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Complex I (NADH:ubiquinone oxidoreductase) is the largest multimeric enzyme complex of the mitochondrial respiratory chain, which is responsible for electron transport and the generation of a proton gradient across the mitochondrial inner membrane to drive ATP production. Eukaryotic complex I consists of 14 conserved subunits, which are homologous to the bacterial subunits, and more than 26 accessory subunits. In mammals, complex I consists of 45 subunits, which must be assembled correctly to form the properly functioning mature complex. Complex I dysfunction is the most common oxidative phosphorylation (OXPHOS) disorder in humans and defects in the complex I assembly process are often observed. This assembly process has been difficult to characterize because of its large size, the lack of a high resolution structure for complex I, and its dual control by nuclear and mitochondrial DNA. However, in recent years, some of the atomic structure of the complex has been resolved and new insights into complex I assembly have been generated. Furthermore, a number of proteins have been identified as assembly factors for complex I biogenesis and many patients carrying mutations in genes associated with complex I deficiency and mitochondrial diseases have been discovered. Here, we review the current knowledge of the eukaryotic complex I assembly process and new insights from the identification of novel assembly factors. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes.

Human NADH-ubiquinione oxidoreductase deficiency can be present in a wide variety of biochemical and symptomatic phenotypes. In fact, the observed spectrum of severity varies from fatal infantile lactic acidosis to adult onset exercise intolerance or optic neuropathy. Since most genetic diseases display a much more narrow set of indices, perhaps this wide variety of clinical presentation requires some explanation. Many of the problems that revolve around the diagnosis of Complex I defects stem from the fact that Complex I is a huge multienzyme complex of 41 separately encoded gene products derived from both w x nuclear and mitochondrial genomes 1,2 . This dual coding system leads to a number of difficulties, misconceptions and pitfalls surrounding etiology and diagnosis. In addition, a further complicating factor related to oxygen free radical generation seems to be an important factor in the determination of pathology in affected individuals.