The mist of ferroptosis: The Orpheus journey of mitochondria - Exploring the symphony of cell fate.

Ferroptosis is a regulated cell death pathway characterized by iron-dependent accumulation of lipid peroxides and distinct mitochondrial morphological alterations, including reduced volume, increased membrane density, elevated membrane potential, cristae loss, and outer membrane rupture. These features starkly contrast with those observed in apoptosis, autophagy, and necrosis. As the cellular energy hub and metabolic nexus, mitochondria play multifaceted regulatory roles in ferroptosis through their integration of metabolic networks and redox homeostasis. This review systematically examines mitochondrial mechanisms driving ferroptosis progression, focusing on three key aspects: (1) metabolic reprogramming involving amino acid, lipid, and glucose metabolism; (2) dynamic regulation of reactive oxygen species (ROS) through electron transport chain activity and antioxidant defenses; and (3) iron/calcium ion flux mediated by mitochondrial membrane transporters and storage proteins. Notably, we propose a novel perspective emphasizing the unique contribution of mitochondrial membrane lipid peroxidation-driven by localized iron pools and specialized phospholipid composition-as a critical amplifier of ferroptotic signaling, distinct from cytoplasmic peroxidation pathways. By elucidating these mechanisms, our analysis identifies mitochondria-targeted strategies-such as ROS scavengers, iron chelators, and cristae-stabilizing compounds-as promising therapeutic avenues for ferroptosis-associated pathologies, including neurodegenerative diseases, ischemia-reperfusion injury, and drug-resistant cancers. This review provides a framework for understanding mitochondrial specificity in ferroptosis regulation and advances translational opportunities for modulating this pathway in clinical contexts.