Korean Red Ginseng Improves Astrocytic Mitochondrial Function by Upregulating HO-1-Mediated AMPKα–PGC-1α–ERRα Circuit after Traumatic Brain Injury |
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| Authors: | Minsu Kim Joohwan Kim Sunhong Moon Bo Young Choi Sueun Kim Hui Su Jeon Sang Won Suh Young-Myeong Kim Yoon Kyung Choi |
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| Affiliation: | 1.Bio/Molecular Informatics Center, Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea; (M.K.); (S.M.); (S.K.); (H.S.J.);2.Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon 24341, Gangwon-do, Korea; (J.K.); (Y.-M.K.);3.Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Gangwon-do, Korea; (B.Y.C.); (S.W.S.) |
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| Abstract: | Heme oxygenase-1 (HO-1) exerts beneficial effects, including angiogenesis and energy metabolism via the peroxisome proliferator-activating receptor-γ coactivator-1α (PGC-1α)–estrogen-related receptor α (ERRα) pathway in astrocytes. However, the role of Korean red ginseng extract (KRGE) in HO-1-mediated mitochondrial function in traumatic brain injury (TBI) is not well-elucidated. We found that HO-1 was upregulated in astrocytes located in peri-injured brain regions after a TBI, following exposure to KRGE. Experiments with pharmacological inhibitors and target-specific siRNAs revealed that HO-1 levels highly correlated with increased AMP-activated protein kinase α (AMPKα) activation, which led to the PGC-1α-ERRα axis-induced increases in mitochondrial functions (detected based on expression of cytochrome c oxidase subunit 2 (MTCO2) and cytochrome c as well as O2 consumption and ATP production). Knockdown of ERRα significantly reduced the p-AMPKα/AMPKα ratio and PGC-1α expression, leading to AMPKα–PGC-1α–ERRα circuit formation. Inactivation of HO by injecting the HO inhibitor Sn(IV) protoporphyrin IX dichloride diminished the expression of p-AMPKα, PGC-1α, ERRα, MTCO2, and cytochrome c in the KRGE-administered peri-injured region of a brain subjected to TBI. These data suggest that KRGE enhanced astrocytic mitochondrial function via a HO-1-mediated AMPKα–PGC-1α–ERRα circuit and consequent oxidative phosphorylation, O2 consumption, and ATP production. This circuit may play an important role in repairing neurovascular function after TBI in the peri-injured region by stimulating astrocytic mitochondrial biogenesis. |
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| Keywords: | Korean red ginseng, heme oxygenase-1, traumatic brain injury, AMPKα – PGC-1α – ERRα circuit, astrocytic mitochondrial function |
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