Mitochondria as the decision makers for cancer cell fate: from signaling pathways to therapeutic strategies

• Mitochondria play a dual-faceted role in cancer cells death and proliferation. • [Ca 2+ ] mito uptake might be either beneficial or detrimental to cancer cell survival. • Mitochondrial metabolic reprogramming is a key feature for cancer cell proliferation. • Mitophagic pathways can both arrest or enhance cancer cell proliferation. • The timing of inflammatory response to mtDNA release can be pro or anti-tumorigenic. As pivotal players in cellular metabolism, mitochondria have a double-faceted role in the final decision of cell fate. This is true for all cell types, but it is even more important and intriguing in the cancer setting. Mitochondria regulate cell fate in many diverse ways: through metabolism, by producing ATP and other metabolites deemed vital or detrimental for cancer cells; through the regulation of Ca 2+ homeostasis, especially by the joint participation of the endoplasmic reticulum in a membranous tethering system for Ca 2+ signaling called mitochondria-ER associated membranes (MAMs); and by regulating signaling pathways involved in the survival of cancer cells such as mitophagy. Recent studies have shown that mitochondria can also play a role in the regulation of inflammatory pathways in cancer cells, for example, through the release of mitochondrial DNA (mtDNA) involved in the activation of the cGAS-cGAMP-STING pathway. In this review, we aim to explore the role of mitochondria as decision makers in fostering cancer cell death or survival depending on the tumor cell stage and describe novel anticancer therapeutic strategies targeting mitochondria.