Ischemic stroke remains a leading cause of death and long-term disability worldwide, yet effective neuroprotective therapies beyond reperfusion strategies are still lacking. Emerging evidence highlights mitochondria as central regulators of neuronal fate, expanding their traditional role in cellular energy homeostasis through ATP production by oxidative phosphorylation (OXPHOS). Together with calcium buffering and redox regulation, these represent canonical mitochondrial functions. Mitochondria also regulate cellular adaptation to stress through mitochondrial quality control (MQC), mitochondrial ferritin-dependent iron buffering, signaling mediated by mitochondrial metabolites and mitochondrial DNA (mtDNA), and intercellular organelle transfer. These non-canonical functions link mitochondrial state to ferroptotic cell death, innate immune activation, and epigenetic regulation of nuclear responses. During cerebral ischemia, mitochondrial dysfunction involves impaired OXPHOS, the generation of reactive oxygen species (ROS), opening of the permeability transition pore, disruption of organelle dynamics, and dysregulation of non-canonical functions, collectively promoting neuronal injury, inflammation, and impaired recovery. These disturbances are further exacerbated by aging, which compromises MQC mechanisms, including fusion/fission balance, mitophagy, and biogenesis, and increases neuronal vulnerability. Mitochondrial signals, including mtDNA, cardiolipin, and ROS, also contribute to inflammasome activation and glial metabolic reprogramming, linking mitochondrial injury to neuroinflammation. Moreover, mitochondrial ferritin and iron buffering may influence oxidative damage and ferroptosis. Therefore, integrating canonical and non-canonical mitochondrial functions provide a broader framework for understanding ischemic injury and underscore the potential of MQC, redox regulation, iron homeostasis, and mitochondrial transfer as therapeutic targets and strategies for stroke recovery.
