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Table of Contents    
Year : 2016  |  Volume : 64  |  Issue : 4  |  Page : 630-632

NFU1 gene mutation and mitochondrial disorders

1 Department of Neuromuscular Disease, Columbia University, 10032, Manhattan, NY, USA
2 Department of Pathology, Columbia University, 10032, Manhattan, NY, USA
3 Department of Biochemistry, Sarikamis Military Hospital, Kars, Turkey
4 Department of Biochemistry, Agri Military Hospital, Agri, Turkey
5 Department of Biochemistry, Sirnak Military Hospital, Sirnak, Turkey

Date of Web Publication5-Jul-2016

Correspondence Address:
Dr. Bulent Kurt
Department of Pathology, Columbia University, Manhattan 10032, NY
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.185402

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 » Abstract 

Mitochondrial respiratory chains consist of approximately 100 structural proteins. Thirteen of these structural proteins are encoded by mitochondrial DNA (mtDNA), and the others by nuclear DNA (nDNA). Mutation in any of the mitochondrial structural-protein related genes, regardless of whether they are in the nDNA or mtDNA, might cause mitochondrial disorders. In the recent past, new nuclear genes required for assembly, maintenance, and translation of respiratory chain proteins have been found. Mutation in these genes might also cause mitochondrial disorders (MD). NFU1 gene is one of such genes and has a role in the assembly of iron–sulfur cluster (ISC). ISCs are included in a variety of metalloproteins, such as the ferredoxins, as well as in enzymatic reactions and have been first identified in the oxidation-reduction reactions of mitochondrial electron transport. It is important to be aware of NFU1 gene mutations that may cause severe mitochondrial respiratory chain defects, mitochondrial encephalomyopathies and death, early in life.

Keywords: FU1; iron–sulfur cluster; mitochondrial disease

How to cite this article:
Kurt YG, Kurt B, Aydin I, Agilli M, Aydin FN. NFU1 gene mutation and mitochondrial disorders. Neurol India 2016;64:630-2

How to cite this URL:
Kurt YG, Kurt B, Aydin I, Agilli M, Aydin FN. NFU1 gene mutation and mitochondrial disorders. Neurol India [serial online] 2016 [cited 2021 Dec 5];64:630-2. Available from:

 » Introduction Top

Mitochondrial respiratory chain (RC) includes approximately 100 proteins, which comprise five complexes. Thirteen of them are encoded by the mitochondrial DNA (mtDNA) and the rest by the nuclear DNA (nDNA).[1] Mitochondrial disorders (MD) can be classified into two major groups, namely, disorders associated with the mtDNA mutations and those with the nDNA mutations.[2] In the recent years, new gene mutations in the nuclear genes required for assembly, maintenance, and translation of respiratory chain proteins have been found.[3],[4]NFU1 gene is one of the assembly genes for iron–sulfur cluster (ISC). In this review, we discuss the role of NFU1 gene in the ISC assembly and its relationship with MDs.

 » Review Top

Mitochondrial RC disorders are genetically heterogeneous.[2] There are approximately 100 proteins in the RC which are encoded by either mtDNA or nDNA. There are some additional proteins that have a role in enzymatic reactions and they are essential for mitochondrial complexes to work properly. Iron–sulfur proteins are one of them and are characterized by the presence of ISC containing sulfide-linked iron centers. ISCs are included in a variety of metalloproteins, such as the ferredoxins, as well as enzymatic reactions such as nicotinamide adenine dinucleotide dehydrogenase (NADH), hydrogenases, coenzyme Q—cytochrome c reductase, succinate—coenzyme Q reductase and nitrogenase. ISCs have been first identified in the oxidation-reduction reactions of the mitochondrial electron transport system. Complex I, II, and III of oxidative phosphorylation have multiple Fe–S clusters. They have many other functions including in aconitase, in generation of radicals, and as sulfur donors in the biosynthesis of lipoic acid. In addition, they have a role in the regulation of gene expression.[5]

Deficiencies in the assembly of the ISCs have been reported to result in the dysfunction of RC complexes.[2] There are two main genes (NFU1 and BOLA3) involved in the production of ISC for RC.[2]NFU1 gene has been mapped to the 2p13-p15 chromosomal region.[6] It codes for the NFU1 protein. It has been demonstrated that NFU1 protein is an ISC scaffold protein assembling one labile 4Fe–4S cluster per two NFU1 monomers [7] and that several human diseases are associated with the dysfunction of iron–sulfur proteins.[5] The most well-known disease amongst them is Friedreich's ataxia, in which glucosidase alpha acid (GAA)-triplet repeat expansion within the first intron of the (frataxin) FXN gene results in a severe decrease of frataxin protein levels. Frataxin is an important protein for the synthesis of ISC and heme.[8] Hereditary myopathy with lactic acidosis is a rare disease characterized by weakness, exercise intolerance, and lactic acidosis.[9] It is caused by a single base substitution in the ISC scaffold, the (iron-sulfur cluster assembly enzyme) ISCU gene.[9] Mitochondrial myopathy, with the deficiency of ferredoxin 2, is an isolated muscle myopathy caused by the defective ISC assembly. In this disease, defective ISC assembly is related with the deficiency of ferredoxin 2.[5] The combined oxidative phosphorylation defect with iron storage disease (ISD) 11 deficiency, and sideroblastic anemia have also been stated to be a part of the ISC-related disease by Stehling et al.[5]

