Mitochondrial Dysfunction and Cell Death: Mechanisms and Implications in Pathology

Mitochondria are crucial regulators of both cellular life and death, influencing ATP production, calcium homeostasis, and multiple forms of regulated cell death (RCD), including apoptosis, necroptosis, mitochondrial permeability transition (MPT)-driven necrosis, pyroptosis, and autophagy-dependent cell death. Dysregulated mitochondrial function not only amplifies oxidative stress and perturbs energy balance but also activates pathogenic cell death pathways that drive neurodegenerative diseases, cancer, and metabolic disorders. This chapter examines key mechanisms by which mitochondria orchestrate regulated cell death and highlights their centrality in disease pathogenesis. We discuss how mitochondrial dysfunction, through the accumulation of reactive oxygen species (ROS), the loss of membrane potential, and the release of pro-death factors, precipitates pathological cell demise. We then explore emerging therapeutic strategies, including mitochondrial antioxidants, inducers of mitochondrial biogenesis and mitophagy, modulation of the mitochondrial unfolded protein response (UPRmt), and the regulation of mitochondrial dynamics. By focusing on both mechanistic insights and translational developments, this chapter aims to provide a comprehensive view of how restoring mitochondrial health may halt disease progression and improve clinical outcomes.