Mammalian mitochondrial DNA (mtDNA) is a maternally inherited, high copy number genome that codes for a small number of essential proteins in the enzyme complexes of the oxidative phosphorylation (OXPHOS) system. Mutations in mtDNA have been linked to a wide variety of multisystem disorders, called encephalomyopathies, with an estimated prevalence of about 1:8000. In patients with mitochondrial disease, mtDNAs containing pathogenic mutations usually co-exist with wild-type mtDNAs. The mutant load determines the severity of clinical symptoms, but it must exceed a threshold level before a biochemical or clinical phenotype is evident. The relative proportion of mutant mtDNAs transmitted from mother to child is thus the key determinant of disease severity; however, the factors that influence the segregation of mtDNA sequence variants in the female germline are poorly understood, and genetic counseling remains problematic. Mammalian oocytes contain at least 100,000 mitochondria and mtDNAs, yet sequence variants segregate rapidly between generations, due to the presence of a bottleneck in development. The size and shape of this bottleneck are not known, nor is it known how decreases in mtDNA copy number or diminished OXPHOS function might affect mtDNA transmission. There is a widespread belief that mitochondria are important for oocyte maturation, and that mitochondrial dysfunction plays a role in germ cell atresia, concepts that seem at odds with the observed transmission of pathogenic mtDNA variants. The goal of this research is to test the hypothesis that the high number of mtDNAs in the oocyte exists as a genetic mechanism to ensure that all cells in the early embryo receive mitochondria at a time when mitochondrial biogenesis is arrested. We propose to use a mouse model to i) define precisely the nature of the bottleneck for mtDNA transmission and ii) test whether changes in mtDNA copy number, or diminished OXPHOS function, at different stages of oogenesis influence oocyte maturation and mtDNA transmission.
|Wai, Timothy; Ao, Asangla; Zhang, Xiaoyun et al. (2010) The role of mitochondrial DNA copy number in mammalian fertility. Biol Reprod 83:52-62|