Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions

Abstract

Mitochondria plays an essential role in regulating cellular metabolic homeostasis, proliferation/differentiation, and cell death. Mitochondrial dysfunction is implicated in many age-related pathologies. Evidence supports that the dysfunction of mitochondria and the decline of mitochondrial DNA copy number negatively affect ovarian aging. However, the mechanism of ovarian aging is still unclear. Treatment methods, including antioxidant applications, mitochondrial transplantation, emerging biomaterials, and advanced technologies, are being used to improve mitochondrial function and restore oocyte quality. This article reviews key evidence and research updates on mitochondrial damage in the pathogenesis of ovarian aging, emphasizing that mitochondrial damage may accelerate and lead to cellular senescence and ovarian aging, as well as exploring potential methods for using mitochondrial mechanisms to slow down aging and improve oocyte quality.

Keywords: aging; fertility preservation; mechanism; mitochondria; oocyte.

Figure 1

Potential mechanisms of ovarian aging (the figure was created with BioRender.com) Telomere shortening: Once telomere length becomes critically short, cellular senescence and apoptosis may occur during ovarian aging in mammals (7, 8); Compromised autophagy: The decrease of autophagic activity with age, likely leads to the accumulation of damaged macromolecules and organelles (9, 10); Mitochondial dysfunction: Mitochondial factors are explained further under subheadings in the text; Loss of proteostasis: Loss of proteostasis may damage the stability of microtubules and the integrity of meiosis in naturally aged mice oocyte (11); Stem cell exhaustion: Due to germ-line stem cells do not exist post-natally in female mammals (–14), the reproductive potential of the ovaries will continue to decline after birth; Altered intercellular communication: There is an Increase In preantral follicles atresia in mice with suppression of intercellular junctions, which may be the cause of premature ovarian failure (15, 16); Epigenetic alteration: Studies have revealed the occurrence of epigenetic changes in the cells within the ovaries as age increases, including abnormal DNA methylation (17), histone modifications (18), and non-coding RNA-regulated modifications (19, 20); Cellular senescence: With the dysfunction of senescent cell, limited mitochondrial energy production, increased apoptosis of ovarian granulosa cells (21), increased inflammatory cytokines secretion (22) etc., would alter the microenvironment of follicle growth and affecting the quality and quantity of oocyte; Nutritional dysregulation: Dietary factors (23), low energy availability and high fat diet can increase the risk of POI; Genomic instability: In aging oocyte deceased efficacy of DNA repair mechanisms could cause low potentiation of anti-oxidant buffering and promote cell death (24).

Figure 2

Mitochondrial quality monitoring and ovarian aging(the figure was created with BioRender.com) (1)mitochondrial fusion: The low expression of MFN1 ang MFN2 in the outer membrane in aging oocyte may affect mitochondrial fusion and inhibit the PI3K-AKT pathway, affecting oocyte-somatic cell communication (108, 109); (2) mitochondrial fission: The decreased expression of DRP1 in oocyte may affect mitochondrial function, leading to a decrease in oocyte quality (110); (3) mitophagy: Mitochondrial autophagy function decreases during ovarian aging (117, 118); (4) UPRmt: The decreased expression of CLPP and PGC1α in aging oocyte may hinder the occurrence of UPRmt (96, 97).

Figure 3

Mitochondria and meiosis in the oocyte (the figure was created with BioRender.com) MCU mediates the rapid entry of Ca²⁺ into mitochondria and provides high energy in an instant (129). MDR1 regulate ROS efflux from the inner mitochondrial membrane to maintain mitochondrial function (133). SPD3 may affect the abnormal pairing of homologous chromosomes which may be caused by the inhibition of mitochondrial function (132). Oxidative stress and mitochondrial ATP production disorders in aging oocyte may lead to abnormal spindle shape and increase chromosomal errors during meiosis in oocyte.

Figure 4

Mitochondrial-mediated oocyte apoptosis pathway (the figure was created with BioRender.com) In aging oocyte, excessive cell apoptosis signals are activated under stimuli such as mitochondrial oxidative stress and decreased mitochondrial membrane potential. At the same time, the expression of anti-apoptotic proteins such as BCL2 decreased, while the expression of apoptotic proteins such as BAK, CytC and Caspase9 increased (–142).

Figure 5

Mitochondria and telomeres in the oocyte (the figure was created with BioRender.com) The cAMP response element-binding protein (CREB) is a co-factor for PGC1 expression. Abnormal telomere function can activate p53, thereby inhibiting the expression of PGC1. The decrease in PGC1 expression in turn inhibits mitochondrial biogenesis, leading to a decrease in the ability of cells to resist oxidative stress (156). In addition, increasement in the proportion of intracellular AMP/ATP and NAD+/NADH also promotes PGC1 expression, but this is not suitable for aging cells, as the content of NAD+ and SIRT1 significantly decreases (53, 54).