The mitochondrial network, as a source and victim of oxidative stress has become a dominant player at the origin of many important diseases, among which cardiomyopathy in diabetic and obese patients ranks as one of the most relevant. Our long-term goal is to identify the critical mechanistic steps involved in the production of mitochondrially-derived reactive oxygen (ROS) and nitrogen (RNS) species in common diseases, such as diabetes, obesity, and heart failure. In the emerging view of the mitochondrion as a key signaling organelle in which ROS and RNS fulfill critical physiological roles, we aim to achieve a more comprehensive and quantitative understanding of its role in the (patho)physiology of diabetes related metabolic, contractile, and electrical dysfunction. The main hypotheses of the current proposal are that: 1) Cardiac myocytes from diabetic animals are more susceptible to mitochondrial dysfunction caused by oxidative/nitrosative stress in response to hyperglycemia, and 2) the diabetic heart is more susceptible to the incidence of conduction disturbances, arrhythmias and contractile dysfunction because of its compromised metabolic status. We base our hypotheses on the following observations: 1) the mitochondrial network of a cardiomyocyte is extremely sensitive to environmental perturbations once a threshold level of ROS is attained, leading to a cell-wide collapse of the mitochondrial membrane potential (??m) and myocyte inexcitability;2) ROS and RNS bioavailability are regulated through common mechanisms;3) oscillations of ??m can be readily prevented by exogenous or endogenous ROS scavengers, or nitric oxide production inhibitors;4) oscillations of mitochondrial energetics drive oscillations of surface KATP current and action potentials, affecting the incidence of post-ischemic arrhythmias and contractile dysfunction in the intact heart.

Public Health Relevance

Diabetes is caused by a deficiency in the secretion or action of insulin, affecting >150 million individuals worldwide and nearly 6% of the US population. A recent study by the World Health Organization estimates that those numbers will grow to 366 million by 2030. Achieving the aims of the present study will lead to a better understanding of how mitochondrial dysfunction affects the incidence and severity of cardiac complications among diabetics, and will identify novel targets for therapeutic strategies against this common disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Kaludercic, Nina; Carpi, Andrea; Nagayama, Takahiro et al. (2014) Monoamine oxidase B prompts mitochondrial and cardiac dysfunction in pressure overloaded hearts. Antioxid Redox Signal 20:267-80
Kaludercic, Nina; Mialet-Perez, Jeanne; Paolocci, Nazareno et al. (2014) Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol 73:34-42
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
Sivakumaran, Vidhya; Stanley, Brian A; Tocchetti, Carlo G et al. (2013) HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox-dependent phospholamban oligomerization. Antioxid Redox Signal 19:1185-97
Xie, Chaoqin; Biary, Nora; Tocchetti, Carlo G et al. (2013) Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs. Am J Physiol Heart Circ Physiol 304:H916-26
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
Cortassa, Sonia; Aon, Miguel A (2012) Computational modeling of mitochondrial function. Methods Mol Biol 810:311-26
Kaludercic, Nina; Carpi, Andrea; Menabo, Roberta et al. (2011) Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. Biochim Biophys Acta 1813:1323-32
Wei, An-Chi; Aon, Miguel A; O'Rourke, Brian et al. (2011) Mitochondrial energetics, pH regulation, and ion dynamics: a computational-experimental approach. Biophys J 100:2894-903

Showing the most recent 10 out of 24 publications