Assistant Professor of Internal Medicine, Adjunct Assistant Professor of Biochemistry, and Adjunct Assistant Professor of Biomedical Engineering
Mitochondria, Heart Failure, ion Channels, Calcium Channels, Mitochondrial Diseases, Voltage-Clamp Electrophysiology, Metabolism, Calcium Imaging, Mitochondrial Calcium Uniporter
We study how cardiac metabolism is altered in heart failure. As contractile function declines following cardiac injury, a well-documented rewiring of metabolism takes place, including a shift towards glycolysis, alterations in mitochondrial metabolism, and an increased tendency towards cardiomyocyte injury. Such rewiring leads to a global decline in ATP synthesis by the end stages of heart failure, when the only therapeutic options are heart transplant or lifelong mechanical support, and the severity of this decline presages mortality. In studying heart failure, we focus on calcium signaling, since this molecule is critical for cardiac contraction, rhythm, and metabolism. In fact, calcium entering the mitochondria potently stimulates ATP synthesis. We hope to define the molecular pathways that control mitochondrial calcium signaling and investigate if pharmacological modulation of these pathways can ultimately prove beneficial in heart failure.
Our current research focuses on two areas:
- Calcium regulation in mitochondrial cardiomyopathies: Mutations affecting mitochondrial function are among the most common forms of inborn errors of metabolism, primarily affecting infants and children. When such mitochondrial dysfunction leads to cardiac involvement, termed the mitochondrial cardiomyopathies, mortality rates increase threefold. In studying animal and cell models of these diseases, we have found that mitochondrial calcium levels are increased and are currently investigating (a) how such regulation occurs, and (b) how such changes affect cardiac function.
- Biophysics of mitochondrial ion channels: Because of their intracellular location, direct assessment of mitochondrial ion channels via classical electrophysiological techniques has been limited. We have overcome this barrier by studying mitoplasts, which are purified mitochondria stripped of their outer membranes. Such mitoplasts can be interrogated via voltage-clamping to allow measurement of ionic currents. Our laboratory is one of the few capable of performing this challenging technique. We use this technique to characterize the behavior of mitochondrial ion channels, including the mitochondrial calcium uniporter, the main portal for calcium entry into the mitochondrial matrix.
For these studies, we have expertise in a range of traditional and novel techniques in mitochondrial biology and calcium signaling, and are happy to share this expertise with our colleagues who are interested in detailed analyses of mitochondrial function or calcium kinetics.
References (Selected Publications)
- Van Keuren AM, Tsai CW, Balderas E, Rodriguez MX, Chaudhuri D, Tsai MF (2020). Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex. Cell Rep, 33(10), 108486.
- Lam PY, Thawani AR, Balderas E, White AJP, Chaudhuri D, Fuchter MJ, Peterson RT (2020). TRPswitch-A Step-Function Chemo-optogenetic Ligand for the Vertebrate TRPA1 Channel. J Am Chem Soc, 142(41), 17457-17468.
- Sommakia S, Houlihan PR, Deane SS, Simcox JA, Torres NS, Jeong MY, Winge DR, Villanueva CJ, Chaudhuri D (2017). Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium. Journal of molecular and cellular cardiology. 113:22-32.
- Chaudhuri D, Artiga DJ, Abiria SA, Clapham DE (2016). Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition. Proc Natl Acad Sci U S A, 113(13), E1872-E1880. PMCID: PMC4822583
- Chaudhuri D, Sancak Y, Mootha VK, Clapham DE (2013). MCU encodes the pore conducting mitochondrial calcium currents. eLife, 2, e00704. PMCID: PMC3673318
- Sancak Y, Markhard AL, Kitami T, Kovacs-Bogdan E, Kamer KJ, Udeshi ND, Carr SA, Chaudhuri D, Clapham DE, Li AA, Calvo SE, Goldberger O, Mootha VK (2013). EMRE is an essential component of the mitochondrial calcium uniporter complex. Science, 342(6164), 1379-82. PMCID: PMC4091629
- Chaudhuri D, Clapham DE (2014). Outstanding questions regarding the permeation, selectivity, and regulation of the mitochondrial calcium uniporter. [Review]. Biochem Biophys Res Commun, 449(4), 367-9. PMID: 24792175