title: Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency.
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.
authors.affiliation: INSERM UMR 1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.affiliation: INSERM UMR 1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Pelhaître
authors.affiliation: INSERM UMR 1124, Centre Universitaire des Saints-Pères, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Saunier
authors.affiliation: INSERM UMR 1124, Centre Universitaire des Saints-Pères, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bortoli
authors.affiliation: INSERM UMR 1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Assetou
authors.initials: A
authors.lastname: Coulibaly
authors.affiliation: INSERM UMR 1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Rak
authors.affiliation: INSERM UMR 1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Reference Center for Inherited Metabolic Diseases, Hôpital Robert Debré, Assistance Publique - Hôpitaux de Paris, 48 Boulevard Sérurier, 75019 Paris, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.affiliation: Equipe11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm 17176, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: MRC-Mitochondrial Biology Unit, Cambridge, Cambridgeshire, United Kingdom.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: INSERM UMR 1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address: pierre.rustin@inserm.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D051033:Apoptosis Inducing Factor; D007004:Hypoglycemic Agents; C494830:AIFM1 protein, mouse; D045162:Thiazolidinediones; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D000077205:Pioglitazone
keywords: AIFM1; Bezafibrate; Glyceraldehyde-3-phosphate dehydrogenase (GAPDH); Melatonin; Pre-clinical trial; X-linked mitochondrial encephalomyelopathy