The Stat transcription factors play pivotal roles in controlling the expression of genes involved in immune responses, cell transformation and maintaining homeostasis. Published results from this lab demonstrate that there is a pool of Stat3 that is localized in the mitochondria (mitoStat3) where it functions to control cellular respiration both in cells and in cardiac tissue. Preliminary results with a transgenic mice that express Stat3 that is targeted heart mitochondria indicate that it the transgenic protein protects hearts from ischemia induced decreases in the activity of complex I of the electron transport chain, production of reactive oxygen species (ROS) from mitochondria and release of cytochrome C from the mitochondria. Preliminary results in this proposal also define a new function of Stat1 as a repressor of mitochondrial gene expression. In addition, Stat1 represses the transcription of nuclear RNAs that encode components of the electron transport chain. It appears that the actions of Stat1 might antagonize the effects of Stat3 in regulation of mitochondrial homeostasis as well as their well knows opposing actions on cell growth and inflammation. Experiments are proposed to define the contribution of mitoStat3 to the cardio-protective effects of this transcription factor in acute and chronic models of heart injury. Since the mechanisms by which Stat1 represses mitochondrial transcription leading to decreased mitochondria function appear to oppose the effects of mitoStat3, we will examine if mitochondrial targeted Stat3 transgenes show enhanced protection in a Stat1-/- background. Completion of these studies will elucidate a mitochondria-nuclear signaling network that is regulated by Stat3's location in the both the nucleus and mitochondria.

Public Health Relevance

Heart disease is one of the primary causes of mortality and morbidity in the United States. The transcription factor Stat3 plays a major role in maintaining normal heart function, and loss of Stat3 either in mice or humans causes severe cardiac dysfunction, especially under conditions of stress. In this proposal we will determine the contribution to heart function of a small pool of Stat3 that is located in the mitochondria and regulates oxidative metabolism, with the goal of better understanding of how Stat3 regulates respiration, providing a new target that can be the manipulated to maintain cardiac health under conditions of stress such as heart attacks.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Anderson, Vernon
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Virginia Commonwealth University
Schools of Medicine
United States
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Meier, Jeremy A; Hyun, Moonjung; Cantwell, Marc et al. (2017) Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduce mitochondrial ROS production. Sci Signal 10:
Sisler, Jennifer D; Morgan, Magdalena; Raje, Vidisha et al. (2015) The Signal Transducer and Activator of Transcription 1 (STAT1) Inhibits Mitochondrial Biogenesis in Liver and Fatty Acid Oxidation in Adipocytes. PLoS One 10:e0144444
Meier, Jeremy A; Larner, Andrew C (2014) Toward a new STATe: the role of STATs in mitochondrial function. Semin Immunol 26:20-8
Ross, Thomas; Szczepanek, Karol; Bowler, Elizabeth et al. (2013) Reverse electron flow-mediated ROS generation in ischemia-damaged mitochondria: role of complex I inhibition vs. depolarization of inner mitochondrial membrane. Biochim Biophys Acta 1830:4537-42
Zhang, Qifang; Raje, Vidisha; Yakovlev, Vasily A et al. (2013) Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. J Biol Chem 288:31280-8
Szczepanek, Karol; Lesnefsky, Edward J; Larner, Andrew C (2012) Multi-tasking: nuclear transcription factors with novel roles in the mitochondria. Trends Cell Biol 22:429-37
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