Dharendra Thapa, PhD

Research Interests

Mitochondrial dysfunction is an important contributing factor in many age-related diseases and is of particular importance in energy-demanding tissues like the heart. Mitochondria supply energy for contractile function via the oxidation of fuel substrates, and complete control of this system is indispensable to maintain cardiac efficiency. Hydroxyacyl-CoA Dehydrogenase (HADHA) and Long Chain Acyl-CoA Dehydrogenase (LCAD) catalyze the oxidation of long chain fatty acids, whereas pyruvate dehydrogenase (PDH) catalyzes glucose oxidation in the heart. Dysregulation of fatty acid oxidation (FAO) and glucose oxidation (GO) is associated with cardiac energy depletion. Despite recent progresses in uncovering the biology underlying age-related diseases, and improvements in research focused on the molecular mechanisms of age-related diseases, our knowledge of the cellular mechanisms that regulate key mitochondrial energy substrate enzymes in the aging heart is greatly underdeveloped. The long-term research goal of our lab is to investigate processes that can regulate the cellular and mitochondrial processes related to cardiac fuel substrate usage to promote a healthy aging process.

One potential mechanism that has been shown to regulate mitochondrial protein function is lysine acetylation, a reversible post-translational mechanism. Our group and several others have shown that lysine acetylation regulates functions of mitochondrial proteins involved in fatty acid oxidation, glucose oxidation and mitochondrial bioenergetics. Specifically, we have shown that a novel mitochondrial acetyltransferase GCN5L1 regulates the function of both FAO, GO and electron transport chain complex proteins. Similarly, Sirt3 is a mitochondrial deacetylase that has been extensively studied for its role in regulating several mitochondrial proteins functions via acetylation. By utilizing genetically modified cardiac KO animal model of mitochondrial acetyltransferase GCN5L1 and deacetylase Sirt3 KO, our lab is in a prime position to genetically manipulate acetylation and examine its effect on cardiac substrate utilization, mitochondrial bioenergetics, and cardiac contractile function of the aged heart. As such, the current experiments in the lab are focused on understanding the role played by mitochondrial acetyltransferase GCN5L1 and deacetylase Sirt3 in aged heart. We aim to investigate: 1) The mechanisms as to how acetylation regulates the activities of FAO and GO proteins in young and old mouse hearts. 2) Investigate how changes in FAO and GO protein acetylation regulate mitochondrial bioenergetics and cardiac contractile function in the aging heart.

These studies will provide us novel insights into the regulatory role of both FAO and GO protein acetylation on mitochondrial bioenergetics and cardiac contractile function in aging heart. Further, the proposed studies will immensely improve our understanding of acetylation mediated regulation of FAO and GO processes in aging. This will significantly close our current knowledge gap on the regulation of fuel substrate usage in the aging heart and may ultimately lead to new therapeutic targets that can prevent the loss of cardiac mitochondrial function in the aging heart.

Some other lab interests involve understanding the role played by acetylation in regulating mitochondrial autophagy, ubiquitin proteasome pathways and balancing the redox milieu in the aged heart.

Grants and Research

Current Grants and Contracts

PI unless otherwise stated

NIH/NHLBI, R00HL146905

• 09/01/2021 - 08/31/24
• Investigating the role of acetylation in mitochondrial bioenergetics and function in the aging heart. The goal of this project is to investigate the role played by lysine acetylation in regulating cardiac substrate utilization and overall cardiac contractile function in the aged heart. Specifically, we will assess the role played by mitochondrial acetyltransferase GCN5L1 in regulating fatty acid and glucose oxidation in the aged heart. 

