Role of mitochondria transmission in ischemic stroke: Friend or foe?

Abstract

Ischemic stroke ranks as the second leading cause of mortality and the third disability worldwide. Disruption of energy metabolism and subsequent inflammation driven by oxidative stress constitute significant barriers to functional recovery. Proper distribution and function preservation of mitochondria are essential for maintaining energy homeostasis and modulating the inflammatory response during cerebral ischemia and reperfusion injury. Accumulating evidence indicates that both dysfunctional mitochondrial fragments and functional mitochondria undergo intracellular and intercellular transmission, significantly influencing stroke outcomes. The review details two contrasting mitochondrial processes in ischemic stroke: the release of dysfunctional mitochondrial fragments into the cytoplasm or extracellular space and the entry of functional mitochondria into damaged cells, which plays a dual role: friend or foe. The release of dysfunctional fragments activates downstream pattern recognition receptors, including the cyclic GMP-AMP synthase–stimulator of interferon genes pathway, NLR family pyrin domain containing 3/absent in melanoma 2 inflammasome, and Toll-like receptors, triggering inflammatory cascades within the neurovascular unit and initiating cell death pathways contributing to cerebral injury. In contrast, the transfer of functional mitochondria plays a protective role by attenuating oxidative stress, preserving mitochondrial quality control, restoring neuronal energy metabolism, inhibiting apoptosis, and maintaining blood-brain barrier integrity. Therapeutic approaches that inhibit the release of dysfunctional mitochondrial fragments, enhance functional mitochondria transfer, or apply mitochondrial transplantation offer significant potential for improving outcomes in ischemic stroke.