Korean Red Ginseng-Induced SIRT3 Promotes the Tom22-HIF-1α Circuit in Normoxic Astrocytes

초록

Astrocytes play a key role in brain functioning by providing energy to neurons. Increased astrocytic mitochondrial functions by Korean red ginseng extract (KRGE) have been investigated in previous studies. KRGE administration induces hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) in astrocytes in the adult mouse brain cortex. VEGF expression can be controlled by transcription factors, such as the HIF-1a and estrogen-related receptor a (ERRa). However, the expression of ERRa is unchanged by KRGE in astrocytes of the mouse brain cortex. Instead, sirtuin 3 (SIRT3) expression is induced by KRGE in astrocytes. SIRT3 is a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase that resides in the mitochondria and maintains mitochondrial homeostasis. Mitochondrial maintenance requires oxygen, and active mitochondria enhance oxygen consumption, resulting in hypoxia. The effects of SIRT3 on HIF-1a-mediated mitochondria functions induced by KRGE are not well established. We aimed to investigate the relationship between SIRT3 and HIF-1a in KRGE-treated normoxic astrocyte cells. Without changing the expression of the ERRa, small interfering ribonucleic acid targeted for SIRT3 in astrocytes substantially lowers the amount of KRGE-induced HIF-1a proteins. Reduced proline hydroxylase 2 (PHD2) expression restores HIF-1a protein levels in SIRT3-depleted astrocytes in normoxic cells treated with KRGE. The translocation of outer mitochondrial membranes 22 (Tom22) and Tom20 is controlled by the SIRT3-HIF-1a axis, which is activated by KRGE. KRGE-induced Tom22 increased oxygen consumption and mitochondrial membrane potential, as well as HIF-1a stability through PHD2. Taken together, in normoxic astrocytes, KRGE-induced SIRT3 activated the Tom22-HIF-1a circuit by increasing oxygen consumption in an ERRa-independent manner.

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