NUCLEAR GENES OF HUMAN COMPLEX I OF THE MITOCHONDRIAL ELECTRON-TRANSPORT CHAIN - STATE-OF-THE-ART

The mitochondrial electron transport chain (mtETC) consists of four mu lti-subunit enzyme complexes, Complex I or NADH:ubiquinone oxidoreduct ase, the largest mtETC multisubunit complex, consists of similar to 41 subunits, Seven of these subunits are encoded by the mitochondrial ge nome, the remainder by the nuclear genome. Among the mitochondriocytop athies, complex I deficiencies are encountered frequently, Although so me complex deficiencies have been associated with mitochondrial DNA mu tations, the genetic defect has not been elucidated in the majority of complex I-deficient patients, It is expected that many of these patie nts have mutations in the nuclear-encoded subunits of this complex, so vital for cellular energy production. After a brief summary of the cu rrent knowledge of complex I from cow, bacteria and fungi, this review presents the state of the art of the knowledge of the human nuclear-e ncoded complex I genes which, in the last 18 months, has made enormous progress. At present, the complete gene structure of four subunits an d the cDNA structure of 18 of the 34 complex nuclear-encoded subunits are known. Mapping of these subunits shows a random distribution over the chromosomes. The chromosomal localization is known for 14 complex I genes. Recently, the first mutation, a 5 bp duplication in the 18 kD a (AQDQ) subunit, has been reported. We expect that within 1 year all human nuclear-encoded complex I subunits will be cloned. Mutational an alysis of these subunits is warranted in complex I-deficient patients and will not only be important far genetic counselling but will also e xtend the knowledge regarding the functional properties of the individ ual human complex I subunits,