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- Title
Heme oxygenase metabolites improve astrocytic mitochondrial function via a Ca<sup>2+</sup>-dependent HIF-1α/ERRα circuit.
- Authors
Choi, Yoon Kyung; Park, Joon Ha; Yun, Jung-A; Cha, Jong-Ho; Kim, Yonghee; Won, Moo-Ho; Kim, Kyu-Won; Ha, Kwon-Soo; Kwon, Young-Guen; Kim, Young-Myeong
- Abstract
Heme oxygenase-1 (HO-1) exerts beneficial effects, including angiogenesis and energy metabolism via the hypoxia-inducible factor-1α (HIF-1α) and peroxisome-proliferator-activating receptor-γ coactivator-1α (PGC-1α)/estrogen-related receptor α (ERRα) pathways, respectively, in astrocytes. However, evidence of cross-talk between both pathways in HO metabolite-mediated mitochondrial biogenesis has not been well elucidated. Here, we found that HIF-1α was upregulated in astrocytes after ischemic brain injury following exposure to the carbon monoxide (CO)-releasing compound CORM-2. Experiments with pharmacological inhibitors and target-specific siRNAs revealed that HIF-1α levels were highly correlated with increased PGC-1α and ERRα levels, which were linked to the HO metabolites CO- and bilirubin-induced activation of apical L-type Ca2+ channel and sequential Ca2+-dependent signal transduction. Moreover, HIF-1α was stabilized in a proline hydroxylase-dependent manner by transient induction of intracellular hypoxia via the PGC-1α/ERRα-induced increases in mitochondrial biogenesis and oxygen consumption. HIF-1α knockdown blocked HO-1 system-mediated transcriptional expression of ERRα, but not of PGC-1α, suggesting a possible involvement of HIF-1α in ERRα-mediated mitochondrial biogenesis. These data suggest that the HO-1-derived metabolites, CO and bilirubin, elevate astrocytic mitochondrial function via a HIF-1α/ERRα circuit coupled with L-type Ca2+ channel activation and PGC-1α-mediated oxygen consumption. This circuit may play an important role in repairing neurovascular function after focal ischemic brain injury by stimulating mitochondrial biogenesis.
- Subjects
HEME oxygenase; ENERGY metabolism; CARBON monoxide; METABOLITES; SMALL interfering RNA
- Publication
PLoS ONE, 2018, Vol 13, Issue 8, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0202039