Electron Leak Through Partial Loss Of NDUFA13 In Mitochondrial Complex I Attenuates Ischemia-Reperfusion Injury Via Dimerized STAT3

Electron leak from mitochondria can react with oxygen to generate reactive oxygen species(ROS)that either serve as signals for triggering various physiological process or cause severe tissue and/or cell damage.Interestingly,downregulated NDUFA13,an accessory subunit of complex ?,has been shown to be able to render the tumor cells more resistant to apoptosis.In the present study,therefore,we aimed to investigate whether and how NDUFA13 downregulation in the heart protects against I/R injury.We generated Myh6Cre+ERTamNDUFA13flox/flox mice and demonstrated that heterozygous NDUFA13 knockout,i.e.Myh6Cre+ERTamNDUFA13flox/-mice exhibited normal cardiac morphology and function at normal state,and were more resistance to apoptosis when exposed to ischemia-reperfusion(I/R)injury,resulting in a significant decrease in infarct size(IS).Interestingly,a decrease in substrate driven oxygen consumption of complex ? was observed,however,a compensation for the total oxygen consumption by complex ? and complex ? was observed,which was associated with an increase in residual oxygen consumption(ROX)when complex ? inhibitor,antimycin A,was used.Interestingly,an increase in H2O2 level at normal state was observed in heterozygous knockout mice which was associated with much less superoxide generation at reperfusion compared with normal control.Importantly,this increase in H2O2 was responsible for STAT3 dimerization,which can be abolished when ROS were scavenged by NAC.The role of ROS mediated STAT3 dimerization in the protection against I/R injury was further confirmed in NDUFA13 and STAT3 double heterozygous knockout mice where the protection offered by NDUFA13 downregulation was absent.