Mitochondrial transplantation strategies in multifaceted induction of cancer cell death.

Otto Warburg hypothesized that some cancer cells reprogram their metabolism, favoring glucose metabolism by anaerobic glycolysis (Warburg effect) instead of oxidative phosphorylation, mainly because the mitochondria of these cells were damaged or dysfunctional. It should be noted that mitochondrial apoptosis is decreased because of the dysfunctional mitochondria. Strategies like mitochondrial transplantation therapy, where functional mitochondria are transplanted to cancer cells, could increase cell death, such as apoptosis, because the intrinsic apoptosis mechanisms would be reactivated. In addition, mitochondrial transplantation is associated with the redox state, which could promote synergy with common anticancer treatments such as ionizing radiation, chemotherapy, or radiotherapy, increasing cell death due to the presence or decrease of oxidative stress. On the other hand, mitochondrial transfer, a natural process for sharing mitochondrial between cells, induces an increase in chemoresistance and invasiveness in cancer cells that receive mitochondria from cells of the tumor microenvironment (TME), which indicates an antitumor therapeutic target. This review focuses on understanding mitochondrial transplantation as a therapeutic outcome induced by a procedure in aspects including oxidative stress, metabolism shifting, mitochondrial function, auto-/mitophagy, invasiveness, and chemoresistance. It also explores how these mechanisms, such as apoptosis, necroptosis, and parthanatos, impact cell death pathways. Finally, it discusses the chemoresistance and invasiveness in cancer cells associated with mitochondria transfer, indicating an antitumor therapeutic target.