NDUFA2 Complex I Mutation Leads to Leigh Disease

Hoefs, Saskia J.G.; Dieteren, Cindy E.; Distelmaier, Felix; Janßen, Rolf; Epplen, A.; Swarts, H.G.P.; Forkink, Marleen; Rodenburg, Richard J.; Nijtmans, Leo; Willems, Peter H.G.M.; Smeitink, Jan A.M.; Heuvel, Lambert P. van den

doi:10.1016/j.ajhg.2008.05.007

Cited by 117 publications

(96 citation statements)

References 37 publications

(43 reference statements)

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“…Defects in complex I assembly are a common cause of mitochondrial disorders (48,50), and mutations in complex I alone are responsible for 23% of all childhood respiratory chain defects in humans (51). Mutations in NDUFA2 affecting complex I activity frequently lead to infant mortality (52). Because proper complex I function requires intricate coordination of subunits, it is possible that post-translational modifications such as carbonylation could disrupt this process.…”

Section: Discussionmentioning

confidence: 99%

Protein Carbonylation and Adipocyte Mitochondrial Function

Curtis

Hahn

Stone

et al. 2012

Journal of Biological Chemistry

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Background: Mitochondrial proteins are covalently modified with bioactive lipids (carbonylation) resulting in reduced metabolic function. Results: iTRAQ-based proteomics identified the phosphate carrier and subunits of Complex I as critical carbonylation targets. Conclusion: Oxidative stress leads to mitochondrial dysfunction through targeted lipid modification of critical proteins involved in phosphate and electron transport. Significance: Identification of carbonylation targets enables evaluation of specific protein modification on mitochondrial function.

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Section: Discussionmentioning

confidence: 99%

Protein Carbonylation and Adipocyte Mitochondrial Function

Curtis

Hahn

Stone

et al. 2012

Journal of Biological Chemistry

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“…Some assembly factor mutations also impair its activity (16). Other pathogenic mutations are found in all of the core subunits, and in 10 supernumerary subunits (NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFB3, NDUFB9, NDUFS4, and NDUFS6) (17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Those in supernumerary subunits NDUFA2, NDUFA10, NDUFS4, and NDUFS6 are associated with a reduced level of intact complex and accumulation of subcomplexes, indicating a defect in assembly or stability of the complex, or both.…”

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confidence: 99%

Assembly factors for the membrane arm of human complex I

Andrews

Carroll

Ding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

129

124

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Mitochondrial respiratory complex I is a product of both the nuclear and mitochondrial genomes. The integration of seven subunits encoded in mitochondrial DNA into the inner membrane, their association with 14 nuclear-encoded membrane subunits, the construction of the extrinsic arm from 23 additional nuclear-encoded proteins, iron-sulfur clusters, and flavin mononucleotide cofactor require the participation of assembly factors. Some are intrinsic to the complex, whereas others participate transiently. The suppression of the expression of the NDUFA11 subunit of complex I disrupted the assembly of the complex, and subcomplexes with masses of 550 and 815 kDa accumulated. Eight of the known extrinsic assembly factors plus a hydrophobic protein, C3orf1, were associated with the subcomplexes. The characteristics of C3orf1, of another assembly factor, TMEM126B, and of NDUFA11 suggest that they all participate in constructing the membrane arm of complex I. mitochondria | respiratory chain | NADH:ubiquinone oxidoreductase

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“…Previous studies identified disease-causing mutations in nuclear structural genes encoding for the seven core subunits (NDUFS1, NDUFS2, NDUFS3, NDUFS7, NDUFS8, NDUFV1, and NDUFV2) and five accessory subunits of complex I (NDUFS4, NDUFS6, NDUFA1, NDUFA2, and NDUFA11). [5][6][7][8] Furthermore, mutations have been described in eight assembly factors (NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, C8orf38, C20orf7, ACAD9, and NDUBPL) of this complex and in an uncharacterized protein (FOXRED1) causing complex I deficiency. [9][10][11][12][13][14][15][16] Although pathogenic mutations have been described in accessory subunits, the function of these subunits is not exactly known yet.…”

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confidence: 99%

NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease

et al. 2010

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Mitochondrial complex I deficiency is the most common defect of the oxidative phosphorylation system. We report a patient with Leigh syndrome who showed a complex I deficiency expressed in cultured fibroblasts and muscle tissue. To find the genetic cause of the complex I deficiency, we screened the mitochondrial DNA and the nuclear-encoded subunits of complex I. We identified compound-heterozygous mutations in the NDUFA10 gene, encoding an accessory subunit of complex I. The first mutation disrupted the start codon and the second mutation resulted in an amino acid substitution. The fibroblasts of the patient displayed decreased amount and activity, and a disturbed assembly of complex I. These results indicate that NDUFA10 is a novel candidate gene to screen for disease-causing mutations in patients with complex I deficiency.

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NDUFA2 Complex I Mutation Leads to Leigh Disease

Cited by 117 publications

References 37 publications

Protein Carbonylation and Adipocyte Mitochondrial Function

Protein Carbonylation and Adipocyte Mitochondrial Function

Assembly factors for the membrane arm of human complex I

NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease

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