The functions of the genes involved in assembly have not been clearly understood but there are strong evidences that the NFU1 protein is an assembly protein for ISCs, which are essential cofactors involved in the enzymatic reactions/electron transfer, and that dysfunction of the NFU1 protein or the ISC proteins may cause mitochondrial disease.[10] In 2011, Navarro-Sastre et al.,[10] reported ten individuals with fatal infantile encephalopathy and/or pulmonary hypertension. All patients died before the age of 15 months. They found a homozygous missense mutation (c.622G>T) in the NFU1 gene in nine patients, and one of them had a compound heterozygous c.622G>T and a splice site c545+5G>T mutation. They also found metabolic acidosis, variable lactic acidosis, hyperglycemia, and biochemically, and an impaired activity of the lipoic acid synthase (LAS). Only the complex II activity was found to be decreased. The results strongly suggested that NFU1 is required for LAS activity and NFU1 protein functions as a late-acting maturation factor for a subset of mitochondrial iron–sulfur proteins.

Ferrer-Cortès et al.,[11] have characterized the protein expression profiles of 7 of Navarro-Sastre's patients carrying the NFU1 mutations using fibroblasts from the patients. The protein expression showed the complete absence of protein-bound lipoic acid and decreased succinate dehydrogenase complexes, subunit A and B. Their study concluded that defects in lipoic acid biosynthesis and complex II deficiency are the main problems of this disease. Further, the same group has reported one more patient with mutations in the NFU1 gene, deficient lipoic acid-dependent enzymatic activities, as well as defects in the assembly and activity of the mitochondrial respiratory chain complexes.[12] Results of these studies [10],[11],[12] strongly suggest that mutation in the NFU1 gene affects lipoic acid biosynthesis, which is required in the ISC assembly. In 2011, Cameron et al.,[13] described four patients with NFU1 mutation. Three of the patients had feeding difficulty, weakness, lethargy, and decreasing responsiveness within a few days after birth and the other one had epileptic seizures. These four patients had a c.545G>A mutation in the NFU1 gene. Three of them had died at the end of the first month and the last one died at the 11th month. Clinico-molecular features of all published cases with NFU1 gene mutation have been presented in [Table 1].
Table 1: Clinical features of patients with NFU1 mutations

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From a biochemical viewpoint, while the function of NFU1 proteins is not clearly known, it appears to have some effect on Fe-S enzyme lipoic acid synthase (LAS).[10] It has been shown that the patients with mutations in the NFU1 gene present with similar biochemical features to that seen in patients with lipoic acid defects.[10] Lipoic acid (LA) is an essential cofactor in the mitochondrial α-ketoacid dehydrogenase complexes, such as the pyruvate dehydrogenase complex and the α-ketoglutarate dehydrogenase complex.[14] Alpha-lipoic acid (1,2-dithiolane-3-pentanoic acid; LA) is endogenously synthesized by the enzyme LAS in the mitochondria.[14] LAS catalyzes the insertion of two sulfur atoms presumably from [4Fe–4S] clusters into the precursor form, octanoic acid, bound to the lipoyl domains of lipoate-dependent enzymes. In other words, ISC are used as sulfur-donors in the lipoic acid synthesis by LAS. NFU1 protein might be related with LAS because NFU1 protein is essential for the assembly of ISCs that are indispensable for LAS. As ISCs are essential not only for LAS but also some other enzymes, the absence of NFU1 protein might cause an interruption of the mitochondrial RC machinery in many aspects. In fact, it has already been shown that some other mitochondrial enzymes other than LAS are decreased in patients with NFU1 gene mutations.[10]

NFU1 gene is not one of the assembly genes for RS but it has a significant role in the assembly of ISC, and it affects mitochondrial functions indirectly and severely. The papers on deficiencies in the assembly of the ISC that generally result in deficiencies of complex I, II, or III,[2],[10],[15],[16] and in complex IV deficiency, have not been reported in humans. However, there are a few cell culture/yeast studies that indicate that the defect in ISC may also cause defect in the cytochrome c oxidase (complex IV).[17],[18]

In conclusion, NFU1 is an ISC assembly protein, and there is a strong evidence that LAS deficiency has an important pathogenetic mechanism in the genesis of NFU1 mutation-related disease. It is important to be aware of this new disease because NFU1 gene mutation may cause severe mitochondrial encephalomyopathies and death early in life.

