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Mechanisms of Cigarette Smoke-Induced Mitochondrial Dysfunction in Striated Muscle and Aorta

Cigarette Smoke is a significant cause of morbidity and mortality in the United States, accounting for over 480,000 annual deaths. Of these deaths, the most common cause of mortality in chronic smokers is cardiometabolic diseases. Likewise, a significant portion of smokers experience some form of cardiac, vascular, or metabolic dysfunction throughout their lifetime. More specifically, smoking is shown to induce mitochondrial dysfunction in these tissues, causing an increase in oxidative damage and poor overall health. However, despite the advances in the health outcomes related to cigarette smoke exposure, the mechanisms underlying mitochondrial dysfunction in striated muscle and the vasculature remain largely unexplained. Particularly, no investigations have been conducted to (1) characterize the acute inhibitory effects of cigarette smoke to the mitochondria in these tissues, (2) assess the changes in mitochondrial substrate oxidation with exposure to cigarette smoke, or (3) identify the mechanisms by which cigarette smoke induces deleterious effects on the mitochondrial electron transport chain. Therefore, the purpose of this dissertation is to use high-resolution respirometry to characterize the toxicity of cigarette smoke in the mitochondria of the aorta, heart, and two types of skeletal muscle, determine the capacity for cigarette smoke to induce a shift in mitochondrial carbohydrate- or fatty acid-stimulated mitochondrial respiration, and further investigate the mechanisms by which cigarette smoke impairs the mitochondrial electron transport chain. Herein, we first demonstrate that cigarette smoke-induced inhibition of mitochondrial respiration is tissue-specific and depends on the intrinsic qualities of the mitochondria in each tissue (e.g. morphology) as well as the tissue-specific mitochondrial content. Second, we show that mitochondrial pyruvate oxidation, not fatty acid oxidation, is a primary mechanism for cigarette smoke-induced mitochondrial dysfunction. Third, we further support the hypothesis that mitochondrial complex I is a primary site of smoke-induced mitochondrial dysfunction. However, we also identify the ADP/ATP transporter, ANT, as another site of smoke-induced mitochondrial impairment. Lastly, we discuss the clinical implications of each of these findings as well as future research directions.
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