Mitochondrial and nuclear genome interactions play a role in many diseases, and are of increasing concern with the advent of mitochondrial transfer techniques to create “three-parent babies”. During gestation in mammals, the placenta regulates growing energetic demands of developing offspring which may have long-term consequences on fertility, fecundity, and fetal programming. In this respect, we were curious about the impact of maternal-offspring mtDNA mismatch upon fetal development and response to nutritional stress. Mitochondrial-Nuclear eXhange (MNX) mouse strains (containing the nucleus from C57BL/6J and the mitochondrial genome from C3H/HeN mice) were used to assess sources of genetic variation that regulate placental (dys)function, fetal programming, and fetal development in response to nutritional stress. Ten two-cell embryos of either mismatched (MNX) or matching (C3H) mitochondrial and nuclear backgrounds were transferred to the ostia of oviducts in C3H pseudopregnant mice and developed to term. Females from each combination were randomly assigned to either ad lib (AL) diet or 30% caloric restriction (CR) during gestation [n=6 surrogate-embryo genotype combination (AL MNX, CR MNX, AL C3H, CR C3H)]. At day 18 of gestation (near full-term) fetuses and placentas were removed by cesarean section and total number of pups, pup body weight and placental weight recorded.
Results: While neither placental weight (0.1007±0.0059g AL MNX, 0.0931g CR MNX, 0.1034±0.005g AL C3H, 0.09722±0.0171g CR C3H), nor average weight (1.049±0.1410g AL MNX, 0.8739g CR MNX, 1.047±0.1342g AL C3H, 0.7020±0.2664g CR C3H) of pups developed to full term were significantly different per group, only one full term pup was recovered from the CR MNX cohort of 60 embryos transferred (1.67%) compared to 9 in the AL MNX (15%) group. The ad libitum groups produced similar numbers (31.67% MNX and 33.3% C3H) of pups that developed normally to embryonic day 18.
Conclusions: In comparing dietary restriction relative to ad lib, fetuses with mismatched mtDNA relative to the nuclear genome were at higher risk of miscarriage. Further studies are ongoing to determine the effects mtDNA mismatch on maternal physiology; however, these data indicate differences in survivability in response to nutritional stress between embryos of matching or mismatched nuclear and mitochondrial genomes, demonstrating that variation in the fetal mitochondrial genome alters placental and fetal development in response to gestational dietary restriction.