Purpose of review: Disturbances in the mitochondrial oxidative phosphorylation pathway most often lead to devastating disorders with a fatal outcome. Of these, complex I deficiency is the most frequently encountered. Recent characterization of the mitochondrial and nuclear DNA-encoded complex I subunits has allowed mutational analysis and reliable prenatal diagnosis. Nevertheless, complex-I-deficient patients without a mutation in any of the known subunits remain. It is assumed that these patients harbour defects in proteins involved in the assembly of this largest member of the oxidative phosphorylation complexes. This review describes current understanding of complex I assembly, new developments and future perspectives.
Recent findings: The first model of human complex I assembly has been proposed recently. New insights into supercomplex assembly and stability may help to explain combined deficiencies. Recent functional characterization of some of the 32 accessory subunits of the complex may link these subunits to complex I biogenesis and activity regulation.
Summary: Research on complex I assembly is increasing rapidly. However, comparison between theoretical and experimental models of complex I assembly is still problematic. The growing understanding of complex I assembly at the subunit and supercomplex level will clarify the picture in the future. The elucidation of complex I assembly, by combining patient data with new experimental methods, will facilitate the diagnosis of (and possibly therapy for) many uncharacterized mitochondrial disorders.