Targeting mitochondria, the engine of life, for treating type 2 diabetes, cancer, and aging
When the engine of your car is broken, you know your car has run its course and it is time to buy a new one. Mitochondria are the engine of eukaryotic cells, and the engine of (eukaryotic) life. Like a car engine, which converts chemical energy stored in gasoline to mechanical energy (through violent oxidative reactions, combustion), mitochondria are responsible for converting the majority of chemical energy stored in glucose, lipids, amino acids to energy that can be directly used by machineries that power life. This happens through an elegant sequential events in mitochondria. First, the metabolites of glucose, lipids, amino acids are oxidized inside mitochondria (matrix). The chemical energy released is first used by electron transport chain on the mitochondrial inner membrane to pump out protons, generating a proton gradient. When the protons flow back across mitochondrial inner membrane through an ATP synthase, they drive the synthesis of ATP, the universal energy currency. Just like combustion in a car engine, which may cause dangerous overheating and damages to other components of a car, the oxidative reactions and electron transport chain reactions in mitochondria are the major source of reactive oxygen species (ROS), the most important intrinsic factors to cell damages.
As the engine that powers eukaryotic life, mitochondria are at the center of the most important medical challenges of our time, such as obesity and type 2 diabetes, cancer, neurodegenerative diseases, and aging. Reduction of mitochondrial metabolic capacity (or a relative insufficiency comparing to excessive intake of food) as we age is the major cause of obesity, insulin resistance, and type 2 diabetes. Accumulation of oxidative damage due to mitochondrial ROS is the major etiological factor of cancer. Oxidative stress as a result of aberrant production of mitochondrial ROS is an important causal factor of many neurodegenerative diseases such as Parkinson’s disease. And an overall deterioration of mitochondrial capacity and function is the cause of aging.
My laboratory is interested in developing practical approaches for modification of mitochondrial activity and function, for the treatment of type 2 diabetes, cancer, other aging related diseases, and even aging itself. One focus is the development of safe mitochondrial uncouplers as investigational drug leads. Mitochondrial uncoupling is a process by which protons enter mitochondrial matrix in a way that bypasses the ATP synthase. As a result, mitochondrial uncoupling leads to reduction in energy efficiency and increase in oxidative capacity, an excellent combination for effective burning away of extra calorie, which is a best solution of obesity and type 2 diabetes. Our recent discovery of using a safe mitochondrial uncoupler, which is a modified formulation of an FDA approved drug, for treating type 2 diabetes (Nature Medicine 20, 1263-1269 (2014)) provided proof-of-principle for this approach. Current projects in this direction include developing new mitochondrial uncouplers for other metabolic diseases including obesity and fatty liver disease (NASH).
Reduction of mitochondrial proton gradient through mitochondrial uncoupling would reduce the resistance of mitochondrial electron transport chain, thereby reducing ROS leakage. This could be a potential powerful strategy for cancer prevention, ageing delaying, as well as treating neurodegenerative diseases caused by aberrant mitochondrial ROS production. We are enthusiastically seeking funding for research in this area.
Finally, my laboratory has extensive experience and expertise in study of mitophagy. Mitophagy is the physiological process of removing damaged mitochondria through targeted autophagic degradation. Mitophagy is critical for the maintenance of a healthy population of mitochondria in cells. It is expected that enhancement in mitophagy would promote mitochondrial health and might be the ultimate solution to many diseases of mitochondria origin. My laboratory is engaging basic research in this area, using a powerful system identified in my laboratory, the adipocyte differentiation system. White adipocytes have a unique cellular structure, in which over 99% of the cell volume is occupied by a gigantic lipid droplet, while the rest of cell structure, including nucleus, occupies little space. The mature white adipocytes are developed from pre-adipocytes, which are fibroblast-like and contain abundant cytoplasmic components such as mitochondria. Drastic cytoplasmic reorganization and cytoplasm elimination occur during adipocyte differentiation. Tremendous mitochondrial biogenesis occurs in the early phase of adipogenesis, which is required for lipogenesis. We found that massive induction of mitophagy is triggered in later stages of adipogenesis, which is responsible for eliminating mitochondria and other cytosolic components, making room for lipid droplet (PNAS, 106 (47): 19860-5, 2009, and Autophagy, 5(8):1118-30, 2009). This well-characterized model system provides an excellent opportunity to identify the molecular components in mitophagy and the regulatory pathways.