The pivotal role of mitochondrial disorders in cancer development with a special focus on mitochondria-mediated apoptosis.

Emerging evidence indicates that mitochondrial dysfunction is not merely a consequence but a driving force in cancer progression. Unlike normal cells, cancer cells rewire their mitochondrial metabolism to support uncontrolled proliferation, a process that includes aerobic glycolysis, persistent reactive oxygen species production, and adaptation to hypoxic conditions. A common hallmark across many tumors is the suppression of the intrinsic apoptotic pathway, primarily achieved through an imbalance between anti-apoptotic and pro-apoptotic BCL-2 family proteins. This evasion of cell death not only facilitates tumor initiation and metastasis but also contributes to resistance against conventional therapies. Here, we provide an overview of major mitochondrial alterations in cancer, with a detailed focus on how the mitochondrial apoptotic machinery is disabled in malignant cells. We then discuss current therapeutic strategies designed to re-activate mitochondria-mediated apoptosis, including BH3 mimetics, direct activators of pro-apoptotic proteins like BAX, immune checkpoint inhibitors, CAR‑T cell therapy, and mitochondria-targeted nanomedicine. Finally, we address the limitations and safety concerns of existing pro-apoptotic drugs and propose future directions to develop more selective and effective cancer treatments. Understanding the molecular mechanisms that govern mitochondrial apoptosis may open new avenues for inducing tumor cell death while minimizing harm to normal tissues.