Co-targeting Mitochondrial Ca2+ Homeostasis and Autophagy Enhances Cancer Cells' Chemosensitivity

• Published in: iScience 2020-07, Vol.23 (7), p.101263-101263, Article 101263
• Main Authors: Dubois, Charlotte, Kondratskyi, Artem, Bidaux, Gabriel, Noyer, Lucile, Vancauwenberghe, Eric, Farfariello, Valério, Toillon, Robert-Allain, Roudbaraki, Morad, Tierny, Dominique, Bonnal, Jean-Louis, Prevarskaya, Natalia, Vanden Abeele, Fabien
• Format: Article
• Language: English
• Subjects: Biological Sciences; Cancer; Cell Biology; Life Sciences
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.101263

Mitochondria are important cell death checkpoints, and mitochondrial Ca2+ overload is considered as a potent apoptotic intrinsic pathway inducer. Here, we report that this Ca2+ apoptosis link is largely ineffective in inducing cell-death just by itself and required a concomitant inhibition of autophagy to counteract its pro-survival action. In such condition, an acute mitochondrial stress revealed by a DRP1-mediated mitochondrial dynamic remodeling is observed concomitantly with mitochondrial depolarization, release of cytochrome c, and efficient apoptosis induction. We also uncover that mitochondrial Ca2+ status modulates the function of autophagy as a sensitizer for chemotherapies. This priming mediated by mitochondrial Ca2+ overload and inhibition of autophagy sensitizes many cancer cells types to different chemotherapies with independent mechanisms of action. Collectively, our results redefine an important cell signaling pathway, uncovering new combined therapies for the treatment of diseases associated with mitochondrial Ca2+ homeostasis disorders such as cancer. [Display omitted] •Mitochondrial Ca2+ overload stimulus alone is ineffective to induce cell death•Autophagy is a gatekeeper of cell fate in response to Ca2+ homeostasis disruption•Mitochondrial Ca2+ overload is a determinant of autophagy as a chemosensitizer Biological Sciences; Cell Biology; Cancer