This resubmission is in response to the program announcement PA-16-088, with the title ?Oocyte Mitochondrial Function in Relation to Fertility, Aging, and Mitochondrial Diseases? by NICHD. Whether paternal mitochondria or paternal mitochondrial DNA (mtDNA) are transmitted to offspring in humans is controversial. Maternal transmission of mtDNA results from the elimination of paternal mitochondria, which is controlled by gene products encoded by the nuclear genome. Due to maternal mtDNA transmission, a woman carrying a mtDNA mutation can pass this mutation to all of her children, with potential clinical consequences. The severity of clinical symptoms in affected children depends on the level of mtDNA heteroplasmy (coexistence of mutant and wild-type mtDNA). Our laboratory has identified two unrelated families with autosomal-dominant inheritance and multiple,high levels of mtDNA heteroplasmy. We have unequivocally demonstrated the existence of biparental mtDNA inheritance in humans. Our results challenge the central dogma of the maternal inheritance of mtDNA. Hereafter, we propose the following: 1) to recruit additional families with potential biparental mtDNA inheritance and examine the possibility of recombination of mtDNA; 2) to investigate gene(s) associated with biparental mtDNA inheritance; 3) to create a CRISPR knock-out mouse model and characterize gene(s) associated with biparental mtDNA inheritance in this model. At least one in every 5,000 people in the general population has an mtDNA mutation that may cause mitochondrial dysfunction and maternally inherited disease. Current clinical options to prevent transmission of mtDNA mutations to offspring are limited. Preimplantation genetic diagnosis to detect pathogenic mtDNA mutations is highly unpredictable. Nuclear transfer (mitochondrial replacement therapy) techniques seem to prevent mutant mtDNA transmission, but are very expensive and not performed clinically due to regulatory constraints. Elucidation of the molecular mechanism of paternal mtDNA transmission may provide an alternative approach to reduce transmission of mutant mtDNA to offspring by carrier women, thereby providing potential treatment options.
Mitochondria, the energy-generating organelles, play a critical role in numerous cellular functions including ATP production, cellular homeostasis and apoptosis. Unlike nuclear DNA, thus far, mitochondria and mtDNA in human are typically transmitted to subsequent generations exclusively through the maternal lineage. Whether paternal mitochondria and mitochondrial DNA (mtDNA) transmission exists is controversial. Here we unequivocally demonstrate biparental mtDNA inheritance and challenged the central dogma of the maternal inheritance of mtDNA. This proposal is to elucidate the genetic mechanism of paternal mtDNA transmission, therefore to provide an alternative approach to reduce the transmission of mutant mtDNA in a carrier women by promoting paternal mtDNA transmission to offspring and develop a potential novel treatment.
