Incompatibility between mitochondrial and nuclear genomes during oogenesis results in ovarian failure and embryonic lethality

Abstract

Mitochondrial dysfunction can cause female infertility. An important unresolved issue is the extent to which incompatibility between mitochondrial and nuclear genomes contributes to female infertility. It has previously been shown that a mitochondrial haplotype from D. simulans (simw 501) is incompatible with a nuclear genome from the D. melanogaster strain Oregon-R (OreR), resulting in impaired development, which was enhanced at higher temperature. This mitonuclear incompatibility is between alleles of the nuclear-encoded mitochondrial tyrosyl-tRNA synthetase (Aatm) and the mitochondrialencoded tyrosyl-tRNA that it aminoacylates. Here, we show that this mito-nuclear incompatibility causes a severe temperature-sensitive female infertility. The OreR nuclear genome contributed to death of ovarian germline stem cells and reduced egg production, which was further enhanced by the incompatibility with simw 501 mitochondria. Mito-nuclear incompatibility also resulted in aberrant egg morphology and a maternal-effect on embryonic chromosome segregation and survival, which was completely dependent on the temperature and mito-nuclear genotype of the mother. Our findings show that maternal mito-nuclear incompatibility during Drosophila oogenesis has severe consequences for egg production and embryonic survival, with important broader relevance to human female infertility and mitochondrial replacement therapy.

Energy demand and the context-dependent effects of genetic interactions underlying metabolism

“…; Zhang et al. ). Here, we show that the phenotypic expression of this genetic interaction is generally environment dependent and depends on intrinsic factors such as life stage and sex in a manner consistent with greater energy demands revealing fitness effects of mutations that compromise metabolism.…”

“…The fecundity defects in ( simw 501 ); OreR females are also strongly temperature dependent and involve defects in the development and maintenance of the ovary (Zhang et al. ). Furthermore, mothers of this genotype developed at 28°C produce defective eggs that have a lower probability of being fertilized and, when fertilized, die during embryogenesis presumably due to insufficient maternal provisioning or the inheritance of subfunctional mitochondria (Zhang et al.…”

“…Furthermore, mothers of this genotype developed at 28°C produce defective eggs that have a lower probability of being fertilized and, when fertilized, die during embryogenesis presumably due to insufficient maternal provisioning or the inheritance of subfunctional mitochondria (Zhang et al. ).…”

“…; Zhang et al. ) with an environmental perturbation designed to manipulate energy demand. Phenotypic effects of variation in the mitochondrial genome (mtDNA) often depend upon variation in the nuclear genome due to the functional interactions between gene products from these two genomes (reviewed in Burton and Barreto ).…”

Influence of Heterologous Transplant of DNA‐lacking Mitochondria from Entamoeba histolytica on Proliferation of Entamoeba invadens

“…In canonical mitochondria, incompatibilities between mitochondrial and nuclear DNA lead to cell death. For example, a mating combination with replacement of mitochondria results in embryonic death in mice (Ma et al 2016), and incompatibility between mitochondrial tRNA and aminoacyl tRNA synthetases encoded in nuclear DNA causes female infertility in Drosophila (Meiklejohn et al 2013;Zhang et al 2017). Sharpley et al (2012) showed that heteroplasmy of mitochondrial DNA leads to unexpected genetic and behavioral instabilities.…”