Reproductive senescence impairs the energy metabolism of human luteinized granulosa cells

Abstract

RESEARCH QUESTION: Female age is the single greatest factor influencing reproductive performance and granulosa cells are considered as potential biomarkers of oocyte quality. Is there an age-effect on the energy metabolism of human mural granulosa cells? DESIGN: Observational prospective cohort and experimental study including 127 women that underwent in vitro fertilization cycles. Women were allocated to two groups: a group of infertile patients aged over 38 years and a control group comprising oocyte donors aged less than 35 years.Individuals with pathologies that could impair fertility were excluded from both groups. Following oocyte retrieval, cumulus and granulosa cells were isolated and their bioenergetic properties (oxidative phosphorylation parameters, rate of aerobic glycolysis and adenine nucleotide levels) were analyzed and compared. RESULTS:Human mural luteinized granulosa and cumulus cells present high rates of aerobic glycolysis that cannot be increased further when mitochondrial ATP synthesis is inhibited. Addition of follicular fluid to the experimental media is necessary to reach the full respiratory capacity of the cells. Granulosa cells from aged women present lower mitochondrial respiration, although mitochondrial mass is not decreased, and lower aerobic glycolysis than those from young donors. The concurrent decrease in the two energy supply pathways leads to a decrease in the cellular ATP levels. CONCLUSIONS:Human mural luteinized granulosa cells exhibit a reduction in their energy metabolism as women age that is likely to influence female reproductive potential.

Deletion of enzymes for de novo NAD+ biosynthesis accelerated ovarian aging

“…Our findings revealed that the expression of genes related to mitochondrial OXPHOS was significantly downregulated in the ovaries of 8-month-old knockout mice as compared to controls, suggesting that disruption of NAD + de novo pathway resulted in mitochondrial dysfunction which was mediated by the suppression of OXPHOS. Our results support the notion that impaired mitochondrial functions lead to ovarian senescence (Cecchino et al, 2021;May-Panloup et al, 2016;van der Reest et al, 2021;Yang, Lin, et al, 2020). Subsequent analysis revealed that deletion of Ido1 or Qprt impaired mitochondria distribution and decreased mitochondrial membrane potential in oocytes.…”

“…Our data demonstrate that the disruption of the NAD + de novo pathway leads to disturbed mitochondrial functions, suppressed granulosa cell proliferation, and decreased oocyte quality, ultimately resulting in reduced fertility. These findings provided further support for the idea that disrupted mitochondrial functions are a key contributor to ovarian senescence (Cecchino et al, 2021 ; May‐Panloup et al, 2016 ; van der Reest et al, 2021 ; Yang, Lin, et al, 2020 ).…”

Aging and oocyte competence: A molecular cell perspective

“…" Spindle defects # Blastocyst rate Xu et al, 2019;Nie et al, 2019;Jia et al, 2020;Ma et al, 2015;Emidio et al, 2014;Zhang et al, 2016;Yang et al, 2018;Wang, Jo, et al, 2017;Xing et al, 2021;Wang, Hassold, et al De Bruin et al, 2004;Liu et al, 2017;Müller-Höcker et al, 1996;Rambags et al, 2014;Simsek-Duran et al, 2013;Wilding et al, 2001;Soares et al, 2020;Xu et al, 2019;Dadarwal et al, 2017;Zhang et al, 2016 Pasquariello et al, 2019;Morimoto et al, 2020;Wilding et al, 2001;Steuerwald et al, 2007;Cecchino et al, 2021;Liu et al, 2017;McReynolds et al, 2012;Takeo et al, 2013;Xu et al, 2019;Sugimura et al, 2012;Ben-Meir et al, 2015 Xing et al, 2021;Yang et al, 2018;Ben-Meir et al, 2019 Fusion and fission alterations Mouse Oocyte (old female, Mfn2À/À, Clpp À/À) " Spindle defects # Maturation rate Altered folliculogenesis # Ovarian reserve Udagawa ...…”

“…Indeed, several alterations in granulosa/cumulus cells (GC/CC) and FF have been identified in association with aging. Research in AMA women provided evidence that oxidative stress and mitochondrial dysfunction are markers of aging in CC (Ávila et al, 2016; Cecchino et al, 2021; Li et al, 2021; Tatone & Amicarelli, 2013). Imbalance of ROS levels in GC/CC is likely a result of higher levels of ROS (Tatone & Amicarelli, 2013) in parallel with decreased levels of antioxidant enzymes.…”

“…Similarly to the oocyte, GC of AMA women have higher levels of abnormal mitochondria (De Bruin et al, 2004; Liu et al, 2017), lower mitochondrial respiration and MMP (Ben‐Meir et al, 2019; Y. Liu et al, 2017; Pasquariello et al, 2019), aerobic glycolysis, and ATP concentrations when compared to younger females (Cecchino et al, 2021). In agreement, CC from AMA women revealed altered gene expression profiles, with a downregulation of genes involved in OXPHOS (McReynolds et al, 2012), antioxidative defense, and DNA repair (Al‐Edani et al, 2014).…”