Commentary on “The Immp2l Mutation Causes Ovarian Aging Through ROS-Wnt/β-Catenin-Estrogen Pathway: Preventive Effect of Melatonin” Free

The shortening of the ovarian lifespan triggers ovarian aging, leading to subfertility and even infertility. The characteristics of ovarian aging include an increase in fibrous tissue, a decreasing ovarian reserve, and reduced oocyte quantity and quality (1). Ovarian aging can be induced by several different factors such as menopause, chemotherapy, endocrinological disorders, genetic mutations, and microenvironmental factors. The different mechanisms of ovarian aging have been summarized by Yang et al (2). One of the mechanisms of ovarian aging mainly focuses on mitochondria. The mitochondrial genome plays an important role in ovarian follicle development, whereas mitochondrial dysfunction can lead to ovarian aging.

Mitochondria are the primary source of reactive oxygen species (ROS), and physiological levels of ROS are essential for ovarian function. However, mitochondrial dysfunction leads to excessive ROS which can lead to oxidative stress (OS) damage. ROS affect ovarian follicle growth, and this is closely related to ovarian aging. High levels of ROS and long-term OS reduces ovarian reserves, decreases ovarian function, and induces ovarian aging-related disorders. Therefore, ROS and OS are important mediators of ovarian aging.

In addition, OS damage initiates the wnt/β-catenin pathway in aging, reduces the expression of P450 aromatase, increases intracellular ROS generation, and alters wnt signaling (3). The wnt/β-catenin pathway plays a vital role in female reproduction, including ovarian follicle development, corpus luteum formation, steroid production, and fertility. The ROS-wnt/β-catenin-estrogen (cyp19a1) axis might play an important role in promoting ovarian follicle growth and development in women with endometriosis (4). As a member of the cytochrome P450 family, cyp19a1 converts androgens into estrogens and is necessary for the development and growth of ovarian follicles. Several studies have suggested that β-catenin is an essential transcriptional regulator of cyp19a1. β-catenin (CTNNB1) is part of a transcription complex that binds to the endogenous gonad-specific cyp19a1 promoter regulating the expression of cyp19a1 and the production of estrogen in granular cells. However, the role of the ROS-wnt/β-catenin-estrogen (cyp19a1) axis in the inhibition of ovarian follicular development and ovarian aging induced by mitochondrial gene mutations has not been determined.

Melatonin is a multipotent target molecule involved in several physiological and pathological processes (2). Specifically, because of its antioxidant capacity, melatonin acts as a mitochondrial protector and thus can be used to treat aging-related diseases through preserving mitochondrial function. Exogenous melatonin administration has no short- or long-term adverse effects and is well tolerated (2). The interaction between melatonin and aging was identified by a previous study showing that melatonin production was reduced during aging, the ovarian cycle in aged females was regulated by the pineal gland (which secretes melatonin), and that aging was delayed by the antioxidant effect of melatonin (5). Therefore, melatonin was used to delay ovarian aging. Melatonin has been shown to delay cyclophosphamide-induced ovarian aging through its antioxidant action, maintaining telomers, and stimulating silent information regulator T expression and ribosome function by reducing autophagy (6). Melatonin improves age-induced fertility decline and attenuates ovarian mitochondrial oxidative stress in mice (7). However, the role and mechanism of melatonin in follicular retardation and ovarian aging induced by mitochondrial gene mutations have not been explored. Mitochondrial gene mutations are closely related to aging. Moreover, previous studies have revealed that inner mitochondrial membrane peptidase 2-like (Immp2l) mutant mice display impaired mitochondrial function through increasing ROS and OS damage. However, the precise role of Immp2l in ovarian follicular development and mitochondrial function remains unclear. Recently, He et al. reported that an Immp2l homozygous mutation caused infertility in female mice resulting from a delayed ovarian follicle development and enhanced ovarian aging (8). Compared with control mice, female mice bearing a homozygous mutation of Immp2l displayed delayed development of ovarian follicles at the secondary follicle stages and had fewer antral follicles at 28 days. RNA-sequencing was used to explore the pathway involved in ovarian aging in female mice with the Immp2l homozygous mutation, and differentially expressed genes were analyzed by gene ontology and related with developmental process, reproduction, and antioxidant activity. Subsequently, Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that 2 pathways were affected: the wnt/β-catenin pathway and the steroid hormone pathway. Therefore, the ROS-wnt/β-catenin-estrogen (cyp19a1) pathway was vital in triggering retardation of ovarian follicle development and ovarian aging in mice bearing the Immp2l homozygous mutation, and antioxidant melatonin was used to reverse these effects. Furthermore, granulosa cells displayed senescence upon RNAi-induced downregulation of Immp2l, which could be delayed by melatonin treatment. Taken together, these findings reveal that the ROS-wnt/β-catenin-estrogen (cyp19a1) axis plays an important role in maintaining mitochondrial function during ovarian follicle development as well as a novel role for melatonin in delaying ovarian aging caused by mutations in a mitochondrial gene.

Additional Information

Disclosure Summary: The authors have nothing to disclose.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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