The energy disruptor metformin targets mitochondrial integrity via modification of calcium flux in cancer cells
2017
Loubière, Camille | Clavel, Stéphan | Gilleron, Jérôme | Harisseh, Rania | Fauconnier, J. | Ben-Sahra, Issam | Kaminski, Lisa | Laurent, Kathiane | Herkenne, Stephanie | Lacas-Gervais, Sandra | Ambrosetti, Damien | Alcor, Damien | Rocchi, Stéphane | Cormont, Mireille | Michiels, Jean-François | Mari, Bernard | Mazure, Nathalie | Scorrano, Luca | Lacampagne, Alain | Gharib, Abdallah | Tanti, Jean-François | Bost, Frédéric | Centre méditerranéen de médecine moléculaire (C3M) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UniCA) | Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN) ; Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon) ; Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM) | Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) | Northwestern University [Evanston] | Università degli Studi di Padova = University of Padua (Unipd) | Dulbecco Telethon Institute ; Telethon Foundation | Centre Commun de Microscopie Appliquée (CCMA) ; Université Côte d'Azur (UniCA) | Hôpital Pasteur [Nice] (CHU) | Institut de pharmacologie moléculaire et cellulaire (IPMC) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UniCA) | Institut de signalisation, biologie du développement et cancer - Institute of Developmental Biology and Cancer (IBDC) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UniCA) | ITMO-Cancer; foundation ARC; French Ministry of Research; Conseil General Alpes-Maritimes (Appel a projets santé); Region PACA (Appel a projets plateforme); French Government (National Research Agency, ANR) through the "Investments for the Future" LABEX SIGNALIFE [ANR-11-LABX-0028-01] | ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011)
International audience
Show more [+] Less [-]English. 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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