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Sci Rep. 2017 Jul 11;7(1):5040. doi: 10.1038/s41598-017-05052-2.

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

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Inserm U1065, C3M, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France.
Université Nice Côte d'Azur, Inserm, Nice, France.
Inserm U1060/ INRA 1235/ Université-Lyon1/ INSA, Lyon, France.
Inserm U1046, UMR CNRS 9214, Université de Montpellier, Montpellier, France.
Northwestern University, Chicago, IL, USA.
Department of Biology, University of Padua, Padua, Italy.
Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padua, Italy.
Centre Commun de Microscopie Appliquée, Université de Nice Sophia-Antipolis, Nice, France.
Centre Hospitalier Universitaire (CHU) de Nice, Hôpital Pasteur, Laboratoire Central d'Anatomo Pathologie, 06002, Nice, France.
Inserm U1065, C3M, Team Biology and pathology of melanocyte cells: From skin pigmentation to melanomas, Nice, France.
CNRS, Institute of Molecular and Cellular Pharmacology, Sophia Antipolis, France.
Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-Inserm U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France.
Inserm U1065, C3M, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France.
Université Nice Côte d'Azur, Inserm, Nice, France.


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.

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