Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency.

TitleParadoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency.
Publication TypeJournal Article
Year of Publication2017
AuthorsBénit, P, Pelhaître, A, Saunier, E, Bortoli, S, Coulibaly, A, Rak, M, Schiff, M, Kroemer, G, Zeviani, M, Rustin, P
JournalEBioMedicine
Volume17
Pagination75-87
Date Published2017 Mar
ISSN2352-3964
KeywordsAnimals, Apoptosis Inducing Factor, Cells, Cultured, Cerebellum, Female, Fibroblasts, Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+), Glycolysis, Humans, Hypoglycemic Agents, Male, Mice, Mitochondria, Mitochondrial Encephalomyopathies, Muscle, Skeletal, Thiazolidinediones
Abstract

Mice with the hypomorphic AIF-Harlequin mutation exhibit a highly heterogeneous mitochondriopathy that mostly affects respiratory chain complex I, causing a cerebral pathology that resembles that found in patients with AIF loss-of-function mutations. Here we describe that the antidiabetic drug pioglitazone (PIO) can improve the phenotype of a mouse Harlequin (Hq) subgroup, presumably due to an inhibition of glycolysis that causes an increase in blood glucose levels. This glycolysis-inhibitory PIO effect was observed in cultured astrocytes from Hq mice, as well as in human skin fibroblasts from patients with AIF mutation. Glycolysis inhibition by PIO resulted from direct competitive inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Moreover, GAPDH protein levels were reduced in the cerebellum and in the muscle from Hq mice that exhibited an improved phenotype upon PIO treatment. Altogether, our results suggest that excessive glycolysis participates to the pathogenesis of mitochondriopathies and that pharmacological inhibition of glycolysis may have beneficial effects in this condition.

DOI10.1016/j.ebiom.2017.02.013
Alternate JournalEBioMedicine
Citation Key10.1016/j.ebiom.2017.02.013
PubMed ID28229909
PubMed Central IDPMC5360583
Grant ListMC_UP_1002/1 / / Medical Research Council / United Kingdom