Considering that the stores of ATP within the heart are sufficient to maintain contraction for only about 50 beats, it is clear that cardiac function directly depends on a high level of energy production that can be achieved only by continual mitochondrial substrate oxidation. Disruption of mitochondrial oxidative phosphorylation as a consequence of ischemia, reperfusion, toxic drugs or cardiac disease leads to cell injury and death, with the latter manifested as either necrosis or apoptosis. While there has been intense investigation of factors involved in the induction of injury or protection from it, as well as of the signaling pathways switched on during programmed cell death, there is very little information available about the earliest triggers of mitochondrial dysfunction. The central theme of this proposal is that metabolic stress initiates changes in mitochondrial inner membrane ion permeability with different degrees of severity that depend upon the opening of particular classes of inner membrane ion channel. Emerging evidence suggests that channels such as the cyclosporin-sensitive permeability transition pore, the Ca uniport and the mitochondrial ATP-sensitive potassium channel play fundamental roles in the life and death of the ardiomyocyte. In addition to these energy dissipating pathways, other classes of inner membrane ion channel exist, but have undefined functional roles. In this proposal, we will test the specific hypothesis that mitochondrial inner membrane anion channels are the primary mediators of redox oscillations, waves and metabolic signaling both within and between cardiomyocytes in the syncytium. Using conventional imaging, the unique capabilities of two-photon laser scanning microscopy, and advanced patch-clamp techniques, we will investigate the physiological mechanisms of mitochondrial communication and metabolic propagation from the level of the single mitochondrion to the intact heart. Understanding this important, but heretofore understudied, problem will ultimately lend insight into all aspects of cardiac pathophysiology.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Ma, Junfeng; Banerjee, Partha; Whelan, Stephen A et al. (2016) Comparative Proteomics Reveals Dysregulated Mitochondrial O-GlcNAcylation in Diabetic Hearts. J Proteome Res 15:2254-64
Tocchetti, Carlo G; Stanley, Brian A; Sivakumaran, Vidhya et al. (2015) Impaired mitochondrial energy supply coupled to increased H2O2 emission under energy/redox stress leads to myocardial dysfunction during Type I diabetes. Clin Sci (Lond) 129:561-74
Zhou, Lufang; Aon, Miguel A; Almas, Tabish et al. (2010) A reaction-diffusion model of ROS-induced ROS release in a mitochondrial network. PLoS Comput Biol 6:e1000657
Aon, Miguel Antonio; Cortassa, Sonia; Akar, Fadi Gabriel et al. (2006) Mitochondrial criticality: a new concept at the turning point of life or death. Biochim Biophys Acta 1762:232-40
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Cortassa, Sonia; Aon, Miguel A; Winslow, Raimond L et al. (2004) A mitochondrial oscillator dependent on reactive oxygen species. Biophys J 87:2060-73
O'Rourke, Brian (2004) Evidence for mitochondrial K+ channels and their role in cardioprotection. Circ Res 94:420-32
Cortassa, Sonia; Aon, Miguel A; Marban, Eduardo et al. (2003) An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. Biophys J 84:2734-55
Aon, Miguel A; Cortassa, Sonia; Marban, Eduardo et al. (2003) Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes. J Biol Chem 278:44735-44
Sasaki, N; Sato, T; Marban, E et al. (2001) ATP consumption by uncoupled mitochondria activates sarcolemmal K(ATP) channels in cardiac myocytes. Am J Physiol Heart Circ Physiol 280:H1882-8

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