Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Genetics & Heredity, Mitochondrial disorder, Complex 1 deficiency, Genetic defects, NADH-UBIQUINONE OXIDOREDUCTASE, RESPIRATORY-CHAIN SUPERCOMPLEXES, MITOCHONDRIAL-DNA DELETIONS, HEREDITARY OPTIC NEUROPATHY, IRON-SULFUR CLUSTERS, LEIGH-SYNDROME, CONFORMATION-DRIVEN, MISSENSE MUTATION, ENCODED SUBUNITS, GENE-PRODUCT, Electron Transport Complex I, Energy Metabolism, Humans, Mitochondrial Diseases, 0604 Genetics, Biochemistry & Molecular Biology, 3101 Biochemistry and cell biology, 3105 Genetics

Abstract:

The oxidative phosphorylation (OXPHOS) system, consisting of five enzyme complexes (I-V) together with 2 electron carriers, has an important role in the energy metabolism of the cell. With 45 subunits, complex I is the first and largest complex of the respiratory chain. It is under bigenomic control and a proper interaction between the mitochondrial and the nuclear genome is important for a good biogenesis and functioning of the complex. Isolated complex I deficiency is the most frequently diagnosed form of mitochondrial disorders caused by the disturbance of the OXPHOS system. It has a wide clinical variety and, at present, in many patients the underlying genetic cause of the complex I deficiency is still not known. In this review, the role of complex I in the oxidative phosphorylation and the localization and function of the different complex I subunits will be described. Furthermore, a brief overview of the assembly process and biochemical studies, performed when a patient is suspected of a mitochondrial disorder is given. Finally, the present knowledge for molecular base of complex I deficiency is described and the findings in a research cohort of patients with complex I deficiency are reported. Identifying new genes encoding proteins involved in complex I biogenesis is challenging and in the near future new powerful techniques will make high throughput screening possible. Progress in elucidating the genetic defect causing complex I deficiencies is important for a better genetic counseling, prenatal diagnostic possibilities and further development of new treatment strategies to cure the complex I deficiencies in the future.