Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome c oxidase deficiency

Péquignot, Marie O.; Dey, Runu; Zeviani, Massimo; Tiranti, Valeria; Godinot, Catherine; Poyau, Alain; Sue, Caroline; Mauro, Salvatore Di; Abitbol, Marc; Marsac, Cécile

doi:10.1002/humu.1112.abs

Cited by 29 publications

(45 citation statements)

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“…Numbers of 2-, 10-, and 20-day-old transformant control flies tested were 69, 64, and 68, respectively. well as in several COX assembly factors such as COX10, COX15, SURF1, SCO1, and SCO2 have been correlated with encephalomyopathies (Barrientos et al 2002;DiMauro and Schon 2003;DiMauro and Hirano 2005). For example, .30 distinct mutations in the SURF1 gene have been associated with COX-deficient LS (Pequignot et al 2001). In light of this, it has been noted with intrigue that no mutations in any of the nuclear-encoded structural subunits of COX have been associated with such disorders and that attempts to find such associations have not been fruitful (Shoubridge 2001;DiMauro and Schon 2003;Schon 2004;Schapira 2006).…”

Section: Discussionmentioning

confidence: 99%

Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

et al. 2007

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Mitochondrial dysfunction is involved in many neurodegenerative disorders in humans. Here we report mutations in a gene (designated levy) that codes for subunit VIa of cytochrome c oxidase (COX). The mutations were identified by the phenotype of temperature-induced paralysis and showed the additional phenotypes of decreased COX activity, age-dependent bang-induced paralysis, progressive neurodegeneration, and reduced life span. Germ-line transformation using the levy 1 gene rescued the mutant flies from all phenotypes including neurodegeneration. The data from levy mutants reveal a COX-mediated pathway in Drosophila, disruption of which leads to mitochondrial encephalomyopathic effects including neurodegeneration, motor dysfunction, and premature death. The data present the first case of a mutation in a nuclear-encoded structural subunit of COX that causes mitochondrial encephalomyopathy rather than lethality, whereas several previous attempts to identify such mutations have not been successful. The levy mutants provide a genetic model to understand the mechanisms underlying COXmediated mitochondrial encephalomyopathies and to explore possible therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

et al. 2007

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“…First and foremost, COX is a vital enzyme, without which oxidative metabolism cannot be carried to completion and mitochondrial ATP cannot be generated (33,34). Dysfunction of this enzyme jeopardizes health, and absence of this enzyme is incompatible with life (35,36). COX is a housekeeping enzyme present in almost every eukaryotic cell (with a few exceptions, such as mature, short lived red blood cells lacking in both nuclei and mitochondria).…”

Section: Table 2 3c Interactions Among All 10 Nucleus-encoded Cox Submentioning

confidence: 99%

Chromosome Conformation Capture of All 13 Genomic Loci in the Transcriptional Regulation of the Multisubunit Bigenomic Cytochrome c Oxidase in Neurons

