Mitochondrial Calcium Regulation of Redox Signaling in Cancer

Calcium (Ca(2+)) uptake into the mitochondria shapes cellular Ca(2+) signals and acts as a key effector for ATP generation. In addition, mitochondria-derived reactive oxygen species (mROS), produced as a consequence of ATP synthesis at the electron transport chain (ETC), modulate cellular signaling pathways that contribute to many cellular processes. Cancer cells modulate mitochondrial Ca(2+) ([Ca(2+)]m) homeostasis by altering the expression and function of mitochondrial Ca(2+) channels and transporters required for the uptake and extrusion of mitochondrial Ca(2+). Regulated elevations in [Ca(2+)]m are required for the activity of several mitochondrial enzymes, and this in turn regulates metabolic flux, mitochondrial ETC function and mROS generation. Alterations in both [Ca(2+)]m and mROS are hallmarks of many tumors, and elevated mROS is a known driver of pro-tumorigenic redox signaling, resulting in the activation of pathways implicated in cellular proliferation, metabolic alterations and stress-adaptations. In this review, we highlight recent studies that demonstrate the interplay between [Ca(2+)]m and mROS signaling in cancer.