title: Mitofusin 2 ameliorates hypoxia-induced apoptosis via mitochondrial function and signaling pathways.
abstract: Mitochondrial dynamics play a critical role in mitochondrial function and signaling. Although mitochondria play a critical role in hypoxia/ischemia, the further mechanisms between mitochondrial dynamics and ischemia are still unclear. The current study aimed to determine the role of mitofusin 2, a key regulator of mitochondrial fusion, in a hypoxic model and to explore a novel strategy for cerebral ischemia via modulation of mitochondrial dynamics. To the best of our knowledge, this is the first study to investigate both mitochondrial function and molecular pathways to determine the role of mitofusin 2 in hypoxia-induced neuronal apoptosis. In vivo, C57BL/6 mice (male, 19-25g) underwent a permanent middle cerebral artery occlusion for 12 or 24h (n=6 per group). In vitro, cobalt chloride was used to mimic hypoxia in immortalized hippocampal neurons. Down- or up-regulation of Mfn2 was induced to investigate the role of Mfn2 in hypoxia, especially in mitochondrial function and signaling pathways. The findings demonstrated that decreased mitofusin 2 occurred both in vivo and in vitro hypoxic models; second, the anti-apoptotic effect of Mfn2 may work via restoration of mitochondrial function; third, the modulation of the B Cell Leukemia 2/Bcl-2 Associated X protein and extracellular signal-regulated kinase 1/2 signaling pathways highlight the role of Mfn2 in signaling pathways beyond fusion. In summary, depletion of mitofusin 2 would lead to apoptosis both in normal or hypoxic conditions; however, mitofusin 2 overexpression could attenuate hypoxia-induced apoptosis, which represents a potential novel strategy for neuroprotection against ischemic brain damage.
authors.affiliation: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Rao
authors.affiliation: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Hui
authors.affiliation: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Su
authors.affiliation: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Luo
authors.affiliation: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Ye-lu
authors.initials: YL
authors.lastname: Hao
authors.affiliation: Department of Neurosurgery, Affiliated Hospital of Logistics, University of Chinese Armed Police Forces, Chenglin Road, Tianjin 300162, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Department of Neurosurgery, Affiliated Hospital of Logistics, University of Chinese Armed Police Forces, Chenglin Road, Tianjin 300162, PR China. Electronic address: zhangsai718@vip.126.com.
authors.forename: Sai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China. Electronic address: zhoufei@fmmu.edu.cn.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Fei
mesh_terms: D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology*; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse
keywords: Apoptosis; Bcl-2/Bax; Ischemic/hypoxic injury; Mitochondrial function; Mitofusin 2