Analysis of Leigh Syndrome Mutations in the Yeast SURF1 Homolog Reveals a New Member of the Cytochrome Oxidase Assembly Factor Family

Bestwick, Megan; Jeong, Mi Young; Khalimonchuk, Oleh; Kim, Hyung L.; Winge, Dennis R.

doi:10.1128/mcb.00228-10

Cited by 35 publications

(46 citation statements)

References 48 publications

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“…Cmc1 and Coa4 are ''twin Cx 9 C'' proteins, which do not share any similarity at the level of their primary sequence except for the four cysteine residues of the Cx 9 C motifs. The data presented in this study confirm a-direct or indirect-role in the biogenesis of cytochrome c oxidase that had been proposed before (7,22). Nevertheless, both mutants exhibit at steadystate levels about 20% to 50% of the cytochrome c oxidase activity found in wild-type cells.…”

Section: Discussionsupporting

confidence: 73%

“…Two strains that showed a strong respiratory growth stimulation by GSH and DTT caught our attention because they lacked genes for the ''twin Cx 9 C'' proteins Cmc1 and Coa4, which were shown before to play a role in the biogenesis of cytochrome c oxidase (7,22,23,32). These strains showed no (Dcmc1) or poor (Dcoa4) growth on glycerol but were strongly stimulated by either GSH or DTT.…”

Section: Reductants Suppress the Growth Defect Of Mutants Lacking Cmcmentioning

confidence: 99%

“…It was previously demonstrated that Cmc1 and Coa4 play a direct or indirect role in the assembly of cytochrome c oxidase (7,22,23). We therefore analyzed the activity of cytochrome c oxidase in Dcmc1 and Dcoa4 mitochondria (Fig.…”

Section: Mutants Lacking Cmc1 or Coa4 Show Reduced Levels Of Cytochromentioning

confidence: 99%

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Inaccurately Assembled CytochromecOxidase Can Lead to Oxidative Stress-Induced Growth Arrest

Bode

Longen

Morgan

et al. 2013

Antioxidants & Redox Signaling

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Aims: To identify yeast mutants that show a strong redox dependence of the ability to respire, we systematically screened a yeast deletion library for mutants that require the presence of reductants for growth on nonfermentable carbon sources. Results: Respirative growth of 44 yeast mutants was significantly improved by the addition of dithiothreitol or glutathione. Two mutants that were strongly stimulated by reductants lacked the proteins Cmc1 and Coa4. Both proteins belong to the family of ''twin Cx 9 C'' proteins present in the intermembrane space of mitochondria. Deletion of CMC1 or COA4 leads to assembly defects of cytochrome c oxidase, in particular to the lack of Cox1 and rapid degradation of Cox2 and Cox3. Interestingly, the presence of the reductants does not suppress these assembly defects and the levels of cytochrome c oxidase remain reduced. Reductants and antioxidants such as ascorbic acid rather counteract the effects of hydrogen peroxide that is produced from partially assembled cytochrome c oxidase intermediates. Innovation: Here we show that oxidative stress generated by the accumulation of partially assembled respiratory chain complexes prevents growth on carbon sources that force cells to respire. Conclusion: Defects in the assembly of cytochrome c oxidase can lead to increased production of hydrogen peroxide, which is sensed in cells and blocks their proliferation. We propose that this redox-regulated feedback regulation specifically slows down the propagation of cells carrying respiratory chain mutations in order to select for cells of high mitochondrial fitness. Antioxid. Redox Signal. 18, 1597-1612.

