The mitochondron is the ?powerhouse of the cell?; oxidative metabolism in the mitochondria supplies ~95% of ATP consumed by the heart, and mitochondrial respiration is also the major source of reactive oxygen species (ROS) in the cell. The heart is a high energy-consuming organ; mitochondrial dysfunction is widely observed in heart failure. To understand its pathogenic role, many studies have focused on the impairment of mitochondrial oxidative metabolism that leads to reduced ATP supply or increased ROS production during the development of heart failure. More recently mitochondria-triggered cell death has been observed in animal models of ischemic-reperfusion injury and/or heart failure but its connection with mitochondrial bioenergetics has been poorly understood. To date, no therapeutic strategies targeting mitochondrial dysfunction (e.g., either ATP, ROS or mitochondria-mediated cell death) have been translated successfully into clinical practice. In the last funding period we demonstrated in a murine model of cardiac-specific mitochondrial Complex I deficiency that impaired oxidative phosphorylation caused an increase in NADH/NAD+ ratio and impaired mitochondria protein deacetylation, resulting in a greater susceptibility to stress. Importantly, we found increases of NADH/ NAD+ ratio and protein acetylation (LysAc) in the heart of mouse models and patients of heart failure. Expanding the NAD+ pool by pharmacological or genetic approaches normalized the changes and blunted the progression of heart failure in these mice. Conversely, increased LysAc due to the loss of mitochondria localized sirtuin deacetylase, Sirt3, led to increased susceptibility to diseases. These observations collectively suggest that NADH/NAD+ ratio and redox sensitive LysAc are key links between mitochondrial dysfunction and cellular stress response. They also add to the rapidly growing enthusiasm of targeting NAD+ levels to treat a variety of pathological conditions. However, the molecular mechanisms underlying the pathogenic role of increased LysAc or the benefits of expanding the intracellular NAD+ pool are poorly understood. We hypothesize that mitochondrial dysfunction caused by chronic stress or signals through an imbalance of the NADH/NAD+ ratio to alter protein modification and cell metabolism resulting in a state of high vulnerability to stress. While the central role of NAD(H) redox state in the vicious circle presents an excellent opportunity for therapy it also presents a challenge. Intracellular NAD(H) are compartmentalized; the size and the NADH/NAD+ ratio in each subcellular pool are tightly controlled as the NADH/NAD+ sensitive functions are essential to the vitality of the cell. The biological consequences of targeting such a critical system need to be fully defined for its ultimate therapeutic application. Here we have identified 3 key areas for testing our hypothesis and advancing the concept of targeting NADH/NAD+ dependent disease mechanisms: 1) tools to assess subcellular NAD(H) pools; 2) system view of NADH/NAD+ sensitive changes of protein interactions and metabolic network; 3) long term therapeutic effects.
The proposed study will determine the role of NAD+/NADH ratioin regulating protein acetylation and mitochondrial function in the heart. By manipulating NAD+ level in the failing hearts, we seek to identify and target novel NAD+/NADH sensitive mechanisms for heart failure therapy.
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