Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency
Year: 2017
Type: article
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.
Source: EBioMedicine
Institutions: Inserm, Sorbonne Paris Cité, Université Paris Diderot, NeuroDiderot, Health and Functional Exposomics, Université Paris Descartes, Assistance Publique – Hôpitaux de Paris, Hôpital Robert-Debré, Karolinska University Hospital, Institut Gustave Roussy, Karolinska Institutet, Centre de Recherche des Cordeliers, La Ligue Contre le Cancer, Hôpital Européen Georges-Pompidou, MRC Mitochondrial Biology Unit
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,902
OpenAlex ID: W2588239956