Mitophagy Activation via the YAP/Parkin Pathway Underlies the Neuroprotective Action of Tetramethylpyrazine in Cerebral Ischemia/Reperfusion Injury

Background: Mitophagy is a critical mitochondrial quality control mechanism that limits neuronal injury following cerebral ischemia/reperfusion injury (CI/RI). Tetramethylpyrazine (TMP), a bioactive alkaloid from Ligusticum chuanxiong Hort., exhibits neuroprotective effects in cerebrovascular disorders. However, whether these effects involve Mitophagy regulation remains unclear.

Methods: CI/RI was induced using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in mice and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in HT22 cells. Neurological function, infarct volume, mitochondrial function, and mitophagy-related markers were assessed. Pharmacological inhibitors and genetic manipulation of YAP and Parkin were used to investigate underlying mechanisms.

Results: TMP treatment significantly reduced infarct volume and improved neurological deficits in MCAO/R mice, accompanied by enhanced Mitophagy, as indicated by increased mitochondrial LC3 recruitment and Parkin expression. In OGD/R-injured HT22 cells, TMP promoted mitophagosome and mitolysosome formation, reduced mitochondrial Reactive Oxygen Species, and restored mitochondrial membrane potential. Inhibition of Mitophagy with Mdivi-1 attenuated TMP-mediated neuroprotection. Mechanistically, TMP promoted YAP nuclear localization, and inhibition of YAP or silencing of Parkin abolished TMP-induced Mitophagy, while Parkin overexpression restored Mitophagy under YAP inhibition.

Conclusions: TMP alleviates CI/RI by promoting Mitophagy through the YAP/Parkin signaling pathway, suggesting Mitophagy modulation as a potential therapeutic strategy for ischemic brain injury.

YAP/Parkin; cerebral ischemia/reperfusion injury; mitophagy; neuroprotection; tetramethylpyrazine.