Astrocytic Mitochondria Transplantation Rescues Neuron Loss and Dendritic Injuries in Acute Cerebral Ischemic Stroke Mouse Model by Flexibly Regulating Mitochondria Dynamics

Objective: Cerebral ischemic stroke causes neuronal oxygen/energy deprivation, disrupting mitochondrial function including reduced membrane potential and bioenergetics, exacerbating neuronal injury. Mitochondrial defects are, therefore, a central neuropathological node and potential therapeutic target. Previous studies have shown that mitochondria transplantation rescued infarction in cerebral ischemic stroke. However, interactions between transplanted and endogenous mitochondria remain unclear. Here, we proposed astrocytic mitochondria as the optional donor for mitochondria transplantation in ischemic stroke treatment because of their ischemic resistance. Methods: We transplanted mitochondria derived from astrocytes into an ischemic stroke cell and mouse model to investigate the feasibility and mechanisms of astrocytic mitochondria transplantation for ischemic cerebral stroke. We assessed the uptake of transplanted mitochondria by neurons, their impact on endogenous mitochondrial dynamics (fusion/fission), mitochondrial functions, neuronal dendritic structure, neuronal survival, and mice motor function. Results: Transplanted astrocytic mitochondria were successfully taken up by neurons, and within neurons, they flexibly regulated endogenous mitochondrial dynamics. This intervention rescued the stroke-induced reduction in mitochondrial membrane potential and oxidative phosphorylation capacity. Consequently, it significantly decreased neuronal dendritic injuries and cell death. These cellular improvements translated into alleviated motor deficits in the stroke model. Interpretation: Astrocytic mitochondria transplantation is an effective therapeutic strategy for ischemic stroke. Its neuroprotective effects stem from the internalization of functional mitochondria into neurons and the subsequent flexibly regulation of endogenous mitochondrial dynamics, restoring bioenergetics and promoting neuronal survival. This approach holds significant promise for treating ischemic stroke and potentially other brain disorders involving mitochondrial dysfunction. ANN NEUROL 2026;99:1571-1588.