) cycle intermediates into methylcitrate cycle intermediates, depletes gluconeogenic precursors, and results in defects of membrane potential and intrabacterial pH. Activation of an alternative vitamin B 12 -dependent pathway of propionate metabolism led to selective corrections of TCA cycle activity, membrane potential, and intrabacterial pH that specifically restored survival, but not growth, of ICL-deficient Mtb metabolizing acetate or propionate. These results thus resolve the biochemical basis of essentiality for Mtb's ICLs and survival on fatty acids. However, our understanding of the pathways and physiologic functions they serve is incomplete. Enzymes catalyze reactions whose identities, rates, and directions are often difficult to determine and, where known, function within the context of complex and extensively interconnected physiologic networks (1). Thus, although recent genetic and biochemical approaches have made it possible to determine the essentiality of a given enzyme, our understanding of the biochemical mechanisms underlying their essentiality remains incomplete.Unlike the case for most microbial pathogens, humans serve as both host and reservoir for Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Within humans, Mtb resides within the biochemically stringent environment of the macrophage phagosome. Growing evidence has separately implicated Mtb's metabolic enzymes as a key determinant of its pathogenicity. Mtb's metabolic network thus appears to have evolved to serve interdependent physiologic and pathogenic roles (2, 3).Isocitrate lyase (ICL) is a metabolic enzyme used by bacteria to sustain growth on even-chain fatty acids through an anaplerotic pathway called the glyoxylate shunt. Mtb encodes two paralogous ICLs, each of which also functions as a methylisocitrate lyase (MCL), and serves a parallel pathway involved in the metabolism of propionyl CoA generated by β-oxidation of oddchain fatty acids, called the methylcitrate cycle. Mtb lacking both ICLs were shown to be incapable of either establishing or maintaining infection in a mouse model of pulmonary TB (4, 5). Although loss of ICL activity is expected to result in the inability to incorporate carbon from fatty acids (a form of starvation), simultaneous loss of MCL activity is predicted to result in the potentially toxic accumulation of propionyl-CoA metabolites (a form of intoxication). Here, we applied 13 C-based metabolomic tra...

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Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins

Cited by 170 publications

References 22 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

3‐Methylglutaconic aciduria—lessons from 50 genes and 977 patients

Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids

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