Genetics of mitochondrial dysfunction and infertility

Abstract

Increasingly, mitochondria are being recognized as having an important role in fertility. Indeed in assisted reproductive technologies mitochondrial function is a key indicator of sperm and oocyte quality. Here, we review the literature regarding mitochondrial genetics and infertility. In many multisystem disorders caused by mitochondrial dysfunction death occurs prior to sexual maturity, or the clinical features are so severe that infertility may be underreported. Interestingly, many of the genes linked to mitochondrial dysfunction and infertility have roles in the maintenance of mitochondrial DNA or in mitochondrial translation. Studies on populations with genetically uncharacterized infertility have highlighted an association with mitochondrial DNA deletions, whether this is causative or indicative of poor functioning mitochondria requires further examination. Studies on the impact of mitochondrial DNA variants present conflicting data but highlight POLG as a particularly interesting candidate gene for both male and female infertility.

Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects

“…Infertility was noted in 2 male cases. Although it is currently uncertain whether this is VPS13D ‐related, infertility is a known feature of mitochondrial disease …”

“…Although it is currently uncertain whether this is VPS13D-related, infertility is a known feature of mitochondrial disease. 38 VPS13D encodes a large protein (4,388 amino acids), whose paralogs cause other neurological disorders; VPS13A mutations cause chorea acanthocytosis, characterized by a severe hyperkinetic movement disorder, myopathy, epileptic seizures, cognitive decline, and behavioral changes, 22,39 and perturb protein homeostasis in the fly. 19 VPS13B is involved in Cohen syndrome 40,41 and VPS13C in rare cases of genetic Parkinson disease with mitochondrial dysregulation and mitophagy.…”

Rewiring of gene expression in circulating white blood cells is associated with pregnancy outcome in heifers (Bos taurus)

“…The enrichment for specific biological processes of genes that formed new negative connections was a clear evidence of the biological relevance of these new connections. Notably, among genes annotated with proteolytic activity, ADAM19 39 , ASRGL1 40 , ATG4B 41 , DPEP2 42 , IMMP2L 43 , PSMB9 44 , SERPINE2 45 , UCHL3 46 , USP42 47 have been implicated in female infertility. A more drastic change in patterns of coexpression was observed with the inversion of gene connections (significant pairwise coexpression in one group with significant coexpression with opposite direction in another group).…”

Article Commentary: Mitochondrial Replacement Techniques: Genetic Relatedness, Gender Implications, and Justice

“…44 At this point in time, clinically offering MST for treating infertility cannot be justified, because there is no clear evidence to suggest that mtDNA mutations due to old age are causative of infertility. 45 Finally, on August 4, 2017 the FDA sent Dr. Zhang a strong worded letter pointing out various regulation violations that Dr. Zhang's team incurred on when they carried out MST, and they also pointed out that Zhang's company ''Darwin Life'' kept on marketing MRTs within the US even when they have said that they would stop doing so. 46 Mexico currently lacks national regulations pertaining to assisted reproduction.…”