In order to provide a continuous supply of ATP, heart cells contain thousands of mitochondria, which may be a source of, and subject to damage by, oxidative stress. We have found that cardiac mitochondria are organized as a network of oscillators, whose degree of coupling and synchronization is influenced by reactive oxygen species (ROS). Under pathological conditions, e.g. ischemia-reperfusion, either an increase in ROS production, or a decrease in the capacity to scavenge ROS, results in the collapse or oscillation of mitochondrial inner membrane potential throughout the cell, and in clusters of cells in the myocardial syncytium. In this way, mitochondrial dysfunction scales to produce organ level heterogeneity that significantly alters the electrophysiological and contractile properties ofthe heart Over the prior award period, we have established that stabilization of mitochondrial inner membrane potential by pharmacological agents targeting mitochondrial benzodiazepine receptors can prevent post-ischemic arrhythmias and decrease ischemia-reperfusion injury and we have suggested that a specific inner membrane anion channel (IMAC) was the primary target of ROS, independent of the classical permeability transition pore (PTP). In the present proposal we seek 1) to identify the key proteins implicated in the mechanism of mitochondrial ROS-induced ROS release using molecular methods and experiments in isolated cells and mitochondria, 2) to define the main biochemical pathways responsible for scavenging ROS in cardiac mitochondria and their impact on the approach to mitochondrial criticality, 3) to elucidate the mechanisms of mitochondrial-to-nuclear communication via the redox status ofthe cell, and 4) to continue to develop and expand our integrated computational models of excitation-contraction coupling, mitochondrial energetics, and ROS-induced ROS release to the tissue level to understand the mitochondrial origin of cardiac arrhythmias and contractile dysfunction in heart disease.

Public Health Relevance

The project will provide fundamental information about the mechanisms of cell injury, death, and arrhythmias In the context of metabolic stressors, such as ischemia-reperfusion and heart failure. The work will develop a basis for the treatment of cardiovascular diseases focused on preservation of mitochondrial function by uncovering the key targets responsible for oxidative Imbalance in the heart.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL054598-19
Application #
8720555
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Zhou, Lufang; Solhjoo, Soroosh; Millare, Brent et al. (2014) Effects of regional mitochondrial depolarization on electrical propagation: implications for arrhythmogenesis. Circ Arrhythm Electrophysiol 7:143-51
Cortassa, Sonia; O'Rourke, Brian; Aon, Miguel A (2014) Redox-optimized ROS balance and the relationship between mitochondrial respiration and ROS. Biochim Biophys Acta 1837:287-95
Gauthier, Laura D; Greenstein, Joseph L; Cortassa, Sonia et al. (2013) A computational model of reactive oxygen species and redox balance in cardiac mitochondria. Biophys J 105:1045-56
Kembro, Jackelyn M; Aon, Miguel A; Winslow, Raimond L et al. (2013) Integrating mitochondrial energetics, redox and ROS metabolic networks: a two-compartment model. Biophys J 104:332-43
Lloyd, David; Cortassa, Sonia; O'Rourke, Brian et al. (2012) What yeast and cardiomyocytes share: ultradian oscillatory redox mechanisms of cellular coherence and survival. Integr Biol (Camb) 4:65-74
Whelan, Russell S; Konstantinidis, Klitos; Wei, An-Chi et al. (2012) Bax regulates primary necrosis through mitochondrial dynamics. Proc Natl Acad Sci U S A 109:6566-71
Cortassa, Sonia; Aon, Miguel A (2012) Computational modeling of mitochondrial function. Methods Mol Biol 810:311-26
Zhou, Lufang; O'Rourke, Brian (2012) Cardiac mitochondrial network excitability: insights from computational analysis. Am J Physiol Heart Circ Physiol 302:H2178-89
Chen, Ying-Bei; Aon, Miguel A; Hsu, Yi-Te et al. (2011) Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J Cell Biol 195:263-76

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