Hundreds of mitochondria are present in every cell, responsible for generating chemical energy store molecules to power cell processes. Mitochondria are the descendants of ancient symbiotic bacteria, still replicate like bacteria, and retain a remnant genome. With age mitochondria become dysfunctional for reasons relating to damage to mitochondrial DNA and changes in the expression of mitochondrial genes in the cell nucleus. This dysfunction is known to contribute to the chronic inflammation of aging via its interaction with innate immune mechanisms, making rejuvenation of mitochondria an important goal in the treatment of aging. While this paper is focused on the aging of the ovaries, most of the discussion of mechanisms is relevant to the rest of the body as well, as mitochondrial dysfunction occurs in all tissues with age.
Ovarian ageing is a key factor in the decline of female fertility. It is primarily characterised by diminished oocyte quality, follicular depletion, and dysregulated hormone levels. In recent years, mitochondria-driven inflammation has emerged as a potential mechanism in ovarian ageing. Mitochondrial dysfunction results in the accumulation of reactive oxygen species (ROS) and the release of mitochondrial DNA (mtDNA), as well as the leakage of mitochondrial components and metabolites into the cytosol or extracellular space. These elements act as damage-associated molecular patterns (DAMPs), activating inflammasomes like NLRP3, thereby initiating and amplifying innate immune responses and contributing to sustained inflammation.
The differential regulation of these signals under physiological versus pathological ageing conditions is particularly poorly characterised. Moreover, existing therapeutic strategies often target isolated pathways. For instance, antioxidant treatments may reduce ROS accumulation but have limited effects on the broader signalling networks involved in ovarian ageing. From a clinical translation perspective, several challenges remain, including insufficient drug targeting, unclear optimal timing of intervention, and limited understanding of long-term safety. For example, during the activation of primordial follicles, augmented mitochondrial biogenesis contributes to the preservation of oocyte energy balance. Conversely, the follicular atresia phase is closely associated with excessive activation of inflammatory signalling, and moderate inhibition of the NLRP3 inflammasome has demonstrated efficacy in retarding granulosa cell apoptosis and decelerating the atresia process. However, current therapeutic strategies lack the precision to temporally regulate these dynamic changes.
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