Nuclear genes of human complex I of the mitochondrial electron transport chain: state of the art

The mitochondrial electron transport chain (mtETC) consists of fourmulti-subunit enzyme complexes. Complex I or NADH:ubiquinoneoxidoreductase, the largest mtETC multisubunit complex, consists ofapproximately 41 subunits. Seven of these subunits are encoded by themitochondrial genome, the remainder by the nuclear genome. Among themitochondriocytopathies, complex I deficiencies are encountered frequently.Although some complex I deficiencies have been associated withmitochondrial DNA mutations, the genetic defect has not been elucidated inthe majority of complex I-deficient patients. It is expected that many ofthese patients have mutations in the nuclear- encoded subunits of thiscomplex, so vital for cellular energy production. After a brief summary ofthe current knowledge of complex I from cow, bacteria and fungi, thisreview presents the state of the art of the knowledge of the humannuclear-encoded complex I genes which, in the last 18 months, has madeenormous progress. At present, the complete gene structure of four subunitsand the cDNA structure of 18 of the 34 complex I nuclear-encoded subunitsare known. Mapping of these subunits shows a random distribution over thechromosomes. The chromosomal localization is known for 14 complex I genes.Recently, the first mutation, a 5 bp duplication in the 18 kDa (AQDQ)subunit, has been reported. We expect that within 1 year all humannuclear-encoded complex I subunits will be cloned. Mutational analysis ofthese subunits is warranted in complex I-deficient patients and will notonly be important for genetic counselling but will also extend theknowledge regarding the functional properties of the individual humancomplex I subunits.