Title :

Mitochondrial dysfunction, ampk activation and peroxisomal metabolism: a coherent scenario for non-canonical 3-methylglutaconic acidurias

Author(s) :

Vamecq, Joseph [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Papegay, Berengere [Auteur]
University Hospital Research Center
Nuyens, Vincent [Auteur]
University Hospital Research Center
Boogaerts, Jean G. [Auteur]
University Hospital Research Center
Leo, Oberdan [Auteur]
Kruys, Veronique [Auteur]

Journal title :

Biochimie

Abbreviated title :

Biochimie

Volume number :

168

Pages :

53-82

Publisher :

Elsevier

Publication date :

2019-10-15

ISSN :

1638-6183

Keyword(s) :

AMPK activation
Mitochondrial ATP and dysfunction
Cardiolipins
Barth syndrome
Secondary 3-methylglutaconic aciduria
Peroxisomal HMG-CoA pool

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille

Collections :

• Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364

Submission date :

2021-09-02T07:02:11Z
2022-06-15T12:09:31Z