Depletion of oocyte dynamin-related protein 1 shows maternal-effect abnormalities in embryonic development

Abstract

Eggs contain about 200,000 mitochondria that generate adenosine triphosphate and metabolites essential for oocyte development. Mitochondria also integrate metabolism and transcription via metabolites that regulate epigenetic modifiers, but there is no direct evidence linking oocyte mitochondrial function to the maternal epigenome and subsequent embryo development. Here, we have disrupted oocyte mitochondrial function via deletion of the mitochondrial fission factor Drp1. Fission-deficient oocytes exhibit a high frequency of failure in peri- and postimplantation development. This is associated with altered mitochondrial function, changes in the oocyte transcriptome and proteome, altered subcortical maternal complex, and a decrease in oocyte DNA methylation and H3K27me3. Transplanting pronuclei of fertilized Drp1 knockout oocytes to normal ooplasm fails to rescue embryonic lethality. We conclude that mitochondrial function plays a role in establishing the maternal epigenome, with serious consequences for embryo development.

Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment

“…Oocytes accumulate both the MARDO and mitochondria during growth. Maternal mitochondria provide energy for oocyte meiotic maturation and early embryonic development (56,57), but they also generate reactive oxygen species (ROS) that can compromise the integrity of genetic material in mitochondria and the nucleus (58,59). Emerging evidence has revealed that interactions between membranebound and membraneless compartments play fundamental roles in cellular organization and function (15,(60)(61)(62)(63)(64)(65)(66)(67)(68)(69).…”

Dynamics of Mitochondrial DNA Copy Number and Membrane Potential in Mouse Pre-Implantation Embryos: Responses to Diverse Types of Oxidative Stress

“…In zygotes, TMRM was highly responsive to mitochondrial disruption by FCCP (mitochondrial uncoupler) and rotenone (Complex I inhibitor; Figure S4 ). Initially, embryos of mice expressing mitochondrial Dendra (a mitochondrial-specific version of Dendra2 green/red photo switchable monomeric fluorescent protein [ 36 ]) were stained with TMRM to co-localize active mitochondria within the ICM and TE. TMRM staining of blastocyst stage embryos flushed from the uteri of Dendra mice at E3.5 showed that MMP was higher in TE cells than in ICM cells ( Figure 2 A).…”

CENP-F-dependent DRP1 function regulates APC/C activity during oocyte meiosis I

“…Our results are supported by the fact that mtDNA copy number does not change during oocyte maturation from the GV to MII stage in mice 64,65 , prepubertal sheep 66 , or humans 67,68 . Knockout or overexpression of DRP1 in mouse oocytes does not affect ATP or mtDNA copy numbers 23,58,69 . But these do not exclude the vital role of mitochondria in chromosome segregation since deletions of mtDNA compromise ATP-dependent energy utilisation and resulting chromosomal non-disjunction in human oocytes 70 .…”

“…Multiple organelles, including mitochondria, aggregate in DRP1-specific knockout oocytes due to accumulating mitochondrial dysfunction during oocyte growth 23 . A recent study showed that DRP1 knockout leads to elongated and aggregated mitochondria and elevated ROS levels in GV stage oocytes 58 . Given that mitochondrial number increases dramatically from 5 thousand in primary follicles to more than 150 thousand in fully grown oocytes 59 , any conclusions derived from DRP1 knockout models will necessarily involve mitochondria dysfunction.…”