Mitochondrial dysfunction, AMPK activation & peroxisomal metabolism: a coherent scenario for non-canonical 3-methylglutaconic acidurias, 2019, Vamecq

Andy · Oct 19, 2019

Highlights

• 3-methylglutaconic acidurias (3MGAs) include primary and secondary (non-canonical) disorders.
• Metabolic genesis of 3MGA is well understood in primary but not secondary 3MGAs.
• Non-canonical 3MGAs are a growing-up group of inherited metabolic diseases (>10).
• These 3MGAs cause a mitochondrial dysfunction known in other instances to activate AMPK.
• AMPK activation blunts cytoplasmic processing of acetyl-CoA via relevant enzyme inhibition.
• Excess amounts of unmetabolized cytoplasmic acetyl-CoA may be pipelined to peroxisomes.
• Peroxisomal metabolism of excess acetyl-CoA to HMG-CoA may drive 3MGA overproduction.

Abstract
The occurrence of 3-methylglutaconic aciduria (3-MGA) is a well understood phenomenon in leucine oxidation and ketogenesis disorders (primary 3-MGAs). In contrast, its genesis in non-canonical (secondary) 3-MGAs, a growing-up group of disorders encompassing more than a dozen of inherited metabolic diseases, is a mystery still remaining unresolved for three decades. To puzzle out this anthologic problem of metabolism, three clues were considered: (i) the variety of disorders suggests a common cellular target at the cross-road of metabolic and signaling pathways, (ii) the response to leucine loading test only discriminative for primary but not secondary 3-MGAs suggests these latter are disorders of extramitochondrial HMG-CoA metabolism as also attested by their failure to increase 3-hydroxyisovalerate, a mitochondrial metabolite accumulating only in primary 3-MGAs, (iii) the peroxisome is an extramitochondrial site possessing its own pool and displaying metabolism of HMG-CoA, suggesting its possible involvement in producing extramitochondrial 3-methylglutaconate (3-MG). Following these clues provides a unifying common basis to non-canonical 3-MGAs: constitutive mitochondrial dysfunction induces AMPK activation which, by inhibiting early steps in cholesterol and fatty acid syntheses, pipelines cytoplasmic acetyl-CoA to peroxisomes where a rise in HMG-CoA followed by local dehydration and hydrolysis may lead to 3-MGA yield. Additional contributors are considered, notably for 3-MGAs associated with hyperammonemia, and to a lesser extent in CLPB deficiency. Metabolic and signaling itineraries followed by the proposed scenario are essentially sketched, being provided with compelling evidence from the literature coming in their support.
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Paywall, https://www.sciencedirect.com/science/article/abs/pii/S0300908419302974
Not currently available via Scihub.

For further reading, https://en.wikipedia.org/wiki/3-Methylglutaconic_aciduria

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Mitochondrial dysfunction, AMPK activation & peroxisomal metabolism: a coherent scenario for non-canonical 3-methylglutaconic acidurias, 2019, Vamecq

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Mitochondrial dysfunction, AMPK activation & peroxisomal metabolism: a coherent scenario for non-canonical 3-methylglutaconic acidurias, 2019, Vamecq

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