Tissue Specific Impact of Organic Cations on Mitochondrial Energy Transduction

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Drug side effects and more severe drug induced injuries are complex multifactorial processes that pose a significant barrier to prescription drug use and design. The gastrointestinal and hepatobiliary systems are the ‘first pass’ of drug absorption and metabolism, resulting in disproportionate occurrences of side effects/toxicities in these tissues. Additionally, highly perfused tissues, such as the heart, are also disproportionately implicated. Mounting evidence suggests that a substantial proportion of common drugs (~10-40%) can modulate mitochondrial energy transduction, highlighting this organelle as an important area of focus. Mitochondria are central to cellular function, as such, small modifications of mitochondrial energy transduction can lead to dramatic changes ranging from altered physiological function to cell death. Emerging evidence suggests that mitochondria from different tissues exhibit bioenergetic phenotypic characteristics that are intrinsically related to the metabolic demands of their source tissue. Additional evidence suggests that mitochondria isolated from different tissues are sensitive to chemical interactions in distinct ways. This is important because this effect may be a significant component of drug side effects/toxicities and may even contribute to the primary mechanisms of action for some drugs. In our preliminary testing we discovered that a common class of drugs, organic cations (i.e. those that carry a net positive charge at physiological pH), accumulate at high concentrations in mitochondria and dose dependently alter mitochondrial respiration and membrane potential in a manner that is (in many cases) tissue specific. From those observations we developed the central hypothesis that that tissue specific mitochondrial bioenergetic phenotypes predispose interactions between organic cation drugs and the respiratory system. To test this hypothesis, we will implement an integrative workflow that leverages our unique mitochondrial phenotyping capabilities in conjunction with mitochondrial proteomics and multivariate statistical analysis to complete the following research aims: 1.) Quantitatively define mitochondrial structure-function relationships in gastrointestinal, hepatic, and cardiac tissues. 2.) Test for tissue specific interactions using a representative panel of organic cation drugs and define specific protein targets associated with the interactions. The completion of these aims will address a critical knowledge gap pertaining to the functional and structural correlates that drive drug interactions with the mitochondrial energy transduction system in tissues that are disproportionately affected by drug side effects/toxicity. The accompanying training plan is designed to prepare the PI (Dr. Schmidt) for a transition to an independent academic faculty position in a medical school. The training will be carried out in a state-of-the-art multi-disciplinary institute (East Carolina Diabetes and Obesity Institute), with the support of a diverse mentoring team with collective experience in physiology, bioenergetics, biochemistry, and applied mathematics.