NDUFS8 explained

NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial also known as NADH-ubiquinone oxidoreductase 23 kDa subunit, Complex I-23kD (CI-23kD), or TYKY subunit is an enzyme that in humans is encoded by the NDUFS8 gene.^[1] ^[2] ^[3] ^[4] The NDUFS8 protein is a subunit of NADH dehydrogenase (ubiquinone) also known as Complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.^[5] Mutations in this gene have been associated with Leigh syndrome.^[3]

Structure

NDUFS8 is located on the q arm of chromosome 11 in position 13.2. The NDUFS8 gene produces a 23.7 kDa protein composed of 210 amino acids.^[6] ^[7] The encoded protein, TYKY, contains two 4Fe4S ferredoxin consensus patterns which are believed to be iron-sulfur cluster N-2 binding sites.^[8] Studies of other subunits of Complex I have suggested that the subunits TYKY, PSST, 49 kDa, ND1, and ND5 interact with iron-sulfur clusters to form the catalytic core of NADH dehydrogenase (ubiquinone).^[9]

Function

This gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process.^[3]

Clinical significance

Mutations in NDUFS8 have been associated with mitochondrial diseases, which can cause any one of a clinically heterogeneous group of disorders arising from dysfunction of the mitochondrial respiratory chain. The phenotypic spectrum ranges from isolated diseases affecting single organs to severe multisystem disorders. Common clinical features include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, encephalopathy, seizures, stroke-like episodes, ataxia, spasticity and lactic acidosis. Mitochondrial disorders can be caused by mutations of mitochondrial DNA or nuclear DNA that either affect oxidative phosphorylation proteins directly, or affect respiratory chain function by impacting the production of the complex machinery needed to run this process.

NDUFS8 mutations have also been associated with Leigh syndrome. Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, dysphagia and lactic acidosis. One case report of a pathogenic mutation in NDUFS8 found that it resulted in complex I mitochondrial deficiency and a diagnosis of Leigh syndrome. The patient’s symptoms included apnea, cyanosis, hypercarbia, hypotonia, brisk tendon reflexes, ankle clonus, and erratic seizures. Further analysis revealed increased lactate, cerebral lesions, and a hypertrophic obstructive cardiomyopathy.

Interactions

In addition to co-subunits for complex I, NDUFS8 has protein-protein interactions with MLH1 and GEM.^[10] ^[11]

Notes and References

de Sury R, Martinez P, Procaccio V, Lunardi J, Issartel JP . Genomic structure of the human NDUFS8 gene coding for the iron-sulfur TYKY subunit of the mitochondrial NADH:ubiquinone oxidoreductase . Gene . 215 . 1 . 1–10 . July 1998 . 9666055 . 10.1016/S0378-1119(98)00275-3 .
Procaccio V, Depetris D, Soularue P, Mattei MG, Lunardi J, Issartel JP . cDNA sequence and chromosomal localization of the NDUFS8 human gene coding for the 23 kDa subunit of the mitochondrial complex I . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1351 . 1–2 . 37–41 . March 1997 . 9116042 . 10.1016/s0167-4781(97)00020-1 .
Web site: Entrez Gene: NDUFS8 NADH dehydrogenase (ubiquinone) Fe-S protein 8, 23kDa (NADH-coenzyme Q reductase).
Web site: NDUFS8 - NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial precursor - Homo sapiens (Human) - NDUFS8 gene & protein]. www.uniprot.org. en. 2018-07-19.
Book: Donald Voet. Judith G. Voet. Charlotte W. Pratt. Fundamentals of biochemistry : life at the molecular level. 2013. Wiley. Hoboken, NJ. 9780470547847. 18 . 581–620. 4th.
Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
Web site: Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information. Yao. Daniel. amino.heartproteome.org. 2018-07-20.
Loeffen J, Smeitink J, Triepels R, Smeets R, Schuelke M, Sengers R, Trijbels F, Hamel B, Mullaart R, van den Heuvel L . The first nuclear-encoded complex I mutation in a patient with Leigh syndrome . American Journal of Human Genetics . 63 . 6 . 1598–608 . December 1998 . 9837812 . 1377631 . 10.1086/302154 .
2001-07-02. Functional coupling of PSST and ND1 subunits in NADH:ubiquinone oxidoreductase established by photoaffinity labeling. Biochimica et Biophysica Acta (BBA) - Bioenergetics. en. 1506. 1. 79–87. 10.1016/S0005-2728(01)00183-9. 11418099. 0005-2728. Schuler. Franz. Casida. John E.. free.
Web site: Cytoskeletal scaffolding proteins interact with Lynch-Syndrome associated mismatch repair protein MLH1. . IntAct.
Web site: Protein interaction data set highlighted with human Ras-MAPK/PI3K signaling pathways.. IntAct.