Publications

Recent Publications in Refereed Journals

1. Thapa D, Bugga P, Mushala BAS, Manning JR, Stoner MW, McMahon B, Zeng X, Cantrell PS, Yates N, Xie B, Edmunds LR, Jurczak MJ, Scott I. GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation. Physiol Rep. 2022 Aug;10(15):e15415. PMID: 35924321
2. Thapa D, Xie B, Mushala BAS, Zhang M, Manning JR, Bugga P, Stoner MW, Jurczak MJ, Scott I. Diet-induced obese mice are resistant to improvements in cardiac function resulting from short-term adropin treatment. Curr Res Physiol. 2022 Jan 25;5:55-62. PMID: 35128468
3. Wu K, Scott I, Wang L, Thapa D, Sack MN. The emerging roles of GCN5L1 in mitochondrial and vacuolar organelle biology. Biochim Biophys Acta Gene Regul Mech. 2021 Feb;1864(2):194598. PMID: 32599084
4. Thapa D, Manning JR, Mushala BAS, Stoner MW, Zhang M, Scott I. Increased fatty acid oxidation enzyme activity in the hearts of mice fed a high fat diet does not correlate with improved cardiac contractile function. Current Research in Physiology. 2020 Dec;3:44-49.
5. Kerr M, Miller JJ, Thapa D, Stiewe S, Timm KN, Aparicio CNM, Scott I, Tyler DJ, Heather LC. Rescue of myocardial energetic dysfunction in diabetes through the correction of mitochondrial hyperacetylation by honokiol. JCI Insight. 2020 Sep 3;5(17):e140326. PMID: 32879143
6. Thapa D, Manning JR, Stoner MW, Zhang M, Xie B, Scott I. Cardiomyocyte-specific deletion of GCN5L1 in mice restricts mitochondrial protein hyperacetylation in response to a high fat diet. Sci Rep. 2020 Jun 30;10(1):10665. PMID: 32606301
7. Manning JR, Thapa D, Zhang M, Stoner MW, Traba J, Corey C, Shiva S, Sack MN, Scott I. Loss of GCN5L1 in cardiac cells disrupts glucose metabolism and promotes cell death via reduced Akt/mTORC2 signaling. Biochem J. 2019 Jun 19;476(12):1713-1724. PMID: 31138772
8. Thapa D, Zhang M, Manning JR, Guimarães DA, Stoner MW, Lai YC, Shiva S, Scott I. Loss of GCN5L1 in cardiac cells limits mitochondrial respiratory capacity under hyperglycemic conditions. Physiol Rep. 2019 Apr;7(8):e14054. PMID: 31033247
9. Thapa D, Xie B, Manning JR, Zhang M, Stoner MW, Huckestein BR, Edmunds LR, Zhang X, Dedousis NL, O’Doherty RM, Jurczak MJ, Scott I. Adropin reduces blood glucose levels in mice by limiting hepatic glucose production. Physiol Rep. 2019 Apr;7(8):e14043. PMID: 31004398
10. Thapa D, Xie B, Zhang M, Stoner MW, Manning JR, Huckestein BR, Edmunds LR, Mullett SJ, McTiernan CF, Wendell SG, Jurczak MJ, Scott I. Adropin treatment restores cardiac glucose oxidation in pre-diabetic obese mice. J Mol Cell Cardiol. 2019 Apr;129:174-178. PMID: 30822408

Recent Conference Abstracts

1. Mushala B, Xie B, McMahon B, Thapa D, Jurczak M, Scott I. Loss of GPR19 drives obesity-related cardiac dysfunction in mice. American Physiology Summit 2023. Long Beach, CA. 2023 Apr. DOI: https://doi.org/10.1152/physiol.2023.38.S1.5696147
2. Scott I, Thapa D, Bugga P, Mushala B, Manning J, Stoner M, McMahon B, Zeng X, Cantrell P, Yates N, Xie B, Edmunds L, Jurczak M. BS3 GCN5L1 promotes diastolic dysfunction by inhibiting cardiac pyruvate oxidation. British Cardiovascular Society Annual Conference. Manchester, United Kingdom. 2022 June. DOI: http://dx.doi.org/10.1136/heartjnl-2022-BCS.183