Madesh Muniswamy , PhD
Assistant Professor, Biochemistry
Assistant Professor, Cardiovascular Research Center
Assistant Professor, Center for Translational Medicine
Department of Biochemistry
Cardiovascular Research Center
Center for Translational Medicine
Mitochondria are biological engines which convert nutrients into a chemical energy that we call ATP. Under certain conditions aberrant mitochondrial function leads to oxidative stress. Oxidative stress is commonly associated with cellular dysfunction during inflammatory conditions, and leads to the development of ischemic injury and sepsis. My laboratory has been applying novel approaches to identify the mechanisms by which superoxide anion (O2·-), a reactive oxygen species (ROS), selectively potentiates pathophysiological endothelial signaling during oxidative stress. Recently, our lab discovered a unique role for O2·- in perturbation of endothelial Ca2+ homeostasis. Specifically, O2·- led an elevation in intracellular calcium [Ca2+]i via inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3R) on the endoplasmic reticulum, resulting in mitochondrial dysfunction and endothelial apoptosis. Our lab has also developed a model in which O2·- can stimulate endothelial signaling independent of inflammatory cytokines and other paracrine factors. To translate this in vitro model and test our hypothesis in vivo, we have developed means to image endothelial signaling in both lung slices and intact organs. Based on these novel approaches, we are currently focusing on the role of O2·- in endothelial homeostasis and endoplasmic reticulum (ER) Ca2+ signaling.
We have also utilized whole-genome shRNA screening to identify candidate molecules that promote lung cell death and chronic obstructive pulmonary disease (COPD) in response to cigarette smoke, inflammation and infection. COPD is the fourth most-prevalent chronic disease in the United States, and is largely caused by smoking. Lung cell injury and death in COPD likely results from a variety of stressors including cigarette smoke, bacterial pathogens and cytokines like interferon g. In turn, lung cell injury and death are believed to underlie COPD exacerbations and progression of the disease. Our lab has identified several previously undescribed candidate molecules involved in cell death during COPD.
Our research also focuses on mitochondrial physiology and mitochondrial dysfunction. Structural, biochemical, and functional abnormalities of mitochondria are widely believed to be important pathogenic factors that underlie ischemic or hypoxic cell injury. Functional impairment of mitochondria contributes to many human diseases including myocardial infarction, stroke, cancer, aging and neurodegeneration. Mitochondrial depolarization occurs following Ca2+ overload, reactive oxygen species (ROS) overproduction, cyclophilin D-dependent permeability transition pore (PTP) opening, pro-apoptotic Bcl-2 family protein outer membrane permeabilization and dissipation of the proton gradient by microbial toxins. For the first time, our studies elucidated a mode of mitochondrial depolarization that is independent of cyclophilin D, Bcl-2 family proteins, and high amplitude swelling. We have termed this mode of mitochondrial dysfunction proton-dependent mitochondrial depolarization (PDMD), and are currently pursuing its mechanism(s).