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Calcium (Ca²⁺) uptake into the mitochondria shapes cellular Ca²⁺ 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 Ca²⁺ ([Ca²⁺]m) homeostasis by altering the expression and function of mitochondrial Ca²⁺ channels and transporters required for the uptake and extrusion of mitochondrial Ca²⁺. Regulated elevations in [Ca²⁺]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 [Ca²⁺]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 [Ca²⁺]m and mROS signaling in cancer.