INSERM UMR 1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
INSERM UMR 1124, Centre Universitaire des Saints-Pères, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
EBioMedicine. 2017 Mar;17:75-87. doi: 10.1016/j.ebiom.2017.02.013. Epub 2017 Feb 16.
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.
携带低功能 AIF-Harlequin 突变的小鼠表现出高度异质性的线粒体病，主要影响呼吸链复合物 I，导致类似于 AIF 功能丧失突变患者的脑部病理学。在这里，我们描述了抗糖尿病药物吡格列酮（PIO）可以改善 Harlequin（Hq）亚组小鼠的表型，这可能是由于抑制糖酵解导致血糖水平升高。这种由 PIO 引起的糖酵解抑制作用在来自 Hq 小鼠的培养星形胶质细胞以及来自 AIF 突变患者的人皮肤成纤维细胞中均有观察到。PIO 通过对甘油醛-3-磷酸脱氢酶（GAPDH）的直接竞争性抑制来抑制糖酵解。此外，在小脑和 Hq 小鼠的肌肉中，GAPDH 蛋白水平降低，而 PIO 治疗后表型得到改善。总的来说，我们的结果表明，过度的糖酵解参与了线粒体病的发病机制，而糖酵解的药理学抑制可能对此类疾病有益。
