New insights on mitochondrial heteroplasmy observed in ovarian diseases

Abstract

Background: The reportedly high mutation rate of mitochondrial DNA (mtDNA) may be attributed to the absence of histone protection and complete repair mechanisms. Mitochondrial heteroplasmy refers to the coexistence of wild-type and mutant mtDNA. Most healthy individuals carry a low point mutation load (<1 %) in their mtDNA, typically without any discernible phenotypic effects. However, as it exceeds a certain threshold, it may cause the onset of various diseases. Since the ovary is a highly energy-intensive organ, it relies heavily on mitochondrial function. Mitochondrial heteroplasmy can potentially contribute to a variety of significant ovarian disorders.

Aim of review: In this review, we have elucidated the close relationship between mtDNA heteroplasmy and ovarian diseases, and summarized novel avenues and strategies for the potential treatment of these ovarian diseases.

Key scientific concepts of review: Mitochondrial heteroplasmy can potentially contribute to a variety of significant ovarian disorders, including polycystic ovary syndrome, premature ovarian insufficiency, and endometriosis. Current strategies related to mitochondrial heteroplasmy are untargeted and have low bioavailability. Nanoparticle delivery systems loaded with mitochondrial modulators, mitochondrial replacement/transplantation therapy, and mitochondria-targeted gene editing therapy may offer promising paths towards potentially more effective treatments for these diseases, despite ongoing challenges.

Keywords: Endometriosis; Mitochondria-targeted therapy; Mitochondrial heteroplasmy; Polycystic ovary syndrome; Premature ovarian insufficiency.

Graphical abstract

Fig. 1

Human mitochondrial DNA and its heteroplasmy. (A) Human mitochondrial DNA (mtDNA) is a double-stranded circular DNA, which is the only genetic material outside the nucleus. (B) The mtDNA in a cell can be either homogeneous or heterogeneous. The number of mutated mtDNA must reach a certain threshold to cause lesions in the corresponding tissue or organ. (C) The structure of mtDNA can be divided into coding and non-coding regions. The non-coding region, also known as the displacement loop (D-Loop), contains mtDNA heavy- and light-strand replication initiation sites and transcription promoters. It is responsible for the regulation of replication and transcription of the entire mtDNA.

Fig. 2

Energy metabolism of the ovary. The energy requirements during normal folliculogenesis are dominated by metabolites derived from granulosa cells through the gap junctions in the cumulus-oocyte complex. Additionally, mitochondria cooperate with endoplasmic reticulum to maintain intracellular calcium homeostasis.

Fig. 3

Mitochondrial heteroplasmy in PCOS. (A) Mitochondrial heteroplasmy in PCOS primarily includes mtDNA copy number variants, sequence alterations, and epigenetic changes. Mitochondrial dysfunction in PCOS is also characterized by deficient fusion and excessive mitophagy. The above-mentioned abnormalities are involved in multiple affected organ disorders as the disease progresses, ranging from hyperandrogenism, ovulation failure, and poor-quality oocytes to insulin resistance and metabolic syndrome. (B) mtDNA mutations potentially related to PCOS. (C, D) The expression of DNA methyltransferase 1(DNMT1) is significantly higher in oocytes from polycystic ovaries (PCO) patients. The mtDNA from PCO is hypermethylated, especially the sequences encoding 12S, 16S rRNA, and ND4, as well as the D-loop region. Reprinted with permission from Ref. . (E) The granulosa cells from PCOS patients exhibited excessive mitophagy according to mitochondrial ultrastructure by transmission electron microscopy (TEM). Reprinted with permission from Ref. .

Fig. 4

Mitochondrial heteroplasmy in POI. (A) The granulosa cells, including cumulus cells and mural cells, play a vital role in follicular development and maturation. Both ROS attacks and mtDNA-related nuclear DNA (nDNA) alterations can induce mitochondrial heteroplasmy, leading to mitochondrial dysfunction and damage as well as subsequent oxidative stress and injury. Under these circumstances, the classical apoptotic signaling pathway would be activated, followed by the release of cytochrome c in granulosa cells and oocytes, known as follicular atresia, which manifests as POI in patients. (B) Some non-synonymous variations in different mtDNA genes. Reprinted with permission from Ref. . (C) The appropriate distribution of mtDNA mutations in various complexes of the mitochondrial electron transport chain. Reprinted with permission from Ref. . (D) Homozygous missense mutation of mtDNA transcription-related gene TFAM leads to a series of symptoms, including gonadal dysplasia, and POI in females, in addition to seizures, intellectual disability, and hearing loss, indicated by two pedigrees from Pakistan. Reprinted with permission from Ref. .

Fig. 5

Mitochondrial heteroplasmy in EMS. (A, B) Mitochondria in ectopic endometrial cells exhibited abnormal connective networks and cristae shape, indicating alterations in mitochondrial dynamics and biogenesis. Reprinted with permission from Ref. . (C) mtDNA mutations that potentially related to EMS. (D) mtDNA copy number variants and sequence alterations represent two aspects of mitochondrial heteroplasmy in EMS, which could lead to mitochondrial dysfunction and dynamics disturbance, accompanied by oxidative stress, and further cause cellular malfunction. Worse still, there could be a vicious cycle among them.

Fig. 6

Mitochondria-targeted nano-delivery systems. (A) Several agents are used to target mitochondria, including alkyltriphenylphosphonium moiety and bioactive compounds. (B) Conceptualization of the design of our research, including the construction of a novel PQQ-loaded nanosystem targeting the ovarian mitochondria and the functional evaluation in vivo.

Fig. 7

Mitochondrial replacement/transplantation. (A) Mitochondrial replacement therapy is the replacement of mitochondria to prevent or ameliorate disease, including spindle transfer, polar body1 transfer, polar body2 transfer, and pronuclear transfer. (B) Mitochondrial transplantation in IVF is a therapeutic approach that entails the injection of healthy mitochondria harvested from oogonia stem cells into the abnormal oocytes to increase fertilization rates.

Fig. 8

Mitochondrial gene-editing technology. General gene-editing techniques to eliminate mtDNA mutations include delivery of wild-type mtDNA, gene editing technologies with various endonucleases, and base editing technology with high target specificity.