title: Carbon monoxide stimulates astrocytic mitochondrial biogenesis via L-type Ca2+channel-mediated PGC-1α/ERRα activation.
abstract: Carbon monoxide (CO), derived by the enzymatic reaction of heme oxygenase (HO), is a cellular regulator of energy metabolism and cytoprotection; however, its underlying mechanism has not been clearly elucidated. Astrocytes pre-exposed to the CO-releasing compound CORM-2 increased mitochondrial biogenesis, mitochondrial electron transport components (cytochrome c, Cyt c; cytochrome c oxidase subunit 2, COX2), and ATP synthesis. The increased mitochondrial function was correlated with activation of AMP-activated protein kinase α and upregulation of HO-1, peroxisome proliferators-activated receptor γ-coactivator-1α (PGC-1α), and estrogen-related receptor α (ERRα). These events elicited by CORM-2 were suppressed by Ca2+chelators, a HO inhibitor, and an L-type Ca2+channel blocker, but not other Ca2+channel inhibitors. Among the HO byproducts, combined CORM-2 and bilirubin treatment effectively increased PGC-1α, Cyt c and COX2 expression, mitochondrial biogenesis, and ATP synthesis, and these increases were blocked by Ca2+chelators. Moreover, cerebral ischemia significantly increased HO-1, PGC-1α, and ERRα levels, subsequently increasing Cyt c and COX2 expression, in wild-type mice, compared with HO-1+/-mice. These results suggest that HO-1-derived CO enhances mitochondrial biogenesis in astrocytes by activating L-type Ca2+channel-mediated PGC-1α/ERRα axis, leading to maintenance of astrocyte function and neuroprotection/recovery against damage of brain function.
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Kangwon-do 200-701, Republic of Korea.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Kangwon-do 200-701, Republic of Korea.
authors.forename: Joon Ha
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Kangwon-do 200-701, Republic of Korea.
authors.forename: Yi-Yong
authors.initials: YY
authors.lastname: Baek
authors.affiliation: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Kangwon-do 200-701, Republic of Korea.
authors.forename: Moo-Ho
authors.initials: MH
authors.lastname: Won
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Kangwon-do 200-702, Republic of Korea.
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Kangwon-do 200-702, Republic of Korea.
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Kangwon-do 200-701, Republic of Korea.
authors.forename: Kwon-Soo
authors.initials: KS
authors.lastname: Ha
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-752, Republic of Korea.
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Kangwon-do 200-701, Republic of Korea. Electronic address: ymkim@kangwon.ac.kr.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002248:Carbon Monoxide / Q000737:chemistry*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004579:Electron Transport; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D000255:Adenosine Triphosphate; D020746:Calcium Channels, L-Type; D002248:Carbon Monoxide; D051546:Cyclooxygenase 2; D045304:Cytochromes c; D051547:Heme Oxygenase-1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C486497:PPARGC1A protein, human; C485290:Ppargc1a protein, mouse; C496541:HMOX1 protein, human; C077623:Ptgs2 protein, mouse; C496540:PTGS2 protein, human
keywords: Carbon monoxide; L-type voltage gated Ca(2+) channel; Mitochondria biogenesis; PGC-1α