RESUMO
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.
Assuntos
Fator de Indução de Apoptose/genética , Glicólise , Hipoglicemiantes/farmacologia , Encefalomiopatias Mitocondriais/tratamento farmacológico , Tiazolidinedionas/farmacologia , Animais , Fator de Indução de Apoptose/deficiência , Fator de Indução de Apoptose/metabolismo , Células Cultivadas , Cerebelo/metabolismo , Feminino , Fibroblastos/metabolismo , Gliceraldeído 3-Fosfato Desidrogenase (NADP+)/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Pioglitazona , Tiazolidinedionas/uso terapêuticoRESUMO
Mitochondria exert crucial physiological functions that create complex links among nutrition, health, and disease. While mitochondrial dysfunction with subsequent impairment of oxidative phosphorylation (OXPHOS) is the hallmark of the rare inherited OXPHOS diseases, OXPHOS dysfunction also plays a central role in the pathophysiology of common conditions such as type 2 diabetes and various neurodegenerative disorders. Dietary interventions, especially calorie restriction, have been shown to improve the course of these diseases and to extend the lifespan. Few data are available on the impact of nutraceuticals (macronutrients, vitamins, and cofactors) on primary inherited OXPHOS diseases. This review presents recent knowledge about the impact of nutritional modulation on mitochondria and lifespan regulation and about the development of potential treatments for mitochondrial dysfunction diseases.
