Paradoxical inhibition of glycolysis by pioglitazone opposes the mitochondriopathy caused by AIF deficiency

Paule Bénit 1 Alice Pelhaître 1 Elise Saunier 2 Sylvie Bortoli 2 Assetou Coulibaly 1 Malgorzata Rak 1 Manuel Schiff 3, 1 Guido Kroemer 4, 5, 6, 7, 8, 9 Massimo Zeviani 10 Pierre Rustin 1, *
* Auteur correspondant
1 PROTECT - Neuroprotection du Cerveau en Développement
2 U1124 - Toxicologie, Pharmacologie et Signalisation Cellulaire
3 Centre Référence des Maladies Héréditaires du Métabolisme [Paris-Robert Debré]
4 Université Paris-Saclay
5 Plateforme de métabolomique
Direction de la recherche [Gustave Roussy]
6 Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 - Apoptose, cancer et immunité
IGR - Institut Gustave Roussy, CRC - Centre de Recherche des Cordeliers
7 HEGP - Hôpital Européen Georges Pompidou [APHP]
8 CRC - Centre de Recherche des Cordeliers
9 Department of Women's and Children's Health
10 MRC - Mitochondrial Biology Unit
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 trial pre-clinical melatonin bezafibrate glyceraldehyde-3-phosphate dehydrogenase (GAPDH) X-linked mitochondrial encephalomyelopathy
Type de document :
Article dans une revue
EBioMedicine, Elsevier, 2017, pp.S2352-3964(17)30072-5. 〈10.1016/j.ebiom.2017.02.013〉
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http://www.hal.inserm.fr/inserm-01477508
Contributeur : Pierre Rustin <>
Soumis le : lundi 27 février 2017 - 14:28:47
Dernière modification le : samedi 1 septembre 2018 - 01:14:54

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Paule Bénit, Alice Pelhaître, Elise Saunier, Sylvie Bortoli, Assetou Coulibaly, et al.. Paradoxical inhibition of glycolysis by pioglitazone opposes the mitochondriopathy caused by AIF deficiency. EBioMedicine, Elsevier, 2017, pp.S2352-3964(17)30072-5. 〈10.1016/j.ebiom.2017.02.013〉. 〈inserm-01477508〉

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