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Madesh Muniswamy, PhD

Madesh Muniswamy , PhD

 

Associate Professor, Biochemistry

Associate Professor, Cardiovascular Research Center

Associate Professor, Center for Translational Medicine

Telephone:  215-707-5465

Fax:  215-707-9890

Email: madeshm@temple.edu

 

Department of Biochemistry

Cardiovascular Research Center

Center for Translational Medicine

 

Educational Background:

 

BS, Biochemistry, University of Madras, India, 1991

 

MS, Biochemistry, University of Madras, India, 1993

 

PhD, Bio-Medical Sciences, The Wellcome Trust Research Laboratory, 1998

 

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Research Interests:

 

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.

 

Muniswamy research interestes


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.

 

During these years, my lab made three seminal discoveries using comprehensive high-throughput screening. For instance, the observation in 1961 by two independent groups insisted that the power house of the cell, the mitochondrion, acts as a sponge and takes up huge amounts of external Ca2+ through an unknown pathway later named as a uniporter. Since then, researchers believed that mitochondria have the capacity to take up enormous amounts of Ca2+ through this uniporter to regulate cellular Ca2+ homeostasis. Nevertheless, the proposed concept of a mitochondrial Ca2+ set-point (year 1978) suggested that mitochondria in cells at rest maintain very low levels of Ca2+ by an unknown mechanism. My laboratory demonstrated that the mitochondrial inner membrane protein MICU1 interacts with and guards the mitochondrial uniporter channel pore subunit MCU from Ca2+ permeation (Cell, October 2012). Without this mechanism, mitochondria accumulate excessive Ca2+ resulting in oxidative stress and increased sensitization to cell death in several cell types including endothelial cells. Additionally, our Nature Cell Biology (highlights in Nature Reviews Molecular Cell Biology) paper published in December 2012 identified a novel mitochondrial inner membrane protein that we named as MCUR1 (mitochondrial Ca2+ Uniporter Regulator 1). We found that MCUR1 positively regulates MCU (channel pore). Notably, these molecules have been sought for over five decades. Two years ago, my laboratory discovered the ROS sensing role of STIM1, distinct from its Ca2+ sensing function (Journal of Cell Biology 2010). Based on the role of STIM1 as a ROS sensor in addition to its ER Ca2+ sensing effect, I generated endothelial specific STIM1 KO mice that were protected against LPS-induced vascular inflammation, a finding that was published in the current issue of Journal of Clinical Investigation, 2013 (Commentary and JCI impact). In summation, our very recent discovery demonstrated that a mitochondrial resident transmembrane protein Mitochondrial Ca2+ Uniporter Regulator 1 (MCUR1) is essential for Mitochondrial Ca2+ Uniporter (MCU)-mediated mitochondrial Ca2+ uptake (Nature Cell Biology, 2012). These components were unknown for over five decades. We also identified the molecular component (Mitochondrial Ca2+ Uptake 1; MICU1) that controls the mitochondrial Ca2+ uptake “set point”, a concept known but uncharacterized for over thirty years (Cell, 2012). Identification of these major Ca2+ signaling components in my laboratory uniquely places us in a privileged position to investigate the mitochondrial bioenergetics both in physiology and in major pathological settings including cardiovascular, cancer, neurodegenerative and metabolic diseases.

 

 

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Lab:

 

mm lab

 

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professional organizations:

 

  • American Society for Biochemistry and Molecular Biology
  • American Association for the Advancement of Science
  • American Association for Cancer Research
  • American Society of Microbiology

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