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

PloS One
Yoon Kyung ChoiYoung-Myeong Kim

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 involvemen...Continue Reading

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Citations

Mar 29, 2020·International Journal of Molecular Sciences·Eunyoung JungYoon Kyung Choi
Apr 5, 2020·International Journal of Molecular Sciences·Franziska Dengler
Dec 8, 2020·Oxidative Medicine and Cellular Longevity·Yang LiuYanfeng Wang
Apr 30, 2021·Frontiers in Cardiovascular Medicine·Yoon Kyung Choi, Young-Myeong Kim
May 11, 2021·Metabolomics : Official Journal of the Metabolomic Society·Gilson Costa Dos SantosNatália Mesquita de Brito
Aug 28, 2021·International Journal of Molecular Sciences·Sunhong MoonYoon Kyung Choi

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Methods Mentioned

BETA
fluorescence imaging
transfection
Assay
electrophoresis
PCR
immunoprecipitation
ChIP

Software Mentioned

GraphPad Prism
Image J
ImageJ

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