I began my career at the Unversity of St Andrews in Scotland, gaining my Ph.D. in 2006 for research into mitochondrial morphology and dynamics in the model plant Arabidopsis thaliana. On completion of my graduate studies I won a competitive fellowship, giving me the opportunity to experience work in an overseas laboratory. Expanding my horizons, I joined the laboratory of Dr. Richard Youle (NINDS, NIH), where I worked on mitochondrial innate immunity in human and fly cells. In 2009, having enjoyed the switch to a medical-related field, I joined the laboratory of Dr. Michael Sack (NHLBI, NIH). Since joining his research group, I have been investigating the role played by lysine residue acetylation in regulating mitochondrial metabolism. With the support of my mentor, and the exceptional research environment of the NHLBI Divison of Intramural Research, I have been able to make an important step forward in this field. We recently identified the first mitochondrial lysine acetyltransferase (GCN5L1), and showed that it countered the activity of SIRT3 (a lysine deacetylase that was previously the only known regulator of mitochondrial lysine acetylation). We also demonstrated that GCN5L1 regulated mitochondrial respiration and bioenergetic output, indicating that it is an important modulator of mitochondrial metabolism overall. In this K22 Career Development Award application, I propose to use the unique tools available in my mentor's laboratory, and the NHLBI as a whole, to investigate the function of GCN5L1 in mitochondrial metabolism. The NHLBI intramural program provides researchers with excellent facilities (in terms of research space, funding and equipment) and a rich intellectual atmosphere, making it a world-class facility in which to work. During the award I will receive training in proteomics techniques, and then use these to identify both the proteins that are acetylated by GCN5L1, and also the proteins which interact with GCN5L1 to aid its function. With help from my collaborators, both inside and outwith the NHLBI, I will then characterize the function of GCN5L1 in vitro and in vivo. I plan to receive training in mouse handling and safe adenoviral infection techniques, so that I can manipulate GCN5L1 protein levels in mouse models that are relevant to human health. These techniques will be particularly helpful in my goal to investigate the role of GCN5L1 and protein acetylation in mitochondrial turnover. Our initial data suggest that GCN5L1 may be a potent regulator of the systems which control mitochondrial protein degradation, a crucial step in the prevention of multiple disease states. Once my training is complete, I will look to find a research position in the extramural environment, where I can continue to develop this research and begin to build my own laboratory. Once the basic biology of GCN5L1 has been examined, I plan to expand the findings into relevant disease models. The institutional support and superior training available at the NHLBI will be invaluable in the early development of these research plans, and therefore my career as an independent investigator.
Human metabolism consists of numerous interwoven pathways, which are all tightly regulated to prevent the development of metabolic diseases. A powerful new mechanism which regulates the activity of metabolic pathways, called lysine acetylation, was recently discovered. This research project will investigate how lysine acetylation controls the activity of mitochondria, the metabolic power-plant found within our cells, in order to prevent conditions that could lead to the development of metabolic disease.
|Thapa, Dharendra; Stoner, Michael W; Zhang, Manling et al. (2018) Adropin regulates pyruvate dehydrogenase in cardiac cells via a novel GPCR-MAPK-PDK4 signaling pathway. Redox Biol 18:25-32|
|Thapa, Dharendra; Wu, Kaiyuan; Stoner, Michael W et al. (2018) The protein acetylase GCN5L1 modulates hepatic fatty acid oxidation activity via acetylation of the mitochondrial ?-oxidation enzyme HADHA. J Biol Chem 293:17676-17684|
|Scott, Iain; Wang, Lingdi; Wu, Kaiyuan et al. (2018) GCN5L1/BLOS1 Links Acetylation, Organelle Remodeling, and Metabolism. Trends Cell Biol 28:346-355|
|Wang, Lingdi; Scott, Iain; Zhu, Lu et al. (2017) GCN5L1 modulates cross-talk between mitochondria and cell signaling to regulate FoxO1 stability and gluconeogenesis. Nat Commun 8:523|
|Thapa, Dharendra; Zhang, Manling; Manning, Janet R et al. (2017) Acetylation of mitochondrial proteins by GCN5L1 promotes enhanced fatty acid oxidation in the heart. Am J Physiol Heart Circ Physiol 313:H265-H274|
|Stoner, Michael W; Thapa, Dharendra; Zhang, Manling et al. (2016) ?-Lipoic acid promotes ?-tubulin hyperacetylation and blocks the turnover of mitochondria through mitophagy. Biochem J 473:1821-30|
|Kumar, Ajay; Corey, Catherine; Scott, Iain et al. (2016) Minnelide/Triptolide Impairs Mitochondrial Function by Regulating SIRT3 in P53-Dependent Manner in Non-Small Cell Lung Cancer. PLoS One 11:e0160783|
|Scott, Iain; Webster, Bradley R; Chan, Carmen K et al. (2014) GCN5-like protein 1 (GCN5L1) controls mitochondrial content through coordinated regulation of mitochondrial biogenesis and mitophagy. J Biol Chem 289:2864-72|
|Webster, Bradley R; Scott, Iain; Traba, Javier et al. (2014) Regulation of autophagy and mitophagy by nutrient availability and acetylation. Biochim Biophys Acta 1841:525-34|
|Webster, Bradley R; Scott, Iain; Han, Kim et al. (2013) Restricted mitochondrial protein acetylation initiates mitochondrial autophagy. J Cell Sci 126:4843-9|