Mitochondrial Complex I Function in Leigh Syndrome and Aging.

McElroy, Gregory Scott

doi:https://doi.org/10.21985/n2-45gq-tr34

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Mitochondrial Complex I Function in Leigh Syndrome and Aging.

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Mitochondrial complex I is the primary entry point for electrons into the mitochondrial electron transport chain that is composed of 45 individual protein subunits that are encoded in both the nuclear and mitochondrial genomes. Mitochondrial complex I sits at an important nexus in the essential bioenergetic, biosynthetic, and signaling functions of mitochondria and is therefore a key regulator of metabolism and cellular and organismal function. Numerous previous studies have identified that severe reductions in mitochondrial complex I function through mutation or pharmacological inhibition can cause neurometabolic mitochondrial diseases such as Leigh syndrome and neurodegeneration in humans and animal models. Mitochondrial complex I function has been shown to decline with aging and is therefore associated with many aging-related pathologies including the common neurodegenerative diseases of aging such as Alzheimer’s disease and Parkinson’s disease. Despite these findings, numerous studies in small, short-lived model organisms have demonstrated that knockdown of mitochondrial complex I function can paradoxically increase lifespan. Furthermore, the anti-diabetic drug metformin, which is currently being investigated as a possible anti-cancer and anti-aging therapeutic, may mediate its effects through mild inhibition of mitochondrial complex I. Therefore, in this study, I sought to further explore the role of mitochondrial complex I function in malignancy, neurodegeneration, and aging with novel animal models and with a hypothesis that the toxic metabolite L-2-hydroxyglutarate may act as an effector of mitochondrial dysfunction-induced pathology. In the first set of experiments, I describe a novel mouse model in which tissue-specific expression of the yeast enzyme NDI1 is possible. I show that NDI1 complements loss of the supernumerary complex I subunit NDUFS4 in the brain of mice to prevent an early fatal phenotype but does not prevent motor impairment that is a hallmark of NDUFS4 loss. In the second set of experiments, I focus on the possible role of 2-hydroxylgutarate as a causative mechanism by which mitochondrial dysfunction can lead to cellular and organismal pathology using human cancer cell lines, genetically modified Drosophila melanogaster, and measurement of 2-hydroxyglutarate in mouse models. Finally, in the last set of experiments I seek to further characterize the impact of mild mitochondrial complex I function on lifespan, organismal function, and cellular gene expression in aged mice with ubiquitous loss of one allele of the essential complex I subunit NDUFS2.

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