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. Our lab is currently utilizing multiple approaches, including confocal imaging and in vitro and in vivo gene overexpression and knockdown models, to elucidate how individual mitochondrion integrates respiration, reactive oxygen species (ROS) production, calcium regulation and dynamics under physiological conditions. Further, we are studying whether dysregulation of these functions in individual mitochondria contributes to cardiovascular, neurodegenerative and metabolic diseases.

One focus of the lab is the fundamental role of mitochondrial calcium in the healthy and failing heart. We found that, in the healthy heart, mitochondria take up and accumulate calcium during excitation-contraction coupling. Besides a global role of activating multiple metabolic enzymes, mitochondrial calcium also triggers transient permeability transition (tMPT) in individual mitochondrion to accelerate electron transport chain (ETC) activity and ROS production. The latter provides compartmentalized ROS signal that promotes SR calcium release. Thus, mitochondrial calcium not only supports the energetics and pumping function of the heart but also participates in local signaling. Pressure overload or chronically elevated catecholamine level induces heart failure, which is accompanied by compromised respiration and calcium handling in individual mitochondria.

A new direction in the lab is to explore new regulatory roles of mitochondrial dynamic proteins in the heart. Mitochondrial dynamism in the heart is relatively less active compared to other tissues, yet mitochondrial dynamic proteins such as Mfn1/2, OPA1 and DRP1 are highly abundant in the heart. Genetic disruption of these fission/fusion proteins exerts dramatic heart phenotype with the underlying mechanism still at large. We found that DRP1 exhibits a novel function to maintain physiologically relevant tMPT opening and respiration in individual mitochondria. DRP1 seems to be an early responsive factor activated by various stresses and mediates a broad range of regulatory functions of the cardiac mitochondria.

Other ongoing projects include role of defective mitochondrial ETC in the development of cardiovascular and neurodegenerative diseases, metabolic remodeling of the myocardium in obesity and diabetes, and the role of tMPT in neurodegeneration.

Current Lab Members

Previous Lab Members

  • Nicolas Gutierrez Cortes, PhD
  • Shangcheng Xu, PhD
  • Guohua Gong, PhD
  • Xiaoyun Liu, PhD
  • Yan Wang, MD

Contact Information

Mitochondria and Metabolism Center
850 Republican St., Room N121
Seattle, WA 98109-8057
Phone: 206-685-4765
Fax: 206-616-4819
Email: Wang Wang

Employment Opportunities

Wang Lab - Post Doctoral Fellowship Position