Alternative Oxidase as Rescue-Mechanism for Mitochondrial Dysfunction in Heart Failure

• Applicant: Dr. Christina Schenkl
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421969070

The mitochondrial electron transport chain (ETC) consists of protein complexes that transfer electrons from NADH/FADH2 to oxygen thereby pumping protons out of the matrix. The backflow of these protons through complex V results in the generation of ATP. A disturbance of electron flow is linked to mitochondrial dysfunction that is related to contractile dysfunction. An alternative oxidase (AOX) that functionally exists only in lower organisms is activated when electron transport is blocked. It bypasses complexes III and IV by transferring electrons to oxygen directly. Thus, the production of reactive oxygen species (ROS) and ATP is reduced. After the transfer into animal models and human cell cultures, a protective effect of AOX was demonstrated in various pathologies. AOX improved the survival of LPS-induced inflammation in mice, alleviated locomotive defects in a model for Parkinson’s disease in Drosophila melanogaster and induced resistance against the ETC toxin antimycine. These results suggest protective effects of AOX in other clinically relevant pathologies. We demonstrated a link between ETC- and contractile dysfunction in a rat model of cardiac pressure overload. The proteome was altered, the activity of the ETC complexes was reduced and the emergence of ROS was heavily increased. We now aim to examine the effects of AOX in cardiac pressure overload. In recently generated AOX-transgenic and in wild type rats, cardiac pressure overload will be induced by transverse aortic constriction. In parallel to survival, cardiac function will be measured by echocardiography after 6 and 10 weeks of pressure overload and cardiac mitochondria will be isolated. Their respiratory capacity, complex activity and ROS-production will be measured. We expect that AOX prevents cardiac dysfunction and improves survival during chronic pressure overload presumably associated with reduced ROS production. These mechanistic analyses of mitochondrial function will set the stage for our further research activities. AOX bears the potential for the generation of new therapeutic options in heart failure.

• DFG Programme: Research Grants