Wang Laboratory

PI: Wang Wang, MD, PhD

Research Description

Mitochondria play a central role in cell bioenergetics, free radical signaling, redox homeostasis, ion regulation, and cell fate determination. Mitochondria dysfunction often accompanies and underlies the pathogenesis of disease. Through developing a genetically encoded superoxide indicator, we discovered bursting superoxide production events, named superoxide flashes, in single mitochondria of intact cells including cardiac myocytes, skeletal muscles, neurons and cell lines, as well as in perfused heart and in vivo ( Superoxide flash serves as a composite function of mitochondria and can be used as a biomarker for evaluating mitochondrial dysfunction in a real time manner and in vivo. Further, studies on the regulation of superoxide flashes revealed that mitochondrial respiration and transient permeability transition pore opening (tMPT) are tightly coupled under physiological conditions.

Our lab is currently utilizing multiple approaches, including confocal imaging, transgenic and gene knockout mice models, virus mediated in vitro and in vivo gene expression and knockdown, to elucidate how multiple mitochondrial functions are integratively regulated under physiological conditions and how mitochondrial dysfunction contributes to cardiovascular, neurodegenerative and metabolic diseases.

One focus of the lab is on the intracellular signaling pathways and therapeutic targets of heart failure. Pressure overload induced heart failure exhibited compromised single mitochondrial dysfunction prior to contractile dysfunction. We identified that defective calcium handling is a critical mechanism for the impaired mitochondrial respiration in heart failure. In the healthy heart, mitochondria take up and accumulate calcium during excitation-contraction coupling. Mitochondrial calcium stimulates energy generation through activating multiple enzymes and triggering tMPT to accelerate electron transport chain (ETC) activity and superoxide flash production. Such a positive feedback mechanism is critical for the sustainability of the pumping function of the heart, and is also highly susceptible to stresses that cause heart failure.

Other ongoing projects in the lab include studying the role of mitochondrial ETC deficiency in excessive reactive oxygen species (ROS) production, identifying the intracellular signaling pathways in modulating myocardial metabolism and mitochondrial respiration, and elucidating the metabolic and mitochondrial pathways associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Parkinson's disease.