Dr. Harper’s laboratory investigates the importance of mitochondria in health and disease. Mitochondria are remarkable organelles within eukaryotic cells, and are referred to as the cellular powerhouses due to their important role in typically providing ~90% of a cell’s ATP. The Harper laboratory’s research focuses on the mechanisms through which mitochondria transduce the energy substrates, like glucose and fatty acids, into ATP, and this field of research is referred to as ‘bioenergetics’. Cellular energy metabolism becomes disordered in many disease states, and disordered energy metabolism can cause many types of disease. Our research has implications for a better understanding of, and possible novel treatment strategies for diseases including diabetes, obesity, cardiomyopathies, neurodegenerative diseases and cancers.
Energy transduction is far-from-perfect in cells, and the mechanisms underlying inefficiencies are of particular interest in our group. The inefficiency caused by the mitochondrial uncoupling proteins (UCPs) can be extremely high in the case of the major UCP found in brown adipose tissue, where energy is released as heat rather than captured as ATP, and this is very important in thermoregulation in many mammals. UCP3, which is found in skeletal muscle, brown adipose tissue and the heart is also of great interest. The molecular control of the UCPs (e.g., glutathionylation) has been a central question in many of our studies.
Inefficiencies in energy conversion are also related to the loss of electrons/ reducing equivalents during the processes of fuel oxidation. When these electrons interact with oxygen, this can result in the formation of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. At low levels, ROS are important signaling molecules in cells; however, at high levels they can damage proteins, DNA and lipids. Glutathione redox plays a major role in keeping ROS at safe levels within cells, and several projects in the Harper lab focus on glutathione metabolomics and redox control.
Another mechanism that is apparently very important for ‘efficient’ and ‘safe’ energy transduction involves the formation of mitochondrial supercomplexes, which are higher order multi-complexes of proteins in the oxidative phosphorylation (OXPHOS) system. Our research has demonstrated that supercomplex formation is disordered in skeletal and cardiac muscle in type 2 diabetes, for example. Ongoing research examines how supercomplex formation is controlled so that these mechanisms can be targeted to prevent and treat disease.
Finally, the overall capacity of a cell to produce ATP is affected by the synthesis of mitochondria (mitochondriogenesis), mitochondrial dynamics (fusion and fission) and mitochondrial degradation (through autophagy and mitophagy) – and thus these also are important areas of investigation in the lab.
Mitochondrial bioenergetics is a hub for many physiological and pathological mechanisms, and our research team welcomes trainees at all levels.