Mitochondria play critical role in modulating cell function through energy metabolism, reactive oxygen species (ROS) generation, calcium (Ca2+) regulation, and cell fate determination. Mitochondria dysfunction often accompanies and underlies the pathogenesis of disease. Recently, we developed a genetically encoded superoxide indicator and discovered transient mPTP opening events coupled with bursting ROS production, named superoxide flashes, in intact cell of various tissues including cardiac myocyte (Figure 1 and online video: http://www.cell.com/supplemental/S0092-8674%2808%2900769-1). This breakthrough strongly supports the existence of physiologically relevant mPTP activities and highlights the regulation of microdomain ROS signaling. Based on these discoveries, the long-term goal of the lab is to understand how mitochondria integrate ROS, Ca2+ and permeability transition pore (mPTP) signaling to impact cell function under normal and disease conditions, especially in the cardiovascular system. Current research efforts are focused on the following three projects:
Figure 1. Discovery of superoxide flash in single mitochondria of intact adult cardiac myocyte. The superoxide indicator, cpYFP is targeted to mitochondrial matrix and fluorescence images taken by dual-wavelength excitation at 488 nm and 405 nm. A superoxide flash is highlighted in upper panel and its time course is shown in the lower traces (Wang et al, 2008, Cell 134:279-290).
Figure 2. Diagram shows the hypothesis of physiological mPTP regulation and function. Mitochondrial Ca2+ uptake ultimately triggers mPTP opening, which in turn releases ROS to modulate local signaling.
Figure 3. Diagram showing multi-level analysis of mitochondrial superoxide flash in health and disease. Indicator bearing transgenic mice will facilitate the evaluation of superoxide flashes under different disease conditions and at different levels from individual cells to intact tissues and to living animals.