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

Abstract

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-1α (HIF-1α) 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-1α and estrogen-related receptor α (ERRα). However, the expression of ERRα 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-1α-mediated mitochondria functions induced by KRGE are not well established. We aimed to investigate the relationship between SIRT3 and HIF-1α in KRGE-treated normoxic astrocyte cells. Without changing the expression of the ERRα, small interfering ribonucleic acid targeted for SIRT3 in astrocytes substantially lowers the amount of KRGE-induced HIF-1α proteins. Reduced proline hydroxylase 2 (PHD2) expression restores HIF-1α 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-1α axis, which is activated by KRGE. KRGE-induced Tom22 increased oxygen consumption and mitochondrial membrane potential, as well as HIF-1α stability through PHD2. Taken together, in normoxic astrocytes, KRGE-induced SIRT3 activated the Tom22–HIF-1α circuit by increasing oxygen consumption in an ERRα-independent manner.

AAV-mediated upregulation of VDAC1 rescues the mitochondrial respiration and sirtuins expression in a SOD1 mouse model of inherited ALS

“…Interestingly, it was recently reported that Sirt3 regulates the level of HIF-1α in astrocytes [ 70 ], an important transcription factor that along with mitochondrial and cell survival also controls the expression of the VDAC1 gene [ 71 ]. Under reduced oxygen levels, Sirt3 stabilizes a HIF-1α/Tom22 circuit that leads to the expression of Tom20, thereby reactivating mitochondrial functions [ 70 ].…”

“…Interestingly, it was recently reported that Sirt3 regulates the level of HIF-1α in astrocytes [ 70 ], an important transcription factor that along with mitochondrial and cell survival also controls the expression of the VDAC1 gene [ 71 ]. Under reduced oxygen levels, Sirt3 stabilizes a HIF-1α/Tom22 circuit that leads to the expression of Tom20, thereby reactivating mitochondrial functions [ 70 ]. Therefore, also considering these literature data, we can hypothesize that in ALS VDAC1 promotes an adaptation signal to disease-induced stress by stabilizing the Complex I-Sirt3 axis, involving also the TOM complex.…”