FUNDC1-dependent mitophagy induced by tPA protects neurons against cerebral ischemia-reperfusion injury
Ying Cai,
Eryan Yang,
Xiuhua Yao,
Xuebin Zhang,
Qixue Wang,
Yunfei Wang,
Ji Liu,
Weijia Fan,
Kaikai Yi,
Chunsheng Kang,
Jialing Wu
Affiliations
Ying Cai
Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, 300350, China
Eryan Yang
Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, 300350, China; Department of Neurology, Tianjin Huanhu Hospital, Tianjin, 300350, China; Graduate School of Tianjin Medical University, Tianjin, 300070, China
Xiuhua Yao
Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, 300350, China
Xuebin Zhang
Department of Pathology, Tianjin Huanhu Hospital, Tianjin, 300350, China
Qixue Wang
Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Tianjin, 300052, China
Yunfei Wang
Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Tianjin, 300052, China
Ji Liu
Department of Neurology, Tianjin Huanhu Hospital, Tianjin, 300350, China
Weijia Fan
Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, 300350, China
Kaikai Yi
Graduate School of Tianjin Medical University, Tianjin, 300070, China; Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Tianjin, 300052, China
Chunsheng Kang
Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Tianjin, 300052, China; Corresponding author. Department of Neurosurgery, Tianjin Medical University General Hospital; Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, 154 Anshan Road, Heping District, Tianjin, 300052, China.
Jialing Wu
Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, 300350, China; Department of Neurology, Tianjin Huanhu Hospital, Tianjin, 300350, China; Corresponding author. Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Department of Neurology, Tianjin Huanhu Hospital, 6 Jizhao Road, Jinnan District, Tianjin, 300350, China.
Autophagy of mitochondria, termed mitophagy, plays an important role in cerebral ischemia-reperfusion (IR) injury, but the mechanism is not yet clear. Tissue-type plasminogen activator (tPA) is the most important thrombolytic drug in the clinical treatment of ischemic stroke and has neuroprotective effects. Here, we explored the effects of tPA on neuronal apoptosis and mitophagy following IR. We found that knocking out the tPA gene significantly aggravated brain injury and increased neuronal apoptosis and mitochondrial damage. Exposure of neurons to tPA reduced injury severity and protected mitochondria. Further studies demonstrated that this protective effect of tPA was achieved via regulation of FUNDC1-mediated mitophagy. Furthermore, we found that tPA enhanced the expression level of FUNDC1 by activating the phosphorylation of AMPK. In summary, our results confirm that tPA exerts neuroprotective effects by increasing the phosphorylation of AMPK and the expression of FUNDC1, thereby inhibiting apoptosis and improving mitochondrial function.
