title: Upregulation of HIF-1α protein induces mitochondrial autophagy in primary cortical cell cultures through the inhibition of the mTOR pathway.
abstract: Cerebral ischemia/reperfusion (I/R) can induce neuronal death, particularly in the hippocampal formation (HF). Molecular genetic studies have suggested that the activities of the transcription factor, hypoxia-inducible factor-1α (HIF-1α), are closely linked to ischemia-induced neuronal death. However, the mechanisms through which HIF-1α functions remain poorly understood. In this study, primary cortical neurons were subjected to oxygen‑glucose deprivation (OGD) to establish a cell model of OGD/reperfusion (RP). HIF-1α mRNA and protein expression was measured by qRT-PCR and western blot analysis. Cell proliferation was detected by MTT assay. Flow cytometric analysis was used to detect cell apoptosis and changes in mitochondrial mass. The expression of LC3-Ⅰ and LC3-Ⅱ was examined by western blot analysis. We found that HIF-1α increased cell proliferation and decreased cell apoptosis in our cell model of OGD/RP using cultured neonatal rat cortical neurons. The overexpression of HIF-1α significantly induced changes in mitochondrial mass and mitochondrial autophagy in cortical neurons. Moreover, the inhibition of HIF-1α markedly suppressed cell proliferation and mitochondrial autophagy. We also demonstrated that the HIF-1α-induced mitochondrial autophagy was accompanied by the inhibition of the mTOR pathway. This study provides direct in vitro evidence that HIF-1α overexpression triggers mitochondrial autophagy, thereby increasing neuronal survival. Our results highlight a novel target molecule toward which anti-ischemic neuroprotective effects can be applied.
authors.affiliation: Department of Anesthesiology, General Hospital of the People's Liberation Army Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China.
authors.forename: Gu
authors.initials: G
authors.lastname: Gong
authors.affiliation: Department of Anesthesiology, General Hospital of the People's Liberation Army Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, General Hospital of the People's Liberation Army Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China.
authors.forename: Yinghai
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, General Hospital of the People's Liberation Army Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China.
authors.forename: Shurong
authors.initials: S
authors.lastname: Bai
authors.affiliation: Department of Anesthesiology, General Hospital of the People's Liberation Army Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Anesthesiology, General Hospital of the People's Liberation Army Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Anesthesiology, General Hospital of the People's Liberation Army Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Center of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Lichao
authors.initials: L
authors.lastname: Hou
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases