SIRT3 attenuates AGEs-induced senescence in human granulosa cells through enhancing mitophagy
Shuhang Li1, Mingge Tang2,3,4, Sihui Zhu4,5
1Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230031, China.
Abstract:
Age-related decreases in follicle numbers and oocyte quality are major contributors to the decline in female fertility, which is associated with increased infertility rates. Emerging evidence suggests that targeting granulosa cell senescence could delay ovarian aging and depletion of the ovarian reserve, highlighting the potential for therapeutic interventions focused on granulosa cells. Advanced glycation end products (AGEs) accumulate with age and result in oxidative stress in the follicular microenvironment, but their direct impact on human granulosa cell (hGC) senescence and the fundamental processes are still mostly unknown. In this study, we found that AGEs treatment significantly exacerbated hGC senescence, impaired mitochondrial function, and suppressed mitophagy in a concentration-dependent manner. Importantly, these deficits were lessened by urolithin A-induced mitophagy activation, whereas Cyclosporine A-induced mitophagy inhibition had the reverse consequences. In addition, silencing Sirtuin 3 (SIRT3) or PINK1 further aggravated these adverse effects, while SIRT3 overexpression attenuated senescence and restored mitochondrial function by enhancing mitophagy. Furthermore, SIRT3 overexpression promoted the synthesis of estradiol-17β and progesterone, key hormones for ovarian function. Our findings demonstrated that AGEs induced hGC senescence by disrupting mitochondrial function and inhibiting mitophagy, with SIRT3 playing a protective role. Enhancing mitophagy by targeting SIRT3 may be a promising treatment approach to counteract age-related declines in female fertility.
Insights
Advanced glycation end products (AGEs) accelerate human granulosa cell (hGC) senescence and impair ovarian function by reducing mitophagy. Targeting Sirtuin 3 (SIRT3) to enhance mitophagy offers a potential therapy for age-related female infertility.
Area of Science:
- Reproductive biology
- Cellular senescence
- Mitochondrial dynamics
Background:
- Female fertility declines with age due to decreased follicle numbers and oocyte quality.
- Granulosa cell senescence is implicated in ovarian aging and reserve depletion.
- Advanced glycation end products (AGEs) accumulate with age, causing oxidative stress, but their role in human granulosa cell (hGC) senescence is unclear.
Purpose of the Study:
- To investigate the impact of AGEs on hGC senescence and mitochondrial function.
- To explore the role of mitophagy and Sirtuin 3 (SIRT3) in AGEs-induced hGC dysfunction.
- To evaluate the therapeutic potential of enhancing mitophagy for age-related female infertility.
Main Methods:
- Treatment of hGCs with AGEs.
- Assessment of hGC senescence, mitochondrial function, and mitophagy.
- Manipulation of mitophagy pathways using urolithin A and Cyclosporine A.
- Genetic modulation of SIRT3 and PINK1 expression.
- Hormone synthesis assays (estradiol-17β and progesterone).
Main Results:
- AGEs treatment exacerbated hGC senescence, impaired mitochondrial function, and suppressed mitophagy in a dose-dependent manner.
- Urolithin A-induced mitophagy activation ameliorated AGEs-induced deficits, while mitophagy inhibition worsened them.
- SIRT3 overexpression attenuated senescence and restored mitochondrial function by enhancing mitophagy.
- SIRT3 overexpression also promoted estradiol-17β and progesterone synthesis.
- Silencing SIRT3 or PINK1 aggravated AGEs-induced hGC dysfunction.
Conclusions:
- AGEs induce hGC senescence by disrupting mitochondrial function and inhibiting mitophagy.
- SIRT3 plays a protective role against AGEs-induced hGC senescence by promoting mitophagy.
- Enhancing mitophagy via SIRT3 activation is a potential therapeutic strategy to counteract age-related female infertility.
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