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Barth syndrome’s unsung phenotype: 3-methylglutaconic aciduria

Elizabeth A. Jennings*, Dylan E. Jones and Robert O. Ryan
Department of Biochemistry and Molecular Biology
University of Nevada, Reno

Urinary excretion of organic acids, primarily 3-methylglutaconic (3MGC) acid, is a phenotypic feature of Barth Syndrome (BTHS). Although inherited deficiencies in leucine catabolism enzymes are a primary cause of 3MGC aciduria, no such deficiencies have been reported in subjects with BTHS. Instead, we hypothesize that compromised mitochondrial energy metabolism, a direct result of a deficiency in tafazzin-mediated cardiolipin remodeling, leads to 3MGC CoA formation via a previously unknown biochemical pathway in humans, termed the acetyl CoA diversion pathway. TAZ mutation-dependent effects on cristae membrane cardiolipin content impair electron transport chain activity and aerobic respiration. This leads to a buildup of reduced cofactors (i.e. NADH and FADH2) which serve as end product inhibitors of TCA cycle enzymes. As a result, acetyl CoA is unable to enter the cycle and, instead, is redirected to 3MGC acid via three enzyme-mediated [T2 thiolase, HMG CoA synthase 2 and 3MGC CoA hydratase(AUH)] and three non-enzymatic, chemical reactions. Recent evidence has revealed that, once trans-3MGC CoA is formed via the enzyme mediated steps, the non-enzymatic phase of the acetyl CoA diversion pathway ensues. In a crucial first step, trans-3MGC CoA isomerizes to cis-3MGC CoA. Subsequently, cis-3MGC CoA undergoes intramolecular cyclization, formingcis-3MGC anhydride and free CoA. This creates a “molecular sink” which promotes further AUH-mediated dehydration of HMG CoA.(1) Finally, hydrolysis of cis-3MGC anhydride yields the product,cis-3MGC acid. Interestingly, this process is consistent with the observation that urine of subjects with 3MGC aciduria contains a mixture of cis- and trans-3MGC acids. Alternatively, cis-3MGC anhydride is susceptible to nucleophilic attack by protein lysine side chain amino groups, generating cis-3MGCylated proteins. Evidence obtained using a recently reported rabbit polyclonal anti-3MGC IgG (2) has revealed that incubation of bovine serum albumin (BSA) with trans-3MGC CoA leads to isomerization, anhydride formation and 3MGCylation of BSA. Whereas the potential significance of protein 3MGCylation in BTHS is yet to be determined, it could affect metabolic pathway flux and/or enzyme activity. Non-enzymatic protein 3MGCylation can be reversed, however, through the activity of sirtuin 4, an NAD+-dependent deacylase that catalyzes release of 3MGC moieties from acylated proteins. Taken together, it is apparent that organic aciduria in BTHS is a direct byproduct of mitochondrial dysfunction caused by mutations in TAZthat lead to defects in cristae membrane structure and function. Thus, it is conceivable that 3MGC acid levels in urine represent a window into mitochondrial function in subjects with BTHS.

1. Jones DE, Romenskaia I, Kosma DK and Ryan RO (2022) Role of non-enzymatic chemical reactions in 3-methylglutaconic aciduria. FEBS J. Online ahead of print, Dec 7, 2021.
2.Young R, Jones DE, Diacovich L, Witkowski A and Ryan, RO (2021) trans-3-methylglutaconyl CoA isomerization-dependent protein acylation. Biochem. Biophys. Res. Commun. 534, 261-265

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