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

초록

Heme oxygenase-1 (HO-1) exerts beneficial effects, including angiogenesis and energy metabolism via the hypoxia-inducible factor-1 alpha (HIF-1 alpha) and peroxisome-proliferator-activating receptor-v coactivator-1 alpha (PGC-1 alpha)/estrogen-related receptor alpha (ERR alpha) 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-1 alpha 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-1 alpha levels were highly correlated with increased PGC-1 alpha and ERRa 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-1 alpha was stabilized in a proline hydroxylase-dependent manner by transient induction of intracellular hypoxia via the PGC-1 alpha/ERR alpha-induced increases in mitochondrial biogenesis and oxygen consumption. HIF-1 alpha knockdown blocked HO-1 system-mediated transcriptional expression of ERR alpha, but not of PGC-1 alpha, suggesting a possible involvement of HIF-1 alpha in ERR alpha-mediated mitochondrial biogenesis. These data suggest that the HO-1-derived metabolites, CO and bilirubin, elevate astrocytic mitochondrial function via a HIF-1 alpha/ERR alpha circuit coupled with L-type Ca2+ channel activation and PGC-1 alpha-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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