Cardiac resynchronization therapy (CRT) is an effective clinical heart failure therapy;though how it works at the myocardial level has been largely unknown. An eariy flnding was that CRT improved chamber-level energetic efficiency, but our work during the prior funding period shows a central role for mitochondria and ATP production. DHF and CRT affect the mitochondrial subproteome by speciflcally altering proteins in cellular redox control and oxidative phosphorylation (OxPhos) pathways, manifested by protein quantity and post-translational modiflcations (PTMs) in the mitochondria. For several important targets, such as the mitochondrial ATP synthase (complex V), we have already made fundamental new discoveries about phosphorylation-dependent regulation. Several of the OxPhos complexes can be organized into high molecular weight supercomplexes which can influence global mitochondrial structure and funcflon. This organizaflon is altered in DHF and CRT and seems to be, in part, regulated by speciflc phosphorylaflon events. Additionally, we have found several ROS/RNS-related PTMs occur on mitochondrial proteins and that CRT can blunt these changes, probably by improving the function of antioxidant/scavenger pathways. As such, our underlying hypothesis is that CRT converts the mitochondrial subproteome to a protected phenotype, reversing detrimental DHF-induced protein alterations that regulate key functions to improve ATP production and redox balance. Use of always synchronous failure and an alternative CRT model further strengthens our ability to hone in on changes from resynchronization.
Aim 1 focuses on the remodeling of mitochondrial OxPhos protein complexes by CRT which improves the assembly and funcflon of respiratory supercomplexes.
Aim 2 invesflgates the modificaflon and regulaflon of mitochondrial proteins by ROS/RNS and their effects on oxidaflon phosphorylation in DHF and CRT hearts.
While Aim 3 compares the intramitochondrial phosphorylation of mitochondrial proteins via speciflc responses to activation of PKA, PKC and PKG and their regulaflon during DHF and CRT. In summary. Project 3 uses a large number of proteomic tools to analyze, characterize and quantify the PTMs and pathways behind the CRT-induced improvements to the failing heart, speciflcally focusing on the proteins of the oxidaflve phosphorylaflon subproteome. This data will drive the physiological and biochemical experiments on isolated enzymes and mitochondria which, with the help of computational models of integrated cell behavior, allowing us to further elucidate the underlying molecular phenotype that drives CRT improvements.

Public Health Relevance

Project 3 will provide important new understanding of how cardiac resynchronization therapy changes the quantity and PTM status of OxPhos protein complexes and supercomplexes driving both function and structural changes. Our research will provide the mechanism for how CRT acts as a metabolic therapy

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Barth, Andreas S; Kumordzie, Ami; Tomaselli, Gordon F (2016) Orchestrated regulation of energy supply and energy expenditure: Transcriptional coexpression of metabolism, ion homeostasis, and sarcomeric genes in mammalian myocardium. Heart Rhythm 13:1131-9
Barth, Andreas S; Tomaselli, Gordon F (2016) Gene scanning and heart attack risk. Trends Cardiovasc Med 26:260-5
O'Rourke, Brian; Liu, Ting; Foster, D Brian (2016) Seeing the Forest for the Trees. Circ Res 119:1170-1172
DeMazumder, Deeptankar; Kass, David A; O'Rourke, Brian et al. (2015) Cardiac resynchronization therapy restores sympathovagal balance in the failing heart by differential remodeling of cholinergic signaling. Circ Res 116:1691-9
Chung, Heaseung Sophia; Murray, Christopher I; Venkatraman, Vidya et al. (2015) Dual Labeling Biotin Switch Assay to Reduce Bias Derived From Different Cysteine Subpopulations: A Method to Maximize S-Nitrosylation Detection. Circ Res 117:846-57
Kaushik, Gaurav; Spenlehauer, Alice; Sessions, Ayla O et al. (2015) Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart. Sci Transl Med 7:292ra99
Kwon, Chulan; Tomaselli, Gordon F (2015) Coins of the realm in atrioventricular junction development. Circ Res 116:386-8
Kirk, Jonathan A; Kass, David A (2015) Cellular and Molecular Aspects of Dyssynchrony and Resynchronization. Card Electrophysiol Clin 7:585-97
Melman, Yonathan F; Shah, Ravi; Danielson, Kirsty et al. (2015) Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis: A Translational Pilot Study. Circulation 131:2202-2216
Tomaselli, Gordon F (2015) Introduction to a compendium on sudden cardiac death: epidemiology, mechanisms, and management. Circ Res 116:1883-6

Showing the most recent 10 out of 123 publications