Mitochondria-associated ferroptosis in ischemic stroke: Pathophysiological evolution, interorganelle crosstalk, and therapeutic targeting.

Abstract

Ischemic stroke (IS) results from an acute interruption of cerebral blood flow and the ensuing collapse of energy metabolism. Although vascular recanalization can salvage the ischemic penumbra, its overall benefit remains constrained by a narrow therapeutic window and reperfusion injury. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, contributes to neuronal injury after IS and can amplify ischemia/reperfusion injury. By integrating energy metabolism, iron homeostasis, and redox balance, mitochondria can shape ferroptosis susceptibility within the energy-depleted, iron-dysregulated, and oxidatively stressed ischemic brain. However, most studies have examined iron metabolism and lipid peroxidation at the whole-cell level, leaving the temporal and interorganelle dimensions of mitochondrial regulation of ferroptosis insufficiently integrated. Here, we organize mitochondria-associated ferroptosis across the pathological course of IS, from metabolic reprogramming and substrate accumulation during ischemia to the reverse electron transport-associated reactive oxygen species burst during early reperfusion and subsequent disruption of mitochondrial quality control. We further examine mitochondrial crosstalk with the endoplasmic reticulum, lysosomes, lipid droplets, and nucleus, compare ferroptosis susceptibility across neurovascular unit cell populations, and map these mechanisms onto pharmacological interventions and mechanistically plausible therapeutic windows. Finally, we assess barriers to the clinical translation of mitochondria-targeted therapies and provide a stage-resolved framework for developing neuroprotective strategies in IS.