The Role of Mitochondrial DNA Copy Number in Mammalian Fertility1

TLDR

Mammalian mitochondrial DNA, a small maternally inherited genome encoding 13 respiratory proteins, is present in over 150,000 copies per oocyte but only about 100 copies per sperm, and its high oocyte copy number is thought to influence oocyte quality and sperm motility, though its functional role remains unclear. To investigate how mtDNA copy number affects fertility, the authors genetically manipulated Tfam copy number during germline development in mice. The study deleted one copy of Tfam, a key mitochondrial nucleoid component, at various germline stages to alter mtDNA copy number. Males tolerate a three‑fold reduction in sperm mtDNA without fertility loss and even favor transmission of the deleted allele, while oocytes can develop to blastocyst with as few as 4,000 copies but require 40–50 k copies for post‑implantation development, indicating that high oocyte mtDNA copy number serves to distribute mitochondria early, whereas reduced copy number supports normal sperm function.

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.