Mitochondria are critical for respiration but in the liver, they also accommodate high capacity anaplerotic/cataplerotic pathways that process metabolic precursors for gluconeogenesis, lipogenesis, and other biosynthetic pathways. Our lab investigates how metabolic pathways in the mitochondria are altered by obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD), and how flux through mitochondrial pathways contributes to the pathology of these diseases. For example, during NAFLD, mitochondria produce reactive oxygen species (ROS) that damage hepatocytes, trigger inflammation, and exacerbate insulin resistance. By discovering what, how, and why metabolic pathways contribute to or protect against this damaging process, we aim to improve strategies for preventing and treating the cellular damage caused by obesity and diabetes. Recent data from our lab indicates that during fatty liver disease and hepatic insulin resistance, the loss of metabolic control over biosynthesis and the related energetic workload in mitochondria may contribute to collateral oxidative stress and inflammation. References Satapati S, Kucejova B, Duarte JAG, Fletcher JA, Reynolds L, Sunny NE, et al. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. JCI. 2015; In Press (online Nov. 15, 2015). Satapati S, Sunny NE, Kucejova B, Fu X, He TT, Mendez-Lucas A, Shelton JM, Perales JC, Browning JD, Burgess SC. Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J Lipid Res. 2012;53(6):1080-92. PMID: 22493093. Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 2011;14(6):804-10. PMID: 22152305. Sunny NE, Satapati S, Fu X, He T, Mehdibeigi R, Spring-Robinson C, Duarte J, Potthoff MJ, Browning JD, Burgess SC. Progressive adaptation of hepatic ketogenesis in mice fed a high-fat diet. Am J Physiol Endocrinology and Metabolism. 2010;298(6):E1226-35. PMID: 20233938. Satapati S, He T, Inagaki T, Potthoff M, Merritt ME, Esser V, et al. Partial resistance to peroxisome proliferator-activated receptor-alpha agonists in ZDF rats is associated with defective hepatic mitochondrial metabolism. Diabetes. 2008;57(8):2012-21. PMID: 18469201.