Carbon monoxide stimulates astrocytic mitochondrial biogenesis via L-type Ca{sup 2+} channel-mediated PGC-1α/ERRα activation

• Published in: Biochemical and biophysical research communications 2016-10, Vol.479 (2)
• Main Authors: Choi, Yoon Kyung, Park, Joon Ha, Baek, Yi-Yong, Won, Moo-Ho, Jeoung, Dooil, Lee, Hansoo, Ha, Kwon-Soo, Kwon, Young-Guen, Kim, Young-Myeong
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; CALCIUM IONS; CARBON MONOXIDE; COBALT; CYTOCHROME OXIDASE; MICE; MITOCHONDRIA
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/J.BBRC.2016.09.063

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.