The Role of Mitochondrial DNA Copy Number in Mammalian Fertility1

Abstract

Mammalian mitochondrial DNA (mtDNA) is a small, maternally inherited genome that codes for 13 essential proteins in the respiratory chain. Mature oocytes contain more than 150 000 copies of mtDNA, at least an order of magnitude greater than the number in most somatic cells, but sperm contain only approximately 100 copies. Mitochondrial oxidative phosphorylation has been suggested to be an important determinant of oocyte quality and sperm motility; however, the functional significance of the high mtDNA copy number in oocytes, and of the low copy number in sperm, remains unclear. To investigate the effects of mtDNA copy number on fertility, we genetically manipulated mtDNA copy number in the mouse by deleting one copy of Tfam, an essential component of the mitochondrial nucleoid, at different stages of germline development. We show that males can tolerate at least a threefold reduction in mtDNA copy number in their sperm without impaired fertility, and in fact, they preferentially transmit a deleted Tfam allele. Surprisingly, oocytes with as few as 4000 copies of mtDNA can be fertilized and progress normally through preimplantation development to the blastocyst stage. The mature oocyte, however, has a critical postimplantation developmental threshold of 40 000-50 000 copies of mtDNA in the mature oocyte. These observations suggest that the high mtDNA copy number in the mature oocyte is a genetic device designed to distribute mitochondria and mtDNAs to the cells of the early postimplantation embryo before mitochondrial biogenesis and mtDNA replication resumes, whereas down-regulation of mtDNA copy number is important for normal sperm function.

A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

“…Aneuploidy incidence rates increase with age in humans and mice, with evidence suggesting age-related degradation of cohesin proteins in the oocyte nucleus is involved (Chiang et al 2010, Lister et al 2010, Kuliev et al 2011, Duncan et al 2012. Oocyte mitochondrial counts also decline in older females, leading to reduced embryo viability (Wai et al 2010, Kushnir et al 2012, Fragouli et al 2015. Additional factors that contribute to the age-related decline in oocyte quality may yet be discovered, but there is no current evidence to suggest that AMH directly affects oocyte quality.…”

Does serum cause lipid-droplet accumulation in bovine embryos produced in vitro, during developmental days 1 to 4?

“…In this sense, the results of Chiaratti et al [13] are consistent with our observations: 1-cell embryos that were able to recover the high mtDNA content removed by centrifugation and advanced to the blastocyst stage, must maintain functional mechanisms of fusion and fission required for the distribution of genetic material. This may also explain on the mouse oocyte model, in which with only 4,000 copies of mtDNA, embryos were able to progress until the blastocyst stage [62].…”

Theory about the Embryo Cryo‐Treatment

“…The presence of mitochondrial dysfunction secondary to mtDNA deletions is tissue‐specific and has been linked to many pathologies, such as diabetes, heart failure, neurodegenerative diseases, and even cancer 42. However, as mtDNA mutations affect only a subset of organelles, usually ≥60% of the mtDNA copies need to contain deletions before any significant biochemical defect would be apparent.…”