Integrative Investigation of Mitochondrial Dysfunction

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DESCRIPTION (provided by applicant): The mitochondrial membrane potential (DYm) is a key regulator of mitochondrial function that drives the production of ATP and reactive oxygen species (ROS). Dynamic oscillations of DYm in isolated cardiac myocytes can result in electrophysiological oscillations that significantly impact myocyte function and lead to inexcitability at the cellular level. However, technical challenges in measuring spatio-temporal gradients in metabolic function within the intact heart have precluded a direct investigation of the functional consequences of unstable mitochondrial properties in mediating global oxidative stress and associated mechano-electrical dysfunction. Since the original submission of this proposal, we have developed a semi-quantitative imaging technique for measuring the spatio-temporal dynamics of DYm with subcellular resolution at the organ level. In this proposal, we extend our measurements to perform ROS imaging in order to investigate if ROS-induced ROS-release is a mechanism of DYm instability within the intact normal and hypertrophied heart. Previous work identified the mitochondrial benzodiazepine receptor (mBZR) as a potentially attractive candidate for preventing arrhythmias. However, pharmacological interventions that target mBzR significantly impact contractile and calcium handling properties by directly suppressing the L-type calcium current. This may limit the clinical utility of these agents and raises important questions regarding the direct relevance of DYm stability per se in altering mechano-electrical properties. We will directly address this important issue by using a gene transfer approach that targets mBZR expression. This will uncover the role of IMAC through mBZR overexpression in altering mitochondrial, mechanical, and electrical properties. From a practical perspective, these studies will help us determine if modulation of mBZR expression is a viable strategy for altering mechano-electrical properties. If so, future gene silencing to mimic IMAC blockade may be warranted. PUBLIC HEALTH RELEVANCE: This proposal is dedicated to: 1) developing integrative imaging techniques to uncover mechanisms by which altered metabolic properties in cardiac hypertrophy predispose to electrical and contractile dysfunction; and 2) using gene transfer approaches to modulate electrical and contractile properties by regulating mitochondrial function through the expression levels of a key receptor.