Maternal exposure to a mitochondrial toxicant results in life-long alterations in DNA methylation and gene expression in the offspring

Mitochondrial-driven alterations of the epigenome have been reported but whether they are relevant at the organismal level remain unknown. The viable yellow agouti mouse () is a powerful epigenetic biosensor model that reports on the DNA methylation status of the locus through the coat color of the animals. Here we show that maternal exposure to rotenone, a potent mitochondrial complex I inhibitor, changes the DNA methylation status of the locus and broadly affects the liver DNA methylome of the offspring. These effects were accompanied by altered gene expression programs that persisted throughout life. Mitochondrial dysfunction was present in the mothers but not in the offspring until 12 months of age, when electron transport and antioxidant defenses were impaired. These results highlight a putative novel role for mitochondria in nuclear epigenetic remodeling during development, raising fundamental questions about the long-term impact of mitochondrial dysfunction to health and disease.