Restoration of L-OPA1 alleviates acute ischemic stroke injury in rats via inhibiting neuronal apoptosis and preserving mitochondrial function
Yongxing Lai,
Peiqiang Lin,
Manli Chen,
Yixian Zhang,
Jianhao Chen,
Mouwei Zheng,
Ji Liu,
Houwei Du,
Ronghua Chen,
Xiaodong Pan,
Nan Liu,
Hongbin Chen
Affiliations
Yongxing Lai
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
Peiqiang Lin
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
Manli Chen
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
Yixian Zhang
Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
Jianhao Chen
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
Mouwei Zheng
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
Ji Liu
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
Houwei Du
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
Ronghua Chen
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
Xiaodong Pan
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
Nan Liu
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China; Corresponding author. Department of Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, PR China.
Hongbin Chen
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China; Corresponding author. Department of Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, PR China.∗
Background: Ischemic stroke can induce changes in mitochondrial morphology and function. As a regulatory gene in mitochondria, optic atrophy 1 (OPA1) plays a pivotal role in the regulation of mitochondrial dynamics and other related functions. However, its roles in cerebral ischemia-related conditions are barely understood. Methods: Cultured rat primary cortical neurons were respectively transfected with OPA1-v1ΔS1-encoding and OPA1-v1-encoding lentivirus before exposure to 2-h oxygen-glucose deprivation (OGD) and subsequent reoxygenation (OGD/R). Adult male SD rats received an intracranial injection of AAV-OPA1-v1ΔS1 and were subjected to 90 min of transient middle cerebral artery occlusion (tMCAO) followed by reperfusion. OPA1 expression and function were detected by in vitro and in vivo assays. Results: OPA1 was excessively cleaved after cerebral ischemia/reperfusion injury, both in vitro and in vivo. Under OGD/R condition, compared with that of the LV-OPA1-v1-treated group, the expression of OPA1-v1ΔS1 efficiently restored L-OPA1 level and alleviated neuronal death and mitochondrial morphological damage. Meanwhile, the expression of OPA1-v1ΔS1 markedly improved cerebral ischemia/reperfusion-induced motor function damage, attenuated brain infarct volume, neuronal apoptosis, mitochondrial bioenergetics deficits, oxidative stress, and restored the morphology of mitochondrial cristae and mitochondrial length. It also preserved the mitochondrial integrity and reinforced the mtDNA content and expression of mitochondrial biogenesis factors in ischemic rats. Interpretation: Our results demonstrate that the stabilization of L-OPA1 protects ischemic brains by reducing neuronal apoptosis and preserving mitochondrial function, suggesting its significance as a promising therapeutic target for stroke prevention and treatment.
