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

Paule Bénit,Alice Pelhaître,Elise Saunier,Sylvie Bortoli,Assetou Coulibaly,Malgorzata Rak,Manuel Schiff,Guido Kroemer,Massimo Zeviani,Pierre Rustin

doi:10.1016/j.ebiom.2017.02.013

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.

Highlights

Mitochondrial disorders represent an expanding group of diseases characterized by wide variability in clinical presentation and course (Turnbull and Rustin, 2015)
To study the effect of melatonin (ML), bezafibrate (BZ) and pioglitazone (PIO) on the Hq mouse, we carried out a 5 months clinical monitoring initially based on the progression of ataxia assessed the Rotarod test (Bénit et al, 2008)
Treatment with ML or BZ was found either inefficient (ML) in halting Hq disease progression or even susceptible (BZ) to worsen its course. This latter result is in line with a prior report showing that BZ can worsen the phenotype of mice that had been rendered deficient for respiratory chain (RC) by genetic engineering (Viscomi et al, 2011)

Summary

Introduction

Mitochondrial (mt) disorders represent an expanding group of diseases characterized by wide variability in clinical presentation and course (Turnbull and Rustin, 2015). With a few exceptions (e.g. primary CoQ10 deficiency), no therapy can currently be offered to the patients and hardly any clinical trial has led to reliable and convincing conclusions (Koopman et al, 2016). This depends in part from the difficulty to collect sufficiently large cohorts of patients with a homogeneous genetic defect and similar clinical presentation. In spite of extensive studies on murine models, very few candidate drugs have shown some positive effects in subsequent

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