Resveratrol protects mitochondrial quantity by activating SIRT1/PGC‐1α expression during ovarian hypoxia

Abstract

Purpose Resveratrol is a well‐known potent activator of sirtuin‐1 (SIRT1). We investigated the direct effects of hypoxia and resveratrol on SIRT1/ peroxisome proliferator‐activated receptor‐gamma coactivator 1α (PGC‐1α) pathways, vascular endothelial growth factor (VEGF), hypoxia‐inducible factor (HIF)‐1α, and mitochondrial quantity in a steroidogenic human ovarian granulosa‐like tumor cell line (KGN) cells. Methods KGN cells were cultured with cobalt chloride (CoCl2; a hypoxia‐mimicking agent) and/or resveratrol. The mRNA and protein levels, protein secretion, and intracellular localization were assessed by real‐time PCR, Western blot analysis, ELISA, and immunofluorescence staining, respectively. Mitochondrial quantity was measured based on the mitochondrial DNA (mtDNA) copy number. Results CoCl2 simultaneously attenuated the levels of SIRT1 and mtDNA expression, and induced the levels of VEGF protein production. In contrast, resveratrol significantly increased the levels of SIRT1 and mtDNA copy number, but reduced VEGF production in normoxia. Resveratrol could recover CoCl2‐suppressed SIRT1 and mtDNA expression and antagonize CoCl2‐induced VEGF production. CoCl2 treatment resulted in a downregulation of PGC‐1α expression, and this effect was recovered by resveratrol. Resveratrol significantly suppressed the production of the CoCl2‐induced HIF‐1α and VEGF proteins. Conclusion These results suggest that resveratrol improves mitochondrial quantity by activating the SIRT1/PGC‐1α pathway and inhibits VEGF induction through HIF‐1α under hypoxic conditions.

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

“…Several studies have confirmed that some drug-resistant tumor cells are particularly strongly dependent on PGC-1α-mediated metabolic activity, and the inhibition of PGC-1α expression sensitizes some tumor cells to treatment, including lung cancer cells ( 153 ). The expression of a subset of known PGC-1α-regulated genes appears to be altered indirectly by changing the metabolic state of cells exposed to hypoxia and nutrient deprivation ( 154 ). Interestingly, PGC-1α is a regulator of PPAR-γ activity, and the dysregulated expression of PGC-1α may affect PPAR-γ function.…”

“…In response to hypoxic conditions, the posttranslational regulation of molecular mediators such as SIRT1, HIF-1α, PGC-1α, and AMPK may play a critical role in the control of the glycolytic-mitochondrial energy axis ( Figure 3 ) ( 171 , 173 ). SIRT1 and PGC-1α are supposed to exist in the mitochondria of tumorigenesis, where they function as critical inducible factors for intercellular energy metabolism and gene regulation ( 154 , 174 ). SIRT1 is known to promote mitochondrial biogenesis.…”

Ovarian tissue damage after grafting: systematic review of strategies to improve follicle outcomes

“…Formation of the antrum then appears to reduce oxygen demands (as the fluid compartment does not consume oxygen) and facilitate oxygen diffusion towards the oocyte (Redding et al, 2007). Granulosa cells also adapt their oxygen consumption during antral follicle growth in order to leave an optimal oxygen supply for the oocyte (Li et al, 2013) by upregulating the hypoxia-inducible factor 1 (HIF1) signaling pathway during their rapid growth (Harris et al, 2007;Kind et al, 2015;Nishigaki et al, 2020;Zhou et al, 2018;). HIF1 is one of the master regulators of response to hypoxia (Takahashi et al, 2016;Zhou et al, 2018).…”

“…During follicle growth, increased VEGF expression not only has a proangiogenic function, carrying blood around follicles, but also plays a role in signaling involved in granulosa cell proliferation (Nishigaki et al, 2020;Yalu et al, 2015). In fact, VEGF is one of the main regulators of granulosa cell proliferation in hypoxic conditions through the PI3K/Akt signaling pathway, with a subsequent upturn in expression of one of its main effectors, mammalian target of rapamycin (mTOR) (Shiratzuki et al, 2016).…”

Mitochondrial DNA and Neurodegeneration: Any Role for Dietary Antioxidants?

“…Remarkably, the mitochondrially-targeted Mito-Q has been demonstrated to protect the intestinal barrier by ameliorating mitochondrial DNA damage via the Nrf2/ARE signaling pathway [238]. Resveratrol can restore the suppressed SIRT1 expression and mtDNA expression in a cellular model of ovarian hypoxia [239]. Flavanones (in particular, naringin) are able to modulate mtDNA copy number in human leukocytes and has been identified as the key factor behind the association between fruit consumption and mtDNA copy number measured in a population based study [240].…”