The role of mitochondrial dysfunction in age-related disease: a human genetic approach

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Project Summary The global disease burden, particularly in the elderly population, is dominated by age-related chronic diseases such as neurodegenerative disease, coronary artery disease, and type 2 diabetes; these three conditions alone accounted for over 850,000 American deaths in 2018. These conditions are highly heritable, however the specific mechanisms linking genetics to age-related disease pathogenesis remain unclear. Mitochondrial dysfunction, and more specifically, energy production impairment, is often invoked as a hallmark of aging and age-related disease in humans and in model organisms. Despite pervasive associations, a rigorous assessment of if mitochondrial dysfunction is causal for age-related diseases has yet to be performed. In fact, the only disorders truly known to be caused by mitochondrial dysfunction are inherited mitochondrial diseases, caused by genetic lesions in ~300 mitochondrial DNA- or nuclear DNA-encoded mitochondrial genes. In addition, the cause of the mitochondrial dysfunction seen in aging and age-related disease remains unclear. In this study, the candidate’s long-term goal is to investigate the mechanisms leading to mitochondrial dysfunction and its causal link with aging and age-related common disease using natural human genetic variation. AIM 1 will systematically assess the association between mitochondrial dysfunction and age-related disease using novel and existing methods; AIM 2 will test for causation between mitochondrial dysfunction and age- related disease using a novel measure of mitochondrial dysfunction; and AIM 3 will assess the genetic mechanism of a readout of mitochondrial dysfunction by elucidating and investigating its genetic architecture. Overall, this work will be the first comprehensive analysis of the mechanism and causal structure linking mitochondrial dysfunction to human age-related disease. The results of this analysis have the potential to uncover novel mechanisms underlying aging and common age-related diseases, potentially paving the way to novel mechanism-based therapeutics. This work will be completed jointly in the well-resourced laboratories of Drs. Vamsi Mootha and Benjamin Neale, benefiting from world-class expertise and mentorship in mitochondrial biology, age-related disease biology, and statistical genetics as required for successful execution of the proposed work. In part by addressing fundamental questions of relevance for the fields of aging, mitochondrial biology, and statistical genetics, the candidate’s training plan will additionally important skills in written and oral communication, teaching and mentorship, and clinical care. The highly collaborative expert scientific community at Harvard Medical School will successfully prepare the candidate for a career as an academic clinician-scientist.