Investigating novel mitochondrial mechanisms of obesity pathogenesis

Obesity causes mitochondrial dysfunction, disrupting lipid homeostasis, adipogenesis, and energy expenditure. The mechanisms underlying mitochondrial dysfunction in obesity are not fully understood. The proposed research will test a novel mechanism to restore mitochondrial function and mitigate metabolic disease caused by obesity. This plan centers on rhodoquinone (RQ), a previously unknown mammalian metabolite that my lab discovered in preliminary work to be enriched in mouse and human adipose tissues. RQ carries electrons in the mitochondrial electron transport chain (ETC) on a noncanonical path whereby fumarate, instead of O2, is the electron acceptor (Valeros et al., In revision). The fundamental role of the RQ/fumarate pathway in adipogenesis, and its therapeutic potential in obesity have never been studied. Preliminary data reveal that RQ levels rise specifically in the adipose depots of obese mice, and that providing RQ to differentiating adipocytes drives lipid accumulation. Moreover, treating mice with RQ during diet-induced obesity profoundly reduces fatty liver, suggesting that reprograming the ETC to the RQ/fumarate pathway improves systemic lipid handling. These preliminary data inspired the overarching hypothesis that adipocytes engage the RQ/fumarate ETC as a defense mechanism during obesity, rewiring mitochondrial metabolism to enable storage of excess lipids. Moreover, we anticipate that further elevating RQ during obesity onset will improve lipid storage in adipose tissue, reduce ectopic lipid deposition, and consequently mitigate metabolic disease. To address these hypotheses, the first aim will elucidate the mechanism by which the RQ/fumarate ETC circuit drives lipid accumulation during adipogenesis. Specifically, this aim will establish the point of differentiation that adipocytes reprogram their ETC to the RQ/fumarate pathway and measure its impact on mitochondrial functions. Additionally, this aim will test how RQ drives lipid buildup by monitoring lipolysis, lipogenesis, and fatty acid oxidation on in-house high resolution mass spectrometers. The second aim will test the therapeutic potential of reprogramming the ETC to the RQ/fumarate pathway in obesity. This aim leverages first-in-class genetic and pharmacologic tools developed by my lab that reprogram the ETC to the RQ/fumarate pathway in vivo. Specifically, we will analyze the impact of RQ on insulin sensitivity, glucose tolerance, and circulating triglyceride levels in lean and obese models. Also, whole-body lipid deposition, weight gain, activity, and respiratory rate will be measured in collaboration with experts at the UMass Chan Medical School Metabolic Disease Research Center. Our toolkit uniquely positions us to address the fundamental role of RQ, a previously unstudied metabolite, in lipid homeostasis throughout adipogenesis. Moreover, this study will use these tools to test, for the first time, the therapeutic potential of reprogramming the ETC as a strategy to treat diseases such as obesity. Regardless of the outcomes, the proposed research will lay the foundation for a new field of adipose biology on flexibility in the mitochondrial ETC that will ignite the field for decades to come.