Mitochondrial DNA Fragmentation Impairs Endothelial Function In Zucker Lean Rats

Abstract

Mitochondrial (mt) oxidative stress is implicated in vascular dysfunction in the metabolic syndrome (MS), a risk factor for ischemic heart disease. We observed increased mt‐oxidative stress in aortae of Zucker Obese Fatty rats (model of human MS), and endothelial dysfunction in microvessels. Because mt‐oxidative stress is associated with excessive production of mt‐ROS and these species can induce mtDNA fragmentation, we tested the hypotheses that mt‐DNA fragmentation is responsible for endothelial dysfunction and that a manifestation of mt‐DNA fragmentation is decreased energy supply in the vascular wall. Accordingly, mitochondrial‐targeted exonuclease III (Mt‐tat‐ ExoIII) was utilized to fragment mt‐DNA in lean rats treated with Mt‐tat‐ExoIII (80 μg/day, iv for 3 days). This treatment produced endothelial dysfunction (impaired endothelial relaxation to acetylcholine) and increased mt‐ROS levels (mitoSox fluorescence). Dilation to nitroprusside was not impaired suggesting smooth muscle function was not altered. In endothelial cell cultures, mt‐tat‐ExoIII increased O2 consumption. This increase appeared to be uncoupled to energy production because phosphorylation of the energy senor, AMP‐kinase was elevated, suggesting decreased ATP levels. Taken together, our study demonstrates the importance mitochondrial DNA integrity in modulating mitochondrial function and bioenergetics.