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

EBioMedicine. 2017 Mar;17:75-87. doi: 10.1016/j.ebiom.2017.02.013. Epub 2017 Feb 16.

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.

Keywords: AIFM1; Bezafibrate; Glyceraldehyde-3-phosphate dehydrogenase (GAPDH); Melatonin; Pre-clinical trial; X-linked mitochondrial encephalomyelopathy.

MeSH terms

  • Animals
  • Apoptosis Inducing Factor / deficiency
  • Apoptosis Inducing Factor / genetics*
  • Apoptosis Inducing Factor / metabolism
  • Cells, Cultured
  • Cerebellum / metabolism
  • Female
  • Fibroblasts / metabolism
  • Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / metabolism
  • Glycolysis*
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Encephalomyopathies / drug therapy*
  • Mitochondrial Encephalomyopathies / genetics
  • Mitochondrial Encephalomyopathies / metabolism
  • Muscle, Skeletal / metabolism
  • Pioglitazone
  • Thiazolidinediones / pharmacology*
  • Thiazolidinediones / therapeutic use

Substances

  • Apoptosis Inducing Factor
  • Hypoglycemic Agents
  • Pdcd8 protein, mouse
  • Thiazolidinediones
  • Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)
  • Pioglitazone