Korean Red Ginseng Improves Astrocytic Mitochondrial Function by Upregulating HO-1-Mediated AMPKα–PGC-1α–ERRα Circuit after Traumatic Brain Injury

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.

Dual Effects of Korean Red Ginseng on Astrocytes and Neural Stem Cells in Traumatic Brain Injury: The HO-1–Tom20 Axis as a Putative Target for Mitochondrial Function

“…We observed Tom20 protein expression in the KRGE-administered TBI peri-injured regions, which was colocalized with GFAP-stained astrocytes ( Figure 1 b,c), thereby suggesting KRGE in astrocytes may regulate Tom20 expression. KRGE-mediated HO-1 can be detected in GFAP-positive astrocytes after TBI [ 6 ]. Tom20 protein levels were detected in HO-1-positive regions in KRGE-administered TBI mouse brain ( Supplementary Figure S1b ).…”

“…KRGE exerts beneficial effects on neuroinflammatory diseases in the CNS [ 1 ]. The transient induction of astrocytic HO-1 by KRGE after TBI may promote mitochondrial functions [ 6 ]. However, researchers have not yet established the molecular mechanisms by which KRGE induces astrocytic HO-1 in TBI.…”

“…Neuroinflammatory brain injury, including TBI, induces the altered remodeling of astrocyte mitochondrial networks [ 5 , 6 ]. Heme oxygenase-1 (HO-1), a downstream target of Nrf2, is a heme-degrading enzyme that produces carbon monoxide (CO), iron, and biliverdin.…”

“…Astrocytes in the CNS contribute to neuroprotection and energy-metabolic activity in CNS-related pathological states [ 5 , 16 ]. Our previous study [ 6 ] demonstrated that KRGE induces HO-1 production in astrocytes post-TBI, which exerts crucial roles in mitochondrial activity, partly through PGC-1α. However, the roles of KRGE-induced astrocytic HO-1 in the mitochondrial components of astrocytes and neural stem cells (NSCs) have not been well studied.…”

Studies on Bioactive Components of Red Ginseng by UHPLC-MS and Its Effect on Lipid Metabolism of Type 2 Diabetes Mellitus

“…Specifically, red ginseng (Ginseng Radix et Rhizoma Rubra; RG), which has a “warming effect” and is used in Chinese medicine to “boost yang” and replenish vital essence, is a thermally processed ginseng product that is obtained by steaming fresh ginseng at a certain temperature followed by drying ( 2 ). Furthermore, RG extract is widely used in healthcare ( 3 ), and its current product forms primarily include natural roots, powder, tablets, tea, extracts, and beverages. Furthermore, the biotransformation and health benefits of ginseng and RGW, and their application in dairy products have also been reported ( 4 ).…”