Obesity-exposed oocytes accumulate and transmit damaged mitochondria due to an inability to activate mitophagy

Abstract

Mitochondria are the most prominent organelle in the oocyte. Somatic cells maintain a healthy population of mitochondria by degrading damaged mitochondria via mitophagy, a specialized autophagy pathway. However, evidence from previous work investigating the more general macroautophagy pathway in oocytes suggests that mitophagy may not be active in the oocyte. This would leave the vast numbers of mitochondria - poised to be inherited by the offspring - vulnerable to damage. Here we test the hypothesis that inactive mitophagy in the oocyte underlies maternal transmission of dysfunctional mitochondria. To determine whether oocytes can complete mitophagy, we used either CCCP or AntimycinA to depolarize mitochondria and trigger mitophagy. After depolarization, we did not detect co-localization of mitochondria with autophagosomes and mitochondrial DNA copy number remained unchanged, indicating the non-functional mitochondrial population was not removed. To investigate the impact of an absence of mitophagy in oocytes with damaged mitochondria on offspring mitochondrial function, we utilized in vitro fertilization of high fat high sugar (HF/HS)-exposed oocytes, which have lower mitochondrial membrane potential and damaged mitochondria. Here, we demonstrate that blastocysts generated from HF/HS oocytes have decreased mitochondrial membrane potential, lower metabolites involved in ATP generation, and accumulation of PINK1, a mitophagy marker protein. This mitochondrial phenotype in the blastocyst mirrors the phenotype we show in HF/HS exposed oocytes. Taken together, these data suggest that the mechanisms governing oocyte mitophagy are fundamentally distinct from those governing somatic cell mitophagy and that the absence of mitophagy in the setting of HF/HS exposure contributes to the oocyte-to-blastocyst transmission of dysfunctional mitochondria.

Mitochondrial network state scales mtDNA genetic dynamics

“…Our theory therefore suggests that inhibition of basal mitophagy may be able to slow down the rate of random genetic drift, and perhaps healthy aging, by locking-in low levels of heteroplasmy. Indeed, it has been shown that mouse oocytes (Boudoures et al, 2017) as well as mouse hematopoietic stem cells (de Almeida et al, 2017) have comparatively low levels of mitophagy, which is consistent with the idea that these pluripotent cells attempt to minimise genetic drift by slowing down mtDNA turnover. A previous modelling study has also shown that mutation frequency increases with mitochondrial turnover (Poovathingal et al, 2009).…”

The 5.8S pre‐rRNA maturation factor, M‐phase phosphoprotein 6, is a female fertility factor required for oocyte quality and meiosis

“…Annexin V is a marker of early apoptosis, and an increased level of annexin V indicates an abnormally high apoptotic level . Mitochondria are the factory that generates ATP, over‐aggregated mitochondria indicate impeded mitochondrial autophagy, and the cellular ATP level might decrease consequently . Our results showed that MPP6 depletion significantly elevated the ROS (Figure A,B, ROS level, Ctrl vs MPP6‐DE, 19.59 vs 37.68) and annexin V (Figure C,D, annexin V intensity, Ctrl vs MPP6‐DE, 15.53 vs 21.21) levels.…”

“…34 Mitochondria are the factory that generates ATP, over-aggregated mitochondria indicate impeded mitochondrial autophagy, and the cellular ATP level might decrease consequently. 35 Our results showed that MPP6 depletion significantly elevated the ROS (Figure 6A Figure 6E).…”

Assisted reproductive technologies to prevent human mitochondrial disease transmission

“…The study reports that mtDNA haplotype influences mitochondrial proteostasis, metabolic syndrome and reactive oxygen species generation 29 . Mouse models suggest that metabolic syndrome is transmitted via mitochondria transgenerationally owing to defective mitophagy (destruction of mitochondria by the cell) 30,31 .…”