Abstract
In previous research, we showed that 16-week-old urea transporter B (UT-B) null mice have an atrial-ventricular conduction block, and hypothesized myocardial mitochondrial dysfunction. To investigate the mechanism of this block, we examined the proteomic differences in the myocardial mitochondria of UT-B null and wild-type mice with nanoscale LC-MS/MS. Of 26 proteins clearly downregulated in the UT-B null mice, 15 are involved in complexes I, III, IV, and V of the respiratory chain, which would strongly reduce the activity of the electron transport chain. Excess electrons from complexes I and III pass directly to O2 to generate ROS and deplete ROS-scavenging enzymes. Myocardial intracellular ROS were significantly higher in UT-B null mice than in wild-type mice (p < 0.01), constituting an important cause of oxidative stress injury in the myocardia of UT-B null mice. The mitochondrial membrane potential (ΔΨm) was also lower in UT-B null mice than in wild-type mice (p < 0.05), causing oxidative phosphorylation dysfunction of complex V and insufficient ATP in the myocardial cells of UT-B null mice. HADHA (a trifunctional protein) and HSP60 were also downregulated in the UT-B null myocardial mitochondria. These results confirm that mitochondrial dysfunction underlies the pathogenesis of the atrial-ventricular conduction block in UT-B null mice.