Using chemistry to understand and prevent superoxide production in cardiac ischemia-reperfusion injury

When
3:30-4:30pm | Thursday 2 March 2023

Where
Charles Perkins Centre Auditorium
The University of Sydney

Abstract

Mitochondrial redox metabolism is central to the life and death of the cell. Consequently  mitochondrial function and dysfunction have turned out to be so central to biomedical questions as diverse as innate immunity, oxygen sensing and response to viral infections. Therefore we want to know more about how mitochondria function and go wrong in vivo as well as developing therapies focused on preventing mitochondrial damage. In both these areas the development of biological chemistry approaches is a clear way to both develop new probes of mitochondrial function in vivo and in coming up with new therapies. For example, mitochondrial production of free radicals and subsequent oxidative damage  has long been known to contribute to damage in conditions such as ischaemia-reperfusion (IR)  injury in stroke and heart attack. Over the past years we have developed a series of mitochondria-targeted compounds designed to ameliorate or determine how these changes occur. I will outline some of this work, which  suggested that ROS production in IR injury during stroke  was mainly coming from complex I. This led us to investigate the mechanism of the ROS production and using a metabolomic approach we found that the ROS production in IR injury  came from the accumulation of  succinate during ischaemia that then drove mitochondrial ROS production by reverse electron transport at complex I during reperfusion. This surprising mechanism led up to develop further new therapeutic approaches to impact on the damage that mitochondrial ROS do in pathology and also to explore how mitochondrial ROS can act as redox signals. I will discuss how these unexpected mechanisms may lead to redox and metabolic  signals from mitochondria in a range of conditions under  both healthy and pathological conditions.