Heme oxygenase metabolites improve astrocytic mitochondrial function via a Ca2+-dependent HIF-1α/ERRα circuit

Yoon Kyung Choi, Joon Ha Park, Jung A. Yun, Jong Ho Cha, Yonghee Kim, Moo Ho Won, Kyu Won Kim, Kwon Soo Ha, Young Guen Kwon, Young Myeong Kim

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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-acti-vating 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.

Original languageEnglish
Article numbere0202039
JournalPloS one
Volume13
Issue number8
DOIs
Publication statusPublished - 2018 Aug

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Choi, Y. K., Park, J. H., Yun, J. A., Cha, J. H., Kim, Y., Won, M. H., Kim, K. W., Ha, K. S., Kwon, Y. G., & Kim, Y. M. (2018). Heme oxygenase metabolites improve astrocytic mitochondrial function via a Ca2+-dependent HIF-1α/ERRα circuit. PloS one, 13(8), [e0202039]. https://doi.org/10.1371/journal.pone.0202039