Intercellular Mitochondrial Transfer as Endogenous Neuroprotection: Mechanisms and Therapeutic Implications in...

Ischemic stroke remains a leading cause of mortality and disability worldwide. Current reperfusion therapies are limited by narrow therapeutic time windows and the risk of secondary reperfusion injury, underscoring the urgent need for novel translatable neuroprotective targets. Mitochondrial dysfunction serves as a central hub in the ischemic cascade, contributing to energy failure, oxidative stress, calcium dysregulation, and various forms of programmed cell death. Recently, intercellular mitochondrial transfer has emerged as a crucial form of metabolic communication within the neurovascular unit (NVU). In the context of ischemia-reperfusion, donor cells can transfer functional mitochondria to compromised cells, facilitating metabolic rescue and remodeling the local microenvironment. Extensive in vivo and in vitro studies have shown that astrocytes, mesenchymal stem cells (MSCs), and pericytes can deliver mitochondria to neurons or brain microvascular endothelial cells (BMECs) through mechanisms such as tunneling nanotubes (TNTs), extracellular vesicles (EVs), and gap junctions. This transfer helps maintain blood-brain barrier (BBB) integrity and promotes neurological recovery. The process is finely regulated by inflammatory signaling, metabolic reprogramming, and epigenetic modulation, all of which influence the directionality and functional outcomes of the transfer. As a result, pharmacotherapies, non-pharmacological interventions, and direct mitochondrial transplantation have demonstrated considerable neuroprotective potential in experimental models and early-stage clinical research. However, challenges related to transfer selectivity, the durability of effects, delivery efficiency, and immune safety still hinder clinical translation. Future efforts must prioritize elucidating the underlying mechanisms, standardizing protocols, and developing precise stratification strategies to advance mitochondrial transfer-based interventions from proof-of-concept to a controllable and evaluable therapeutic option for stroke treatment.