EXPRESS: Intercellular Mitochondrial Transfer in Ischemic Stroke: Emerging Roles of Microglia

Mitochondrial dysfunction is a central driver of injury following cerebral ischemia-reperfusion, linking energy failure, oxidative stress, and inflammation. Intercellular mitochondrial transfer has been proposed as an adaptive mechanism to support metabolic homeostasis in the injured brain. While astrocyte-to-neuron transfer is supported by in vivo evidence, microglia-mediated transfer stays less well defined. Here, we review three proposed pathways: tunneling nanotube (TNT)-mediated transfer of intact mitochondria, extracellular vesicle (EV)-mediated transfer of mitochondrial components, and gap junction-associated signaling. TNT-mediated transfer is most closely associated with bioenergetic rescue, whereas EV-mediated processes primarily influence intercellular signaling. In parallel, mitochondrial damage-associated molecular patterns (DAMPs), including mitochondrial DNA, cardiolipin, and cytochrome c, can activate innate immune pathways and contribute to post-ischemic inflammation. The functional consequences of mitochondrial exchange vary according to donor-cell state, cargo integrity, and disease stage.