scholarly journals Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice

Science ◽  
2020 ◽  
Vol 368 (6491) ◽  
pp. 620-625 ◽  
Author(s):  
Liam M. Guthrie ◽  
Shivatheja Soma ◽  
Sai Yuan ◽  
Andres Silva ◽  
Mohammad Zulkifli ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Small Molecule ◽  
Murine Model ◽  
Copper Deficiency ◽  
Menkes Disease ◽  
Neurological Injury ◽  
Loss Of Function ◽  
Brindled Mouse ◽  
The Brain

Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse—a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.

scholarly journals Effects of vitamin E on mitochondrial dysfunction and asthma features in an experimental allergic murine model

2009 ◽  
Vol 107 (4) ◽  
pp. 1285-1292 ◽  
Author(s):  
Ulaganathan Mabalirajan ◽  
Jyotirmoi Aich ◽  
Geeta Devi Leishangthem ◽  
Surendra Kumar Sharma ◽  
Amit Kumar Dinda ◽  
...  
Keyword(s):  
Vitamin E ◽  
Cytochrome C ◽  
Mitochondrial Dysfunction ◽  
Cytochrome C Oxidase ◽  
Murine Model ◽  
Ultrastructural Changes ◽  
Mitochondrial Dysfunctions ◽  
The Third ◽  
Bronchial Epithelia ◽  
Experimental Allergic

We showed recently that IL-4 causes mitochondrial dysfunction in allergic asthma. IL-4 is also known to induce 12/15-lipoxygenase (12/15-LOX), a potent candidate molecule in asthma. Because vitamin E (Vit-E) reduces IL-4 and inhibits 12/15-LOX in vitro, here we tested the hypothesis that Vit-E may be effective in restoring key mitochondrial dysfunctions, thus alleviating asthma features in an experimental allergic murine model. Ovalbumin (OVA)-sensitized and challenged male BALB/c mice showed the characteristic features of asthma such as airway hyperresponsiveness (AHR), airway inflammation, and airway remodeling. In addition, these mice showed increase in the expression and metabolites of 12/15-LOX, reduction in the activity and expression of the third subunit of mitochondrial cytochrome- c oxidase, and increased cytochrome c in lung cytosol, which indicate that OVA sensitization and challenge causes mitochondrial dysfunction. Vit-E was administered orally to these mice, and 12/15-LOX expression, key mitochondrial functions, ultrastructural changes of mitochondria in bronchial epithelia, and asthmatic parameters were determined. Vit-E treatment reduced AHR, Th2 response including IL-4, IL-5, IL-13, and OVA-specific IgE, eotaxin, transforming growth factor-β1, airway inflammation, expression and metabolites of 12/15-LOX in lung cytosol, lipid peroxidation, and nitric oxide metabolites in the lung, restored the activity and expression of the third subunit of cytochrome- c oxidase in lung mitochondria and bronchial epithelia, respectively, reduced the appearance of cytochrome c in lung cytosol, and also restored mitochondrial ultrastructural changes of bronchial epithelia. In summary, these findings show that Vit-E reduces key mitochondrial dysfunctions and alleviates asthmatic features.

scholarly journals Effects of dietary copper deficiency on male offspring of heterozygous brindled mice

1989 ◽  
Vol 62 (1) ◽  
pp. 177-184
Author(s):  
Joseph R. Prohaska
Keyword(s):  
Copper Deficiency ◽  
Menkes Disease ◽  
Male Offspring ◽  
Dietary Copper ◽  
Cu Deficiency ◽  
C57bl Mice ◽  
Brindled Mouse ◽  
Normal Males ◽  
Cell Volumes ◽  
Brindled Mice

Female C57BL mice heterozygous for the brindled gene were mated to normal males and fed on a purified diet low in copper throughout gestation and lactation with (+ Cu) or without (−Cu) Cu-supplemented drinking water. Male offspring of two genotypes (control, + /y and brindled, Mobr/y) were compared when 10–12 d old. Brindled mice from dams on the – Cu treatment were smaller and had lower packed cell volumes than brindled mice from dams on the + Cu treatment. The −Cu brindled mice were smaller than their littermate brothers (+/y) but had equivalent biochemical features consistent with severe Cu deficiency. Compared with control mice from dams on the +Cu treatment, caeruloplasmin (EC1.16.3.1) activity was lower in offspring of all three other groups including Mobr/y mice who were not anaemic. Iron levels were similar in organs and bone marrow from all four groups of offspring. When dietary Cu is limiting in brindled mice a more severe Cu deficiency ensues. Thus, appropriate Cu nutriture is important to the management of Menkes' disease in humans, a genetic analogue of the brindled mouse.

Cytochrome-c oxidase isolated from the brain of swayback-diseased sheep displays unusual structure and uncharacteristic kinetics

1998 ◽  
Vol 34 (2-3) ◽  
pp. 233-247 ◽  
Author(s):  
Trevor Alleyne ◽  
Jerome Joseph ◽  
Anthony Lalla ◽  
Valerie Sampson ◽  
Andrew Adogwa
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Unusual Structure ◽  
The Brain

Loss of function of Sco1 and its interaction with cytochrome c oxidase

2009 ◽  
Vol 296 (5) ◽  
pp. C1218-C1226 ◽  
Author(s):  
Lukas Stiburek ◽  
Katerina Vesela ◽  
Hana Hansikova ◽  
Helena Hulkova ◽  
Jiri Zeman
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Copper Homeostasis ◽  
Copper Binding ◽  
Loss Of Function ◽  
Muscle Mitochondria ◽  
Juxtamembrane Region ◽  
Cellular Copper ◽  
The Impact ◽  
Blue Native

Sco1 and Sco2 are mitochondrial copper-binding proteins involved in the biogenesis of the CuA site in the cytochrome c oxidase (CcO) subunit Cox2 and in the maintenance of cellular copper homeostasis. Human Surf1 is a CcO assembly factor with an important but poorly characterized role in CcO biogenesis. Here, we analyzed the impact on CcO assembly and tissue copper levels of a G132S mutation in the juxtamembrane region of SCO1 metallochaperone associated with early onset hypertrophic cardiomyopathy, encephalopathy, hypotonia, and hepatopathy, assessed the total copper content of various SURF1 and SCO2-deficient tissues, and investigated the possible physical association between CcO and Sco1. The steady-state level of mutant Sco1 was severely decreased in the muscle mitochondria of the SCO1 patient, indicating compromised stability and thus loss of function of the protein. Unlike the wild-type variant, residual mutant Sco1 appeared to migrate exclusively in the monomeric form on blue native gels. Both the activity and content of CcO were reduced in the patient's muscle to ∼10–20% of control values. SCO1-deficient mitochondria showed accumulation of two Cox2 subcomplexes, suggesting that Sco1 is very likely responsible for a different posttranslational aspect of Cox2 maturation than Sco2. Intriguingly, the various SURF1-deficient samples analyzed showed a tissue-specific copper deficiency similar to that of SCO-deficient samples, suggesting a role for Surf1 in copper homeostasis regulation. Finally, both blue native immunoblot analysis and coimmunoprecipitation revealed that a fraction of Sco1 physically associates with the CcO complex in human muscle mitochondria, suggesting a possible direct relationship between CcO and the regulation of cellular copper homeostasis.

Sign in / Sign up

Export Citation Format

Share Document