RhoA and mitophagy

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Dr. Shigeki Miyamoto is directing this project in collaboration with the Brown lab.  

 

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Mitochondria are essential organelles involved in energy metabolism. Preservation of mitochondrial quality is critical in ensuring cell survival, and even more so in cardiomyocytes which have limited regenerative capacity. Mitochondria damaged in response to stress release reactive oxygen species (ROS) and other toxic molecules which induce cell death. Mitophagy (mitochondria-specific autophagy) eliminates these damaged mitochondria and prevents cell death. Mitophagy is facilitated by mitochondrial fission which segregates damaged mitochondria for elimination.

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Although there is great interest in developing therapeutic interventions targeting mitochondrial quality control mechanisms to treat ischemic heart disease, intracellular signaling pathways regulating these mitochondrial quality control mechanisms have been elusive and the ideal targets are still unclear. RhoA, a small GTPase regulating diverse cellular functions, is activated in response to stress including ROS increase in the heart. We have designed studies to test the hypothesis that RhoA activation in cardiomyocytes serves an adaptive function by engaging two separate signaling pathways that regulate mitophagy and mitochondrial fission to prevent cardiac damage against stress such as myocardial infarction and aging.

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Selected Publications:

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Shirakabe A, Fritzky L, Saito T, Zhai P, Miyamoto S, Gustafsson AB, Kitsis RN, and Sadoshima J. Evaluating mitochondrial autophagy in the mouse heart. J. Mol. Cell. Cardiol. 2016, 92:134-9