Heart failure affects six million people in the United States, and is listed as a causative factor in more than 10% of deaths. The development of heart failure is linked to several risk factors (including coronary artery disease, obesity and diabetes), which are increasingly prevalent in Western societies due to diet and other lifestyle choices. While clinical outcomes have improved over the last three decades, there remain gaps in our knowledge surrounding the cellular mechanisms that regulate cardiac function. One such gap, and the scientific focus of this application, is the regulation of fuel substrate utilization by mitochondria in the heart. Mitochondria provide 95% of the energy required by healthy hearts to maintain contractility, and defects in mitochondrial bioenergetic activity lead to cardiac energy starvation and heart failure. Mitochondria in the heart normally provide this energy through the oxidation of fatty acids; however, during heart failure cardiomyocytes switch to other fuels like glucose. While changes in cardiac substrate preference in heart failure have been well characterized, we do not fully understand the cellular mechanisms that regulate this process. Our data, and the current literature, show that mitochondrial function is regulated by lysine acetylation, a post-translational modification that uses fuel-derived acetyl-CoA as a substrate. We recently identified GCN5L1 as the first component of the mitochondrial acetyltransferase machinery, and showed that GCN5L1-mediated acetylation controls mitochondrial bioenergetics in vitro. The objective of this proposal is to understand how GCN5L1 acetylation impacts mitochondrial bioenergetics in the heart, and to investigate how dysregulated energy substrate utilization can lead to mitochondrial dysfunction, cardiac energy depletion and heart failure. We will achieve this objective by addressing the following questions: (1) How does GCN5L1 control fatty acid oxidation in healthy hearts? (2) How does GCN5L1 control substrate utilization during heart failure progression? (3) How does GCN5L1 regulate cardiac mitochondrial degradation? To answer these questions, we will use a series of in vivo murine heart failure models and in vitro cell culture studies, combined with metabolic, proteomic and biochemical techniques, to examine the biology of GCN5L1. We expect that this series of experiments will provide important new insights on mitochondrial energy substrate regulation, and will highlight GCN5L1 as a crucial component in the control of metabolic fuel choice, bioenergetics and mitochondrial turnover in the heart.
Heart failure affects six million people in the United States, and is characterized by the declining ability of cardiac muscle to meet the energetic demands of the heart. In these studies we will investigate a novel mechanism that regulates the bioenergetic output of cardiac muscle, in order to understand where energy deficiencies occur. By understanding these fundamental cellular systems, we will be in a better position to tackle the energetic causes of heart failure, and potentially identify new therapeutic targets for clinicians to investigate in future studies.
| 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 |
| 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 |
| 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 |
