title: SIRT3 protects cells from hypoxia via PGC-1α- and MnSOD-dependent pathways.
abstract: Reports suggest that silent information regulation 2 homolog 3 (SIRT3) protects cardiomyocytes from oxidative stress-mediated death. SIRT3, a mitochondrial protein, is an essential regulator of mitochondrial function, and this regulation is important in many cerebrovascular diseases, especially stroke. Here, we investigated the role of SIRT3 in ischemia-induced neuronal death due to oxygen-glucose deprivation (OGD) using an in vitro model of cerebral ischemia. We found that exposure of differentiated PC12 cells to OGD for 6h caused a marked decrease in cell viability and up regulated SIRT3. SIRT3 knockdown using short interfering RNA (siRNA) exacerbated OGD-induced injury whereas application of recombinant SIRT3 protected against OGD-induced cell death. Pre-treatment of the cells in which the SIRT3 gene was knocked down with recombinant SIRT3 before OGD partially restored cell viability and concomitantly reduced lactate dehydrogenase (LDH) release and increased ATP generation in mitochondria. Recombinant SIRT3 treatment resulted in increased expression of peroxisome proliferator activated receptor (PPAR)-γ co-activator 1-α (PGC-1α) and manganese superoxide dismutase (MnSOD). After knockdown of PGC-1α or MnSOD, recombinant SIRT3 failed to protect against OGD-induced injury. We also found that the protein and mRNA expression of PGC-1α was down regulated following SIRT3 knockdown. The expression level of SIRT3 was reduced when the PGC-1α gene was knocked down. Both SIRT3 and PGC-1α knockdown led to reduced mitochondrial membrane potential (Δψ) and Ca(2+) transients, especially under OGD conditions. Thus, our data suggest that SIRT3 protects PC12 cells from hypoxic injury via a mechanism that may involve PGC-1α and MnSOD. SIRT3 and PGC-1α regulate each other under physiologic and OGD conditions, thereby partially protecting against hypoxia or ischemia.
authors.affiliation: Department of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department, National Key Discipline, First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, China. Electronic address: wangq0724@163.com.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department, National Key Discipline, First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, China. Electronic address: wangqianmaomao@163.com.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurology, Affiliated Jiangmen Hospital, Sun Yat-Sen University, No. 23 Haibang Street, Beijie, Jiangmen City, Guangdong Province 529030, China. Electronic address: cly11157@126.com.
authors.forename: C Y
authors.initials: CY
authors.lastname: Li
authors.affiliation: Department of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department, National Key Discipline, First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, China. Electronic address: peizhong@mail.sysu.edu.cn.
authors.forename: Z
authors.initials: Z
authors.lastname: Pei
authors.affiliation: Department of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department, National Key Discipline, First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, China. Electronic address: april1987@live.cn.
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Rehabilitation, Third Affiliated Hospital, Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou 510630, China. Electronic address: ln8639@163.com.
authors.forename: N
authors.initials: N
authors.lastname: Li
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000860:Hypoxia; D016716:PC12 Cells; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D015398:Signal Transduction; D056566:Sirtuin 3 / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D013482:Superoxide Dismutase; D056566:Sirtuin 3
keywords: manganese superoxide dismutase; oxygen-glucose deprivation; peroxisome proliferator-activated receptor γ coactivator-1α; reactive oxygen species; silent information regulation 2 homolog 3