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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 1

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Heme Oxygenase (Decyclizing)
Hypoxia-Inducible Factor 1
heme
oxygenases
Metabolites
Estrogen Receptors
estrogens
Estrogens
metabolites
calcium
receptors
Organelle Biogenesis
Networks (circuits)
Heme Oxygenase-1
heme oxygenase (biliverdin-producing)
Carbon Monoxide
carbon monoxide
Bilirubin
Oxygen Consumption
Astrocytes

All Science Journal Classification (ASJC) codes

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

Cite this

Choi, Y. K., Park, J. H., Yun, J. A., Cha, J. H., Kim, Y., Won, M. H., ... 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
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. / Heme oxygenase metabolites improve astrocytic mitochondrial function via a Ca2+-dependent HIF-1α/ERRα circuit. In: PloS one. 2018 ; Vol. 13, No. 8.
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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.",
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Choi, YK, Park, JH, Yun, JA, Cha, JH, Kim, Y, Won, MH, Kim, KW, Ha, KS, Kwon, Y-G & Kim, YM 2018, 'Heme oxygenase metabolites improve astrocytic mitochondrial function via a Ca2+-dependent HIF-1α/ERRα circuit', PloS one, vol. 13, no. 8, e0202039. https://doi.org/10.1371/journal.pone.0202039

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

In: PloS one, Vol. 13, No. 8, e0202039, 01.08.2018.

Research output: Contribution to journalArticle

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T1 - Heme oxygenase metabolites improve astrocytic mitochondrial function via a Ca2+-dependent HIF-1α/ERRα circuit

AU - Choi, Yoon Kyung

AU - Park, Joon Ha

AU - Yun, Jung A.

AU - Cha, Jong Ho

AU - Kim, Yonghee

AU - Won, Moo Ho

AU - Kim, Kyu Won

AU - Ha, Kwon Soo

AU - Kwon, Young-Guen

AU - Kim, Young Myeong

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

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M3 - Article

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