The energy disruptor metformin targets mitochondrial integrity via modification of calcium flux in cancer cells

Abstract Mitochondrial integrity is critical for the regulation of cellular energy and apoptosis. Metformin is an energy disruptor targeting complex I of the respiratory chain. We demonstrate that metformin induces endoplasmic reticulum (ER) stress, calcium release from the ER and subsequent uptake...

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Autores principales: Camille Loubiere, Stephan Clavel, Jerome Gilleron, Rania Harisseh, Jeremy Fauconnier, Issam Ben-Sahra, Lisa Kaminski, Kathiane Laurent, Stephanie Herkenne, Sandra Lacas-Gervais, Damien Ambrosetti, Damien Alcor, Stephane Rocchi, Mireille Cormont, Jean-François Michiels, Bernard Mari, Nathalie M. Mazure, Luca Scorrano, Alain Lacampagne, Abdallah Gharib, Jean-François Tanti, Frederic Bost
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2017
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Acceso en línea:https://doaj.org/article/3c81dba573894f44b340dafd88a5e78b
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Sumario:Abstract Mitochondrial integrity is critical for the regulation of cellular energy and apoptosis. Metformin is an energy disruptor targeting complex I of the respiratory chain. We demonstrate that metformin induces endoplasmic reticulum (ER) stress, calcium release from the ER and subsequent uptake of calcium into the mitochondria, thus leading to mitochondrial swelling. Metformin triggers the disorganization of the cristae and inner mitochondrial membrane in several cancer cells and tumors. Mechanistically, these alterations were found to be due to calcium entry into the mitochondria, because the swelling induced by metformin was reversed by the inhibition of mitochondrial calcium uniporter (MCU). We also demonstrated that metformin inhibits the opening of mPTP and induces mitochondrial biogenesis. Altogether, the inhibition of mPTP and the increase in mitochondrial biogenesis may account for the poor pro-apoptotic effect of metformin in cancer cells.