Reducing embryonic mtDNA copy number alters epigenetic profile of key hepatic lipolytic genes and causes abnormal lipid accumulation in adult mice

Abstract

Adverse fetal environment, in particular a shortage or excess of nutrients, is associated with increased risks of metabolic diseases later in life. However, the molecular mechanisms underlying this developmental origin of adult diseases remain unclear. Here, we directly tested the role of mitochondrial stress in mediating fetal programming in mice by enzymatically depleting mtDNA in zygotes. mtDNA‐targeted plasmid microinjection is used to reduce embryonic mtDNA copy number directly, followed by embryo transfer. Mice with reduced zygote mtDNA copy number were born morphologically normal and showed no accelerated body weight gain. However, at 5 months of age these mice showed markedly increased hepatic lipidosis and became glucose‐intolerant. Hepatic mRNA and protein expressions of peroxisome proliferator‐activated receptor α (Pparα), a key transcriptional regulator of lipid metabolism, were significantly decreased as a result of increased DNA methylation in its proximal regulatory region. These results indicate that perturbation of mitochondrial function around the periconceptional period causes hypermethylation and thus suppressed expression of PPARα in fetal liver, leading to impaired hepatic lipid metabolism. Our findings provide the first direct evidence that mitochondrial stress mediates epigenetic changes associated with fetal programming of adult diseases in a mammalian system.

Maternal zinc alleviates tert-butyl hydroperoxide-induced mitochondrial oxidative stress on embryonic development involving the activation of Nrf2/PGC-1α pathway

“…Moreover, targeted metabolomics analysis reveals that 600 μmol/L BHP in ovo inhibited the TCA cycle characterized by the decreased fumarate, L -malic acid and succinate, but enhanced the glycolysis characterized by the increased D -glucose, 6-phosphate, dihydroxyacetone phosphate, and lactate. The bio-maker of mtDNA copy is more vulnerable due to the absence of the protection of the electron transport chain [ 35 ]. The results indicate that oxidative damage reduces the mtDNA copy number of ATP6 associated with the impaired mitochondrial biosynthesis.…”

Increased mtDNA mutation frequency in oocytes causes epigenetic alterations and embryonic defects

“…Mitochondria are crucial in providing intermediate metabolites necessary to modify epigenetic marks, which in turn can integrate environmental stimuli to fine-tune gene expression and affect later health. It has been reported that mtDNA copy number reduction in the embryo causes hypermethylation of Pparα in fetal liver, leading to impaired hepatic lipid metabolism in adult mice [ 58 ]. In combination with our data, these observations suggest that mitochondria genome may act as a receiver and integrator that links environmental exposures in early life to health in adults.…”