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Madesh

Contact

210-450-8249

muniswamy@uthscsa.edu

Programs

M.D./Ph.D. in South Texas Medical Scientist Training Program
M.S. in Immunology & Infection
Ph.D. in Integrated Biomedical Sciences
Physiology and Pharmacology

Departments & Divisions

Department of Medicine
Janey & Dolph Briscoe Division of Cardiology

Currently seeking M.S. & Ph.D. students.

Madesh Muniswamy, MS, PhD

Long Endowed Tenured Professor in Medicine

Division of Cardiology

Mitochondrial metabolism in health and disease, ion channels, oxidative stress, molecular signaling research

My laboratory is an integrated molecular, cell and biochemistry laboratory studying mitochondrial physiology, calcium signaling, and redox biology in cell function. Our 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; Highlights Nature Reviews Molecular Cell Biology, Cell Reports 2016). In another study, we identified the molecular component (Mitochondrial Ca2+ Uptake 1; MICU1) that controls mitochondrial Ca2+ uptake “set-point” a concept known over thirty years (Cell 2012 and Cell Reports 2013). These components were unknown for over five decades. MICU1 and MCUR1 negatively and positively control the mitochondrial Ca2+ uniporter pore submit (MCU) activity under resting and active state, respectively. MCU interacts with MICU1 and MCUR1 independently and forms MCU complex in the mitochondrial inner membrane. Dysregulation of mitochondrial Ca2+ uptake have been linked to numerous cellular dysfunction including chronic oxidative burden, autophagy and sensitization for cell death (Science Signaling 2015). Therefore, it is reasonable to speculate that [Ca2+]m overload in environmental stress conditions could lead to increased mROS levels, thereby altering proliferation and differentiation.

Recently, we revealed that loss of MCU resulted in cell survival against hypoxia (Cell Reports 2015). Conversely, deletion of MCU in vasculature offered perturbation of cell proliferation and migration (Cell Reports 2016). Our collaborative effort provided the first structural insights into the regulation of MCU and avenues to the development of MCU blockers that control the cell death (Cell Chemical Biology 2016). Our discovery published in Molecular Cell 2017 (previews) reveals for the first time the bifunctional role for MCU as an ion channel and mitochondrial ROS sensor. Given the critical importance of mitochondrial Ca2+ and MCU interactome, we hypothesize that mitochondrial Ca2+ overload elicits mitochondrial permeability transition pore opening and necrosis. Using unbiased RNA interference-based (RNAi) screen to identify genes that modulate Ca2+ and ROS-induced opening of the PTP, we identified a necessary and conserved role of spastic paraplegia 7 (SPG7). Our studies demonstrated that the IMM resident SPG7 promotes PTP opening, and the regulatory component CypD interacts with and activate SPG7 to induce death following Ca2+ and oxidative stress (Molecular Cell 2015). We propose that SPG7 is the major “hub” of the PTP complex and interacts with a network of proteins to form the functional PTP complex. 

Based on these findings, we have generated CRISPR/Cas9-mediated in vitro deletion of SPG7 caused a remarkable amount of mitochondrial Ca2+ retention capacity with sustained m during Ca2+ overload and oxidative stress. In another past studies, we discovered STIM1 as a ROS sensor besides its canonical ER Ca2+ sensing role (Journal of Cell Biology 2010, Nature Chemical Biology 2012, Nature Reviews Molecular Cell Biology 2012, Journal of Clinical Investigation 2013 and Science Signaling 2015). Several of our discoveries have been chosen for Faculty of 1000. Additionally, our recent collaborative effort revealed the role of mitochondrial Na+/Ca2+ exchanger in Ca2+ homeostasis and cell viability (Nature 2017). My laboratory also explores cutting-edge optical imaging-based methods to address major questions pertaining to cytosolic and mitochondrial signaling. 

Although we established the RNAi based screening approach for identifying the MCU and PTP complex components, we recently adapted high through-put CRISPR/Cas9-based screen to identify the mitochondrial shape transition (we referred here after MIST), that is independent of fission or fusion. We also test our in vitro discovery work in in vivo model systems (conditional knockout, CRISPR/Cas9-mediated knock-out and knock-in). The anticipated outcome of this work will significantly enhance our knowledge on the compendium of major mitochondrial set-points and sensors in health and disease.

Related diseases: Cardiovascular, inflammation, cancer metabolism, acute and chronic kidney diseases, sepsis

Techniques: NAi and CRISPR/Cas9  high throughput screening, molecular, cell and biochemical techniques, confocal and super-resolution imaging, metabolomics