title: Cardiac deficiency of single cytochrome oxidase assembly factor scox induces p53-dependent apoptosis in a Drosophila cardiomyopathy model.
abstract: The heart is a muscle with high energy demands. Hence, most patients with mitochondrial disease produced by defects in the oxidative phosphorylation (OXPHOS) system are susceptible to cardiac involvement. The presentation of mitochondrial cardiomyopathy includes hypertrophic, dilated and left ventricular noncompaction, but the molecular mechanisms involved in cardiac impairment are unknown. One of the most frequent OXPHOS defects in humans frequently associated with cardiomyopathy is cytochrome c oxidase (COX) deficiency caused by mutations in COX assembly factors such as Sco1 and Sco2. To investigate the molecular mechanisms that underlie the cardiomyopathy associated with Sco deficiency, we have heart specifically interfered scox expression, the single Drosophila Sco orthologue. Cardiac-specific knockdown of scox reduces fly lifespan, and it severely compromises heart function and structure, producing dilated cardiomyopathy. Cardiomyocytes with low levels of scox have a significant reduction in COX activity and they undergo a metabolic switch from OXPHOS to glycolysis, mimicking the clinical features found in patients harbouring Sco mutations. The major cardiac defects observed are produced by a significant increase in apoptosis, which is dp53-dependent. Genetic and molecular evidence strongly suggest that dp53 is directly involved in the development of the cardiomyopathy induced by scox deficiency. Remarkably, apoptosis is enhanced in the muscle and liver of Sco2 knock-out mice, clearly suggesting that cell death is a key feature of the COX deficiencies produced by mutations in Sco genes in humans.
authors: Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red (CIBERER), c/ Arzobispo Morcillo s/n,Universidad Autónoma de Madrid, Madrid 28029, Spain.
authors: Leticia
authors: L
authors: Martínez-Morentin
authors: Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red (CIBERER), c/ Arzobispo Morcillo s/n,Universidad Autónoma de Madrid, Madrid 28029, Spain.
authors: Lidia
authors: L
authors: Martínez
authors: Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 N Torrey Pine Rd, San Diego, CA 92037, USA.
authors: Sarah
authors: S
authors: Piloto
authors: Department of Neurology and Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, 630 West 168th Street P&S 4-449, New York, NY, USA and.
authors: Hua
authors: H
authors: Yang
authors: Department of Neurology and Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, 630 West 168th Street P&S 4-449, New York, NY, USA and.
authors: Eric A
authors: EA
authors: Schon
authors: Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red (CIBERER), c/ Arzobispo Morcillo s/n,Universidad Autónoma de Madrid, Madrid 28029, Spain, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid 28041, Spain.
authors: Rafael
authors: R
authors: Garesse
authors: Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 