NDUFAF2

NADH:ubiquinone oxidoreductase complex assembly factor 2 (NDUFAF2), also known as B17.2L or NDUFA12L is a protein that in humans is encoded by the NDUFAF2, or B17.2L, gene. The NDUFAF2 protein is a chaperone involved in the assembly 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. Mutations in this gene have been associated with progressive encephalopathy and Leigh disease resulting from mitochondrial complex I deficiency.

Structure

NDUFAF2 is located on the q arm of chromosome 5 in position 12.1. The NDUFAF2 gene produces a 20 kDa protein composed of 169 amino acids. The protein is a chaperone of the complex I NDUFA12 subunit family.

Function

NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. The NDUFAF2 gene encodes a complex I assembly factor, B17.2L, that is important for the correct function of the mitochondrial respiratory chain. Specifically, B17.2L acts as a molecular chaperone, associating with an 830 kDa subassembly in the late stages of complex I assembly.

Clinical Significance

Mutations in NDUFAF2 have been associated with complex I deficiency and mitochondrial diseases. These disorders are a result of the dysfunction of the mitochondrial respiratory chain and can cause a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. Clinically, NDUFAF2 mutations have been associated with progressive encephalopathy and Leigh disease.

Progressive encephalopathy was diagnosed in a female patient with a homozygous C182T mutation in exon 2 of B17.2L. This patient presented at 12-14 months with horizontal nystagmus and wide-based gait. Signs and symptoms included ataxia, lethargy and weakness, muscle wasting, optic atrophy, lactic acidosis, absent deep tendon reflexes, hypertrophic cardiomyopathy, hypertension, tachycardia, hypotonia, dysphagia, severe osteoporosis, scoliosis, elevated T4 and TSH, cerebral lesions and atrophy (especially in the thalamus and hypothalamus), severe axonal sensorimotor polyneuropathy, extensive myelomalacia, and white matter encephalomalacia. The patient died at 13 years of age. In another case, a male patient had a diagnosis of Leigh disease with a homozygous nonsense mutation c.9G>A at position 3 of NDUFAF2. Signs and symptoms included delayed psychomotor development, nystagmus, bilateral positive Babinski signs, elevated lactate, pale optic discs, brainstem necrosis, and lesions of the spinal cord, medulla oblongata, midbrain, and white matter. The patient was found to be apnoeic, cyanotic and comatose and eventually died from cardiorespiratory arrest at 27 months of age. In another diagnosis of Leigh syndrome, a female patient was found to have a nonsense mutation in NDUFAF2 was found. Signs and symptoms included nystagmus, developmental retardation, renal tubular acidosis, hypotonia, elevated lactate, dyskinetic movements, and abnormal cerebral signaling. The patient developed respiratory alkalosis and, at 1 year of age, died due to respiratory failure. Another case described two patients with mutations in NDUFA12L, who had hypotonia, nystagmus, ataxia, and encephalopathy, which resulted in early death. It has also been suggested that neurometabolic deficiencies due to disruptions in NDUFAF2 can result in an ADHD phenotype.

Interactions

In addition to co-complexes, NDUFAF2 has protein-protein interactions with CYB5B, LAT, SEC22B, TMEM97, TMEM201, SPG21, LPAR3, STX8, and OPTN.

Further reading

• Tsuneoka M, Teye K, Arima N, Soejima M, Otera H, Ohashi K, Koga Y, Fujita H, Shirouzu K, Kimura H, Koda Y (May 2005). "A novel Myc-target gene, mimitin, that is involved in cell proliferation of esophageal squamous cell carcinoma". J. Biol. Chem. 280 (20): 19977–85. doi:10.1074/jbc.M501231200. PMID 15774466.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Vogel RO, van den Brand MA, Rodenburg RJ, van den Heuvel LP, Tsuneoka M, Smeitink JA, Nijtmans LG (June 2007). "Investigation of the complex I assembly chaperones B17.2L and NDUFAF1 in a cohort of CI deficient patients". Mol. Genet. Metab. 91 (2): 176–82. doi:10.1016/j.ymgme.2007.02.007. PMID 17383918.
• Wang L, McDonnell SK, Hebbring SJ, Cunningham JM, St Sauver J, Cerhan JR, Isaya G, Schaid DJ, Thibodeau SN (December 2008). "Polymorphisms in mitochondrial genes and prostate cancer risk". Cancer Epidemiol. Biomarkers Prev. 17 (12): 3558–66. doi:10.1158/1055-9965.EPI-08-0434. PMC 2750891. PMID 19064571.
• Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR (2010). "Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score". Mol. Med. 16 (7–8): 247–53. doi:10.2119/molmed.2009.00159. PMC 2896464. PMID 20379614.
• Hendrickson SL, Lautenberger JA, Chinn LW, Malasky M, Sezgin E, Kingsley LA, Goedert JJ, Kirk GD, Gomperts ED, Buchbinder SP, Troyer JL, O'Brien SJ (September 2010). "Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression". PLoS ONE. 5 (9): e12862. doi:10.1371/journal.pone.0012862. PMC 2943476. PMID 20877624.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Chen M, Huang H, He H, Ying W, Liu X, Dai Z, Yin J, Mao N, Qian X, Pan L (August 2015). "Quantitative proteomic analysis of mitochondria from human ovarian cancer cells and their paclitaxel-resistant sublines". Cancer Sci. 106 (8): 1075–83. doi:10.1111/cas.12710. PMC 4556398. PMID 26033570.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.