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Section: Discussionsupporting

confidence: 73%

Section: Reductants Suppress the Growth Defect Of Mutants Lacking Cmcmentioning

confidence: 99%

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Inaccurately Assembled CytochromecOxidase Can Lead to Oxidative Stress-Induced Growth Arrest

Bode

Longen

Morgan

et al. 2013

Antioxidants & Redox Signaling

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“…This defect leads to Leigh syndrome in humans, a fatal neuromuscular disorder (23,24). Shy1/SURF1 is required for Cox1 biogenesis and hence is part of early assembly intermediates in yeast and human mitochondria, termed COA and MITRAC complexes, respectively (7,11,12,(25)(26)(27). A study of Paracoccus denitrificans SURF1 indicated that SURF1 is capable of binding heme a, thus linking its function to the heme incorporation step for Cox1 during cytochrome c oxidase biogenesis (28).…”

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confidence: 99%

The Heme a Synthase Cox15 Associates with Cytochrome c Oxidase Assembly Intermediates during Cox1 Maturation

Bareth

Dennerlein

Mick

et al. 2013

Molecular and Cellular Biology

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e Cox1, the core subunit of the cytochrome c oxidase, receives two heme a cofactors during assembly of the 13-subunit enzyme complex. However, at which step of the assembly process and how heme is inserted into Cox1 have remained an enigma. Shy1, the yeast SURF1 homolog, has been implicated in heme transfer to Cox1, whereas the heme a synthase, Cox15, catalyzes the final step of heme a synthesis. Here we performed a comprehensive analysis of cytochrome c oxidase assembly intermediates containing Shy1. Our analyses suggest that Cox15 displays a role in cytochrome c oxidase assembly, which is independent of its functions as the heme a synthase. Cox15 forms protein complexes with Shy1 and also associates with Cox1-containing complexes independently of Shy1 function. These findings indicate that Shy1 does not serve as a mobile heme carrier between the heme a synthase and maturing Cox1 but rather cooperates with Cox15 for heme transfer and insertion in early assembly intermediates of cytochrome c oxidase.

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“…8 In yeast strains with ablated SHY1, the SURF1 ortholog, adaptative changes with interacting partners (i.e., other COX assembly factors or cytochrome c), and/or adaptive mechanisms such as increased mitochondrial copper level can suppress, at least in part, the COX defect. 28 Likewise, the variable severity of the phenotype associated with the virtual absence of SURF1 may well depend on the efficiency of compensatory genetic or epigenetic mechanisms in humans.…”

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confidence: 99%

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

et al. 2013

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Objective: To investigate whether mutations in the SURF1 gene are a cause of Charcot-MarieTooth (CMT) disease. Methods:We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A.G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A.G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed.Results: Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities ,25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2A.G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. Conclusions:We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy. Peripheral neuropathies are a well-known complication of mitochondrial DNA and nuclearencoded mitochondrial gene mutations. For instance, patients with mutations in the nuclearencoded mitochondrial genes MFN2 and GDAP1, which encode outer mitochondrial membrane proteins, usually present with axonal and demyelinating forms of Charcot-Marie-Tooth (CMT) disease, respectively.1 Moreover, patients with mutations in the mitochondrial DNA gene MTATP6, which encodes the ATP6 subunit of the mitochondrial respiratory chain (MRC) complex V, may present with axonal CMT (CMT2). 2The determination of the genetic cause is a major challenge in rare neuromuscular diseases such as autosomal recessive demyelinating CMT (CMT4). We investigated a consanguineous family in which 2 patients with CMT4 harbored a homozygous splice site mutation in SURF1, encoding an assembly factor of the MRC complex IV (cytochrome c oxidase [COX]). Despite this defect, we detected some residual assembly and function of COX in fibroblasts and muscle of both patients. We then screened for SURF1 mutations in a cohort of 40 unrelated patients

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Analysis of Leigh Syndrome Mutations in the Yeast SURF1 Homolog Reveals a New Member of the Cytochrome Oxidase Assembly Factor Family

Cited by 35 publications

References 48 publications

Inaccurately Assembled CytochromecOxidase Can Lead to Oxidative Stress-Induced Growth Arrest

Inaccurately Assembled CytochromecOxidase Can Lead to Oxidative Stress-Induced Growth Arrest

The Heme a Synthase Cox15 Associates with Cytochrome c Oxidase Assembly Intermediates during Cox1 Maturation

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

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