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Conflicts of interest

There are no conflicts of interest.

 » References Top

DiMauro S, Tanji K, Schon EA. The many clinical faces of cytochrome c oxidase deficiency. Adv Exp Med Biol 2012;748:341-57.  Back to cited text no. 1
Rötig A. Genetics of mitochondrial respiratory chain deficiencies. Rev Neurol (Paris) 2014;170:309-22.  Back to cited text no. 2
Brosel S, Yang H, Tanji K, Bonilla E, Schon EA. Unexpected vascular enrichment of SCO1 over SCO2 in mammalian tissues: Implications for human mitochondrial disease. Am J Pathol 2010;177:2541-8.  Back to cited text no. 3
Farhan SM, Wang J, Robinson JF, Lahiry P, Siu VM, Prasad C, et al. Exome sequencing identifies NFS1 deficiency in a novel Fe–S cluster disease, infantile mitochondrial complex II/III deficiency. Mol Genet Genomic Med 2014;2:73-80.  Back to cited text no. 4
Stehling O, Wilbrecht C, Lill R. Mitochondrial iron–sulfur protein biogenesis and human disease. Biochimie 2014;100:61-77.  Back to cited text no. 5
Lorain S, Lécluse Y, Scamps C, Mattéi MG, Lipinski M. Identification of human and mouse HIRA-interacting protein-5 (HIRIP5), two mammalian representatives in a family of phylogenetically conserved proteins with a role in the biogenesis of Fe/S proteins. Biochim Biophys Acta 2001;1517:376-83.  Back to cited text no. 6
Tong WH, Jameson GN, Huynh BH, Rouault TA. Subcellular compartmentalization of human Nfu, an iron–sulfur cluster scaffold protein, and its ability to assemble a [4Fe–4S] cluster. Proc Natl Acad Sci USA 2003;100:9762-7.  Back to cited text no. 7
Evans-Galea MV, Lockhart PJ, Galea CA, Hannan AJ, Delatycki MB. Beyond loss of frataxin: The complex molecular pathology of Friedreich ataxia. Discov Med 2014;17:25-35.  Back to cited text no. 8
Sanaker PS, Toompuu M, McClorey G, Bindoff LA. Antisense oligonucleotide corrects splice abnormality in hereditary myopathy with lactic acidosis. Gene 2012;494:231-6.  Back to cited text no. 9
Navarro-Sastre A, Tort F, Stehling O, Uzarska MA, Arranz JA, Del Toro M, et al. A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe–S proteins. Am J Hum Genet 2011;89:656-67.  Back to cited text no. 10
Ferrer-Cortès X, Font A, Bujan N, Navarro-Sastre A, Matalonga L, Arranz JA, et al. Protein expression profiles in patients carrying NFU1 mutations. Contribution to the pathophysiology of the disease. J Inherit Metab Dis 2013;36:841-7.  Back to cited text no. 11
Tort F, Ferrer-Cortès X, Thió M, Navarro-Sastre A, Matalonga L, Quintana E, et al. Mutations in the lipoyltransferase LIPT1 gene cause a fatal disease associated with a specific lipoylation defect of the 2-ketoacid dehydrogenase complexes. Hum Mol Genet 2014;23:1907-15.  Back to cited text no. 12
Cameron JM, Janer A, Levandovskiy V, Mackay N, Rouault TA, Tong WH, et al. Mutations in iron–sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. Am J Hum Genet 2011;89:486-95.  Back to cited text no. 13
Reed LJ. From lipoic acid to multi-enzyme complexes. Protein Sci 1998;7:220-4.  Back to cited text no. 14
Morán M, Marín-Buera L, Gil-Borlado MC, Rivera H, Blázquez A, Seneca S, et al. Cellular pathophysiological consequences of BCS1L mutations in mitochondrial complex III enzyme deficiency. Hum Mutat 2010;31:930-41.  Back to cited text no. 15
Moreadith RW, Batshaw ML, Ohnishi T, Kerr D, Knox B, Jackson D, et al. Deficiency of the iron–sulfur clusters of mitochondrial reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase (complex I) in an infant with congenital lactic acidosis. J Clin Invest 1984;74:685-97.  Back to cited text no. 16
Diaz F, Enríquez JA, Moraes CT. Cells lacking Rieske iron–sulfur protein have a reactive oxygen species-associated decrease in respiratory complexes I and IV. Mol Cell Biol 2012;32:415-29.  Back to cited text no. 17
Lange H, Mühlenhoff U, Denzel M, Kispal G, Lill R. The heme synthesis defect of mutants impaired in mitochondrial iron–sulfur protein biogenesis is caused by reversible inhibition of ferrochelatase. J Biol Chem 2004;279:29101-8.  Back to cited text no. 18


  [Table 1]

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