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

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.