Iain Scott, PhD
Iain Scott, PhD
Assistant Professor of Medicine,
Dr. Scott received his Ph.D. in 2006 from the University of St. Andrews in the United Kingdom, for research into the machinery regulating mitochondrial morphology and dynamics. He then moved to the National Institutes of Health in Bethesda MD, where he worked with Dr. Richard Youle on mitochondrial-based apoptosis and innate immunity. In 2009, he moved to the laboratory of Dr. Michael Sack in the NHLBI Cardiovascular and Pulmonary Branch, where he worked on mitochondrial metabolism and lysine acetylation. In August 2014, Dr. Scott joined the University of Pittsburgh School of Medicine as an Assistant Professor in the Division of Cardiology.
Mitochondria are ubiquitous organelles, playing a vital role in bioenergetics, metabolite biosynthesis and overall cellular homeostasis. Their functional activity needs to be tightly regulated, as evidenced by the growing number of pathologies in which mitochondrial dysfunction is either a causative or compounding factor. Mitochondria are highly susceptible to environmental stresses, with overnutrition being a particular problem in the developed world. A high caloric intake leads to a surge in available acetyl-CoA (the final breakdown product of fats, carbohydrates and proteins in the mitochondria), which cannot be utilized for energetic or synthetic purposes. This excess acetyl-CoA is instead used as the substrate for acetylation (a post-translational modification of lysine residues), which acts to reduce the activity of a vast number of mitochondrial metabolic enzymes (Figure 1).
Our work focuses on the intrinsic mechanisms that regulate mitochondrial protein acetylation, and how this fundamental alteration affects organelle function at the cellular and tissue level. In particular, we are interested in the coordination between acetylation levels and mitophagy, a quality control mechanism that mediates the removal of dysfunctional mitochondrial organelles. We have recently discovered that GCN5L1, a mitochondrial protein that promotes lysine acetylation, regulates the transcriptional machinery of mitophagy (Figure 2).
Our future work will aim to elucidate the pathways that link nutritional inputs, GCN5L1-mediated lysine acetylation, and mitochondrial quality control systems. These findings will then be translated into studies involving metabolically-relevant disease models, such as heart failure and diabetes, in order to achieve a better understanding of the role played by dysfunctional mitochondria in these processes.
Scott, I., Webster, B.R., Chan, C.K., Okonkwo, J.U., Han, K., Sack, M.N. (2014) GCN5-like protein 1 (GCN5L1) controls mitochondrial content through coordinated regulation of mitochondrial biogenesis and mitophagy. Journal of Biological Chemistry 289: 2864-2872 (PMID: 24356961)
Webster, B.R., Scott, I., Traba, J., Han, K., Sack, M.N. (2014) Caloric Restriction, Acetylation and the Regulation of Autophagy and Mitophagy. Biochimica et Biophysica Acta: Molecular and Cell Biology of Lipids 1841: 525-534 (PMID: 24525425)
Webster, B.R., Scott, I., Stevens, M.V., Lu, Z., Li, J.H., Han, K., Sack, M.N. (2013) Restricted mitochondrial protein acetylation initiates mitochondrial removal by autophagy. Journal of Cell Science 126: 4843-4849 (PMID: 24006259)
Scott, I., Webster, B.R., Li, J.H., Sack, M.N. (2012) Identification of a molecular component of the mitochondrial acetyltransferase programme; a novel role for GCN5L1. Biochemical Journal 443: 655-661 (PMID: 22309213)
Scott, I. (2012) Regulation of cellular homeostasis by reversible lysine acetylation. Essays in Biochemistry 52: 13-22 (PMID: 22708560)
Webster, B.R., Lu, Z., Sack, M.N., Scott, I. (2012) The role of sirtuins in modulating redox stress. Free Radical Biology and Medicine 52: 281-290 (PMID: 22085655)
Bao, J., Scott, I., Lu, Z., Pang, L., Dimond, C.C., Gius, D., Sack, M.N. (2010) SIRT3 is regulated by nutrient excess and modulates hepatic susceptibility to lipotoxicity. Free Radical Biology and Medicine 49: 1230-1237 (PMID: 20647045)
Scott, I., Youle, R.J. (2010) Mitochondrial Fission and Fusion. Essays in Biochemistry 47: 85-98 (PMID:20533902)
Scott, I. (2009) Degradation of RIG-I following cytomegalovirus infection is independent of apoptosis. Microbes and Infection 11: 973-979 (PMID: 19591957)
Lu, Z., Scott, I., Webster, B.R., Sack, M.N. (2009) The Emerging Characterization of Lysine Residue Deacetylation on the Modulation of Mitochondrial Function and Cardiovascular Biology. Circulation Research 105: 830-841 (PMID: 19850949)