Mitochondrial DNA Mutations and Their Effects on Complex I Biogenesis: Implications for Metabolic Disease

NADH-ubiquinone oxidoreductase (complex I) is a large, multimeric enzyme complex involved in the generation of ATP by oxidative phosphorylation (OXPHOS). It is comprised of 45 different polypeptide subunits, seven of which are encoded by the mitochondrial genome. For complex I to function efficiently it must be assembled correctly from these subunits in a coordinated manner. Disruption of this assembly process can result in complex I deficiency and a wide range of different mitochondrial disorders, including ophthalmological syndromes and fatal childhood encephalomyopathies. This chapter will describe our current understanding of complex I structure, function, and assembly. In particular, how mutations in mtDNA-encoded subunits disrupt complex I assembly and contribute to human disease pathogenesis will be discussed.