Dhar

Ongwijitwat

Wong‐Riley

2009

Journal of Biological Chemistry

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Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain composed of 13 subunits; three are mitochondria-encoded, and 10 are nucleus-inscribed on nine different chromosomes within the mammalian genome. The transcriptional regulation of such a multisubunit, multichromosomal, and bigenomic enzyme is mechanistically challenging. Transcription factories have been proposed as one mechanism by which genes from different genomic loci congregate to transcribe functionally related genes, and chromosome conformation capture (3C) is a means by which such interactions can be revealed. Thus far, however, only loci from the same chromosome or at most two chromosomes have been co-localized by 3C. The present study used 3C to test our hypothesis that not only the 10 genomic loci from nine chromosomes encoding the 10 nuclear subunits of COX, but also genes from three chromosomes encoding mitochondrial transcription factors A and B (Tfam, Tfb1m, and Tfb2m) critical for the transcription of the three mitochondria-encoded COX subunit genes all occupy common intranuclear sites in the murine neuronal nuclei. The pairing of various COX subunit genes and Tf genes indicates that interactions are present among all of them. On the other hand, genes for a non-mitochondrial protein (calreticulin) as well as a mitochondrial enzyme (citrate synthase) did not interact with COX genes. Furthermore, interactions between COX subunit and Tf genes were up-regulated by depolarizing stimulation and down-regulated by impulse blockade in primary neurons. Thus, a viable mechanism is in place for a synchronized, coordinated transcriptional regulation of this multisubunit, bigenomic COX enzyme in neurons.Cytochrome c oxidase (COX) 2 or complex IV of the mitochondrial electron transport chain is made up of three subunits encoded in the mitochondrial genome and 10 nucleus-encoded subunits located on nine different chromosomes (1-3). The 10 nucleus-encoded COX subunits are 4, 5a, 5b, 6a, 6b, 6c, 7a, 7b, 7c, and 8a. Subunits 4, 6a, 6b, 7a, and 8a each has a ubiquitous isoform and a tissue-specific isoform. Transcription of all ubiquitously expressed subunits in neurons are coordinately regulated according to the cell's ATP requirement (4). Transcriptional regulators of COX in rats, mice, and humans include NRF-1 and NRF-2 (nuclear respiratory factors 1 and 2) (5-8).In particular, both NRF-1 and NRF-2 activate the transcription of all 10 nucleus-encoded COX subunits and modulate the level of transcription in response to changing cellular energy demands in neurons (9 -14). Additionally, NRF-1 and NRF-2 indirectly activate the three mitochondria-encoded COX subunit genes by regulating Tfam, Tfb1m, and Tfb2m (mitochondrial transcription factors A, B1, and B2) critical for mitochondrial DNA transcription and replication (15-18). Transcriptional coactivators, such as PGC-1␣ (peroxisome proliferator-activated receptor ␥-coactivator 1␣) (19,20), also play an important role in stimulating COX transcription in the presence of upstream signals i...

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“…Mutations in the SURF1 gene are a relatively common cause of mitochondrial disease (13)(14)(15). Nearly all reported patients carry mutations that introduce premature termination codons, resulting in loss of expression.…”

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confidence: 99%

Cytochrome c Oxidase Subassemblies in Fibroblast Cultures from Patients Carrying Mutations in COX10, SCO1, or SURF1

Williams

Valnot

Rustin

et al. 2004

Journal of Biological Chemistry

127

135

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Cytochrome c oxidase contains two redox-active copper centers (Cu A and Cu B ) and two redox-active heme A moieties. Assembly of the enzyme relies on several assembly factors in addition to the constituent subunits and prosthetic groups. We studied fibroblast cultures from patients carrying mutations in the assembly factors COX10, SCO1, or SURF1. COX10 is involved in heme A biosynthesis. SCO1 is required for formation of the Cu A center. The function of SURF1 is unknown. Immunoblot analysis of native gels demonstrated severely decreased levels of holoenzyme in the patient cultures compared with controls. In addition, the blots revealed the presence of five subassemblies: three subassemblies involving the core subunit MTCO1 but apparently no other subunits; a subassembly containing subunits MTCO1, COX4, and COX5A; and a subassembly containing at least subunits MTCO1, MTCO2, MTCO3, COX4, and COX5A. As some of the subassemblies correspond to known assembly intermediates of human cytochrome c oxidase, we think that these subassemblies are probably assembly intermediates that accumulate in patient cells. The MTCO1⅐COX4⅐COX5A subassembly was not detected in COX10-deficient cells, which suggests that heme A incorporation into MTCO1 occurs prior to association of MTCO1 with COX4 and COX5A. SCO1-deficient cells contained accumulated levels of the MTCO1⅐COX4⅐COX5A subassembly, suggesting that MTCO2 associates with the MTCO1⅐COX4⅐COX5A subassembly after the Cu A center of MTCO2 is formed. Assembly in SURF1-deficient cells appears to stall at the same stage as in SCO1-deficient cells, pointing to a role for SURF1 in promoting the association of MTCO2 with the MTCO1⅐COX4⅐COX5A subassembly.

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Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome c oxidase deficiency

Cited by 29 publications

References 0 publications

Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

Chromosome Conformation Capture of All 13 Genomic Loci in the Transcriptional Regulation of the Multisubunit Bigenomic Cytochrome c Oxidase in Neurons

Cytochrome c Oxidase Subassemblies in Fibroblast Cultures from Patients Carrying Mutations in COX10, SCO1, or SURF1

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