Carbon monoxide stimulates astrocytic mitochondrial biogenesis via L-type Ca{sup 2+} channel-mediated PGC-1α/ERRα activation
- Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Kangwon-do 200-701 (Korea, Republic of)
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Kangwon-do 200-701 (Korea, Republic of)
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Kangwon-do 200-702 (Korea, Republic of)
- Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Kangwon-do 200-702 (Korea, Republic of)
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-752 (Korea, Republic of)
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 Ca{sup 2+} chelators, a HO inhibitor, and an L-type Ca{sup 2+} channel blocker, but not other Ca{sup 2+} 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 Ca{sup 2+} 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{sup +/−} mice. These results suggest that HO-1-derived CO enhances mitochondrial biogenesis in astrocytes by activating L-type Ca{sup 2+} channel-mediated PGC-1α/ERRα axis, leading to maintenance of astrocyte function and neuroprotection/recovery against damage of brain function. - Highlights: • CORM-pretreated astrocytes induces mitochondrial biogenesis by activating L-type Ca{sup 2+} channel-mediated PGC-1α stabilization. • Cerebral ischemia increased electron transport chain proteins (e.g. Cyt c and COX2), in WT mice, compared with HO-1{sup +/−} mice. • CO/HO-1 pathway increases astrocytic mitochondrial functions via a PGC-1α/ERRα axis.
- OSTI ID:
- 22696646
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 479, Issue 2; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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