The Impact of Mitochondrial Fission-Stimulated ROS Production on Pro-Apoptotic Chemotherapy

SIMPLE SUMMARY: Mitochondria are the core energy-generating units found within a cell. In addition, mitochondria harbor molecular factors that are essential, upon their release from these organelles, for triggering cell suicide program or apoptosis. Recent research has pointed to the critical role that the mitochondrial shape, which is dynamically flexible rather than rigid, plays in regulating both, bioenergetics metabolism and programmed cell death. Given that activating apoptosis specifically in tumor cells can be an advantage for eradicating cancer by chemotherapy, we address the simple idea of whether pharmacological stimulation of mitochondrial dynamics can benefit cancer patients with solid tumors. We propose a model, in which mitochondrial fragmented phenotype and mitochondrial reactive oxygen species (ROS) production are interconnected within a self-propagating cycle that relies for its function on nuclear stress signaling pathways. We conclude that manipulation of mitochondrial dynamics may be at the heart of chemotherapeutic approaches targeting cancers with elevated oxidative stress. ABSTRACT: Cancer is one of the world’s deadliest afflictions. Despite recent advances in diagnostic and surgical technologies, as well as improved treatments of some individual tumor types, there is currently no universal cure to prevent or impede the uncontrolled proliferation of malignant cells. Targeting tumors by inducing apoptosis is one of the pillars of cancer treatment. Changes in mitochondrial morphology precede intrinsic apoptosis, but mitochondrial dynamics has only recently been recognized as a viable pharmacological target. In many cancers, oncogenic transformation is accompanied by accumulation of elevated cellular levels of ROS leading to redox imbalance. Hence, a common chemotherapeutic strategy against such tumor types involves deploying pro-oxidant agents to increase ROS levels above an apoptotic death-inducing threshold. The aim of this chapter is to investigate the benefit of stimulating mitochondrial fission-dependent production of ROS for enhanced killing of solid tumors. The main question to be addressed is whether a sudden and abrupt change in mitochondrial shape toward the fragmented phenotype can be pharmacologically harnessed to trigger a burst of mitochondrial ROS sufficient to initiate apoptosis specifically in cancer cells but not in non-transformed healthy tissues.