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Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency
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 piogl...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360583/ https://www.ncbi.nlm.nih.gov/pubmed/28229909 http://dx.doi.org/10.1016/j.ebiom.2017.02.013 |
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author | Bénit, Paule Pelhaître, Alice Saunier, Elise Bortoli, Sylvie Coulibaly, Assetou Rak, Malgorzata Schiff, Manuel Kroemer, Guido Zeviani, Massimo Rustin, Pierre |
author_facet | Bénit, Paule Pelhaître, Alice Saunier, Elise Bortoli, Sylvie Coulibaly, Assetou Rak, Malgorzata Schiff, Manuel Kroemer, Guido Zeviani, Massimo Rustin, Pierre |
author_sort | Bénit, Paule |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5360583 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-53605832017-03-30 Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency Bénit, Paule Pelhaître, Alice Saunier, Elise Bortoli, Sylvie Coulibaly, Assetou Rak, Malgorzata Schiff, Manuel Kroemer, Guido Zeviani, Massimo Rustin, Pierre EBioMedicine Research Paper 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. Elsevier 2017-02-16 /pmc/articles/PMC5360583/ /pubmed/28229909 http://dx.doi.org/10.1016/j.ebiom.2017.02.013 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Paper Bénit, Paule Pelhaître, Alice Saunier, Elise Bortoli, Sylvie Coulibaly, Assetou Rak, Malgorzata Schiff, Manuel Kroemer, Guido Zeviani, Massimo Rustin, Pierre Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency |
title | Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency |
title_full | Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency |
title_fullStr | Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency |
title_full_unstemmed | Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency |
title_short | Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency |
title_sort | paradoxical inhibition of glycolysis by pioglitazone opposes the mitochondriopathy caused by aif deficiency |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360583/ https://www.ncbi.nlm.nih.gov/pubmed/28229909 http://dx.doi.org/10.1016/j.ebiom.2017.02.013 |
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