The assembly of mitochondrial Complex I. A product of nuclear-mitochondrial synergy.
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[S.l. : s.n.]
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RU Radboud Universiteit Nijmegen, 14 november 2007
Promotor : Smeitink, J.A.M. Co-promotor : Nijtmans, L.G.J.
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SubjectUMCN 5.3: Cellular energy metabolism
Mitochondria are essential to cellular energy production. Embedded in the mitochondrial inner membrane, the engine of the mitochondrial powerhouse is formed by the five enzymatic complexes of the oxidative phosphorylation (OXPHOS) system. Dysfunction of this system results in mitochondrial disease, affecting organs such as brain, eyes, heart, muscle, liver and kidneys, often resulting in early childhood death. Most frequently affected is the largest multi-protein complex of the OXPHOS system, termed complex I (NADH:ubiquinone oxidoreductase, EC 22.214.171.124). Its assembly is a formidable cellular achievement. The process encompasses the combination of 38 nuclear DNA-encoded and seven mitochondrial DNA-encoded constituents, eight iron-sulfur clusters and a noncovalently bound flavine mononucleotide, resulting in one of the most complex structures in the mitochondrion. This thesis describes studies which demonstrate key stages in the assembly process and which identify and characterize chaperone proteins which aid the process. This has led to a detailed model for complex I assembly and the identification of a new chaperone protein, Ecsit. Ecsit was previously known from its role in the immune system. Its mitochondrial function in the assembly of complex I provides yet another link between the assembly of OXPHOS complexes and cellular processes, such as previously demonstrated for regulated cell death (apoptosis) and fatty acid synthesis. Hopefully, these insights will contribute to the understanding of why mitochondrial dysfunction is so important in e.g. diabetes, Alzheimer's and Parkinson's disease, ageing and cancer.
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