TY - JOUR
T1 - The energy disruptor metformin targets mitochondrial integrity via modification of calcium flux in cancer cells /631/67/2327 /631/80 /13/106 /14/28 /96/95 /38/39 article
AU - Loubiere, Camille
AU - Clavel, Stephan
AU - Gilleron, Jerome
AU - Harisseh, Rania
AU - Fauconnier, Jeremy
AU - Ben-Sahra, Issam
AU - Kaminski, Lisa
AU - Laurent, Kathiane
AU - Herkenne, Stephanie
AU - Lacas-Gervais, Sandra
AU - Ambrosetti, Damien
AU - Alcor, Damien
AU - Rocchi, Stephane
AU - Cormont, Mireille
AU - Michiels, Jean François
AU - Mari, Bernard
AU - Mazure, Nathalie M.
AU - Scorrano, Luca
AU - Lacampagne, Alain
AU - Gharib, Abdallah
AU - Tanti, Jean François
AU - Bost, Frederic
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85023164413&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85023164413&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-05052-2
DO - 10.1038/s41598-017-05052-2
M3 - Article
C2 - 28698627
AN - SCOPUS:85023164413
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 5040
ER -
