Sunny lab: Uncovering the Secrets of the Mitochondria
Mitochondria, considered the powerhouse of our cells, integrates nutrient metabolism and energy production to maintain normal cell function. Optimal mitochondrial function promotes growth and development, while mitochondrial dysfunction is a key feature of the metabolic diseases including obesity, diabetes and fatty liver. Sunny lab focuses on identifying strategies to enhance mitochondrial function targeted towards a) healthy growth and development and b) treatment of metabolic diseases. Sunny lab utilizes a variety of in vitro cell culture systems with in vivo animal models to tease out mechanisms regulating the mitochondrial function. These animal models include diet-induced/ transgenic mice models to probe mitochondrial dysfunction during metabolic disease and novel developing chicken embryo/ neonatal chick model to probe metabolic transition of mitochondrial networks during growth and development. Sunny lab profiles mitochondrial metabolism utilizing a combination of techniques including the state-of-the-art stable isotope based metabolic flux analysis, targeted metabolomics and tissue protein and gene profiling.
Project 1: To identify key mechanisms to attenuate unregulated mitochondrial metabolism in the liver, and thus provide a better paradigm to treat fatty liver disease and type 2 diabetes mellitus (T2DM). Hepatic insulin resistance is characterized by fat accumulation which progressively transform to nonalcoholic steatohepatitis (NASH), with inflammation and fibrosis. This major public health problem affects over 70% of the obese and T2DM patients. Defects in mitochondrial oxidative metabolism are central to the etiology of fatty liver disease. Uregulated activity of mitochondrial pathways can be a chronic source of free radicals and oxidative stress. We believe that mechanisms to abate unregulated mitochondrial metabolism will be of major benefit towards alleviating oxidative stress and inflammation during fatty liver disease.
Project 2: Regulation of mitochondrial metabolism and lipogenesis in embryonic to post-hatch chicken. The late term embryonic chicken (>day-16 of incubation) derives >90% of its energy through oxidation of yolk lipids in the liver. Furthermore, metabolic transition of an embryo to a neonatal chick is also associated with up-regulation of new lipid synthesis. Interestingly, despite this metabolic milieu favoring high rates of mitochondrial lipid oxidation and the dramatic up-regulation of lipid synthesis in the liver, the chicken embryo manages to efficiently transition and develop into a healthy hatchling. Thus, we believe that the embryonic to post-hatch transition period in chicken, is a novel model to investigate mechanisms balancing fat oxidation by the mitochondria and new lipid synthesis. Our long term goal is to develop a ‘dual-intent’ research program utilizing this model to a) probe the etiology of fatty liver disease and T2DM, and b) identify mechanisms for improving the metabolic efficiency during embryonic-neonatal transition: a question which is also of significant interest to poultry production and management.
Project 3: Modulation of mitochondrial function by branched chain amino acids (BCAAs) Branched chain amino acids (leucine, isoleucine, valine) are among the most responsive amino acids to insulin. Consequently disturbances in BCAA metabolism has been described in several insulin resistant states including obesity, diabetes mellitus, kidney and liver dysfunction. Defects in intracellular BCAA oxidation, particularly by muscle and adipose tissue is considered to be a major contributor to elevated plasma BCAAs during insulin resistance. These global changes in BCAA degradation and higher systemic BCAAs can impact the nutrient milieu available to the liver and alter mitochondrial metabolism. Degradation of BCAA proceeds through several acyl-CoA intermediates with the terminal products being acetylCoA, ketones and metabolic intermediates of TCA cycle. Further, BCAAs serve as major precursors for the synthesis of alanine and glutamine through transamination, mainly in the muscle and adipose tissue. The end products of BCAA degradation and nonessential amino acids are potential anaplerotic substrates (fuels) for hepatic TCA cycle. More importantly, BCAA have the ability to signal through a variety of molecular mediators of mitochondrial metabolism including mTORC1, AMPK, PGC1α and PPARα. Understanding mechanisms connecting BCAAs and hepatic mitochondrial function, in order to modulate growth and development and also to manage metabolic diseases, is our major objective .