Copper supplementation restores cytochrome c oxidase activity in cultured cells from patients with SCO2 mutations

Salviati, Leonardo; Hernandez-Rosa, Evelyn; Walker, Winsome F; SACCONI, Sabrina; DiMauro, Salvatore; Schon, Eric A.; Davidson, Mercy M.

doi:10.1042/bj3630321

Cited by 44 publications

(15 citation statements)

References 28 publications

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“…The EPI-743 treatment was beneficial to patients with LS due to mutations in SURF1 and in LS with secondary COX deficiency due to mutated ETHE1. 17 In vitro studies in patient fibroblasts showed that copper 18 and copper with bezafibrate supplementation rescued cells harboring mutations in SCO2 encoding a COX copper-chaperone 19 while L-cystein supplementation improved mitochondrial function in cells with TRMU mutations. 20 However, as the COX6B1 defect does not cause LS and the protein is not a copper chaperone but an integral COX subunit, we evaluated a number of other potentially beneficial molecules for their ability to improve mitochondrial function in the patient's fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

et al. 2014

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Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5-aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

et al. 2014

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“…Histochemistry-For histochemical staining of cytochrome c oxidase activity (35), cells grown on glass coverslips were airdried for 1 h at room temperature and then preincubated with 1 mM CoCl 2 in 50 mM Tris-HCl, pH 7.6, containing 10% sucrose for 15 min at room temperature. After rinsing with 0.1 M sodium phosphate, pH 7.6, containing 10% sucrose, the cells were incubated for 6 h at 37°C in incubation medium (10 mg of cytochrome c, 10 mg 3,3Ј-diaminobenzidine hydrochloride, 2 mg of catalase, 10% sucrose in 0.1 M sodium phosphate, pH 7.6).…”

Section: Methodsmentioning

confidence: 99%

“…Subfragments of each coactivator denoted as A, B, C, or D with their amino acid coordinates shown in parentheses were used in S-tag pulldown assays with 35 S-labeled transcription factor. Binding of the various subfragments to each 35 S-radiolabeled factor was compared with that of S-tagged thioredoxin (Trdx) as a negative control. Bound proteins were eluted from the S-protein-agarose and visualized by autoradiography.…”

Section: Similarities and Differences In Transcription Factormentioning

confidence: 99%

PGC-1-related Coactivator Complexes with HCF-1 and NRF-2β in Mediating NRF-2(GABP)-dependent Respiratory Gene Expression

Vercauteren

Gleyzer

Scarpulla

2008

Journal of Biological Chemistry

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The PGC-1 family of regulated coactivators (PGC-1␣, PGC-1␤, and PRC) plays an important role in directing respiratory gene expression in response to environmental signals. Here, we show that PRC and PGC-1␣ differ in their interactions with nuclear hormone receptors but are highly similar in their direct binding to several nuclear transcription factors implicated in the expression of the respiratory chain. Surprisingly, neither coactivator binds NRF-2(GABP), a multisubunit transcriptional activator associated with the expression of many respiratory genes. However, the NRF-2 subunits and PRC are co-immunoprecipitated from cell extracts indicating that the two proteins exist in a complex in vivo. Several lines of evidence indicate that HCF-1 (host cell factor 1), a major chromatin component, mediates the association between PRC and NRF-2. Both PRC and NRF-2␤ bind HCF-1 in vitro, and the molecular determinants required for the interactions of each with HCF-1 are also required for PRC trans-activation through promoter-bound NRF-2. These determinants include a consensus HCF-1 binding site on PRC and the NRF-2 activation domain. In addition, PRC and NRF-2␤ can complex with HCF-1 in vivo, and all three associate with NRF-2-dependent nuclear genes that direct the expression of the mitochondrial transcription factors, TFB1M and TFB2M. Finally, short hairpin RNA-mediated knock down of PRC protein levels leads to reduced expression of TFB2M mRNA and mitochondrial transcripts for cytochrome oxidase II (COXII) and cytochrome b. These changes in gene expression coincide with a marked reduction in cytochrome oxidase activity. The results are consistent with a pathway whereby PRC regulates NRF-2-dependent genes through a multiprotein complex involving HCF-1.

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“…Histochemistry. Histochemical staining for cytochrome c oxidase (COX) activity was done as described (20). Briefly, cells grown on glass coverslips were air-dried for 1 h at room temperature and preincubated with 1 mmol/L CoCl 2 and 50 AL of DMSO in 50 mmol/L Tris-HCl (pH 7.6), containing 10% sucrose, for 15 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Arsenic Induced Mitochondrial DNA Damage and Altered Mitochondrial Oxidative Function: Implications for Genotoxic Mechanisms in Mammalian Cells

Partridge¹,

Huang

Hernandez-Rosa

et al. 2007

Cancer Research

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Arsenic is a well-established human carcinogen that is chronically consumed in drinking water by millions of people worldwide. Recent evidence has suggested that arsenic is a genotoxic carcinogen. Furthermore, we have shown that mitochondria mediate the mutagenic effects of arsenic in mammalian cells, as arsenic did not induce nuclear mutations in mitochondrial DNA (mtDNA)-depleted cells. Using the human-hamster hybrid A L cells, we show here that arsenic alters mitochondrial function by decreasing cytochrome c oxidase function and oxygen consumption but increasing citrate synthase function. These alterations correlated with depletion in mtDNA copy number and increase in large heteroplasmic mtDNA deletions. In addition, mtDNA isolated periodically from cultures treated continuously with arsenic did not consistently display the same deletion pattern, indicating that the mitochondrial genome was subjected to repeated and continuous damage. These data support the theory that the mitochondria, and particularly mtDNA, are important targets of the mutagenic effects of arsenic in mammalian cells. [Cancer Res 2007;67(11):5239-47]

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Copper supplementation restores cytochrome c oxidase activity in cultured cells from patients with SCO2 mutations

Cited by 44 publications

References 28 publications

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

PGC-1-related Coactivator Complexes with HCF-1 and NRF-2β in Mediating NRF-2(GABP)-dependent Respiratory Gene Expression

Arsenic Induced Mitochondrial DNA Damage and Altered Mitochondrial Oxidative Function: Implications for Genotoxic Mechanisms in Mammalian Cells

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