Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

Telomere elongation during embryogenesis is regulated by oocyte mitochondria (#244)

Yasmyn E Winstanley 1 , Darryl L Russell 1 , Rebecca L Robker 1
  1. The Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia

Telomeres are protective DNA sequences at chromosome ends that control cellular proliferation potential and senescence. Telomere length is an important determinant of health, with short telomeres associated with diminished tissue function and short lifespan. Telomeres shorten with every cell division, therefore telomere length must be regenerated in offspring to ensure viability of each new generation, however exceedingly little is known about this process and how it is regulated. Characterisation of telomere length in individual mouse oocytes and embryos using a novel qPCR assay revealed elongation occurs rapidly within the first three cell divisions and again at the blastocyst stage. Parthenotes exhibited telomere elongation indicating the necessary factors are present in oocytes. We tested whether oocyte mitochondria regulated this process by measuring telomere elongation in mice with compromised mitochondrial activity and in response to mitochondrial activators.  Aged or obese female mice exhibit reduced oocyte mitochondria membrane potential (using TMRM potentiometric dye), that is similarly reduced by in vivo rotenone (Complex I inhibitor) exposure or high oxygen embryo culture. Telomere length per cell was reduced in blastocysts, specifically in the inner cell mass (ICM), from each of the mitochondria dysfunction models compared to controls, indicating deficient telomere resetting in these embryos. Following embryo transfer, shorter telomeres were maintained in fetal tissues, predicting shorter lifespan in these offspring. Aged or obese female mice were treated with compounds known to activate oocyte mitochondria (BGP-15, Metformin, MitoQ) prior to ovulation to determine if the deficiency is reversible. Remarkably, mitochondria-activating compounds prior to fertilisation restored telomere lengths in ICMs of aged and obese females to similar levels as those from young lean controls. Thus, embryo telomere resetting is impaired in the presence of mitochondria dysfunction, including with female obesity and reproductive ageing, and likely contributes to poorer health outcomes, including reduced lifespan, documented in these offspring.