Mitochondrial Dysfunction and Its Role in Ferroptosis: Molecular Mechanisms and Therapeutic Targets.

Abstract

Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death, characterized morphologically by mitochondrial shrinkage, increased membrane density, and diminished cristae. As a central regulator of cellular energy metabolism, redox homeostasis, and iron handling, mitochondria are closely implicated in ferroptotic signaling. Mitochondrial dysfunction may contribute to the initiation and progression of ferroptosis through multiple interrelated mechanisms. Mitochondrial metabolic reprogramming (e.g., abnormal glutaminolysis and tricarboxylic acid cycle disturbances) is associated with elevated reactive oxygen species (ROS) production, whereas impaired mitochondrial quality control-including imbalanced fission-fusion dynamics and defective mitophagy-may further amplify oxidative stress and modulate cellular sensitivity to ferroptosis. This review summarizes current evidence supporting the molecular interplay between mitochondrial dysfunction and ferroptosis, and addresses the pathological implications of the mitochondria-ferroptosis axis in multiple disease contexts, including cancer drug resistance, neurodegenerative disorders, and ischemia-reperfusion injury. We also highlight potential therapeutic strategies targeting this axis, such as mitochondria-targeted antioxidants, iron chelators, and modulators of key mitochondrial quality control proteins. Deepened understanding of mitochondria-ferroptosis crosstalk may provide a rational theoretical basis for the development of novel precision therapies for ferroptosis-associated diseases.