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.
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BibTeX
@article{benit2026paradoxical,
title = {{Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency}},
author = {Paule Bénit and Alice Pelhaître and Elise Saunier and Sylvie Bortoli and Assetou Coulibaly and Malgorzata Rak and Manuel Schiff and Guido Kroemer and Massimo Zeviani and Pierre Rustin},
journal = {EBioMedicine},
year = {2026},
month = sep,
doi = {10.1016/j.ebiom.2017.02.013},
url = {https://hal.science/hal-05755995v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency
AU - Paule Bénit
AU - Alice Pelhaître
AU - Elise Saunier
AU - Sylvie Bortoli
AU - Assetou Coulibaly
AU - Malgorzata Rak
AU - Manuel Schiff
AU - Guido Kroemer
AU - Massimo Zeviani
AU - Pierre Rustin
PY - 2026
DA - 2026/09/20
JO - EBioMedicine
DO - 10.1016/j.ebiom.2017.02.013
UR - https://hal.science/hal-05755995v1
AB - 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.
SN - 2352-3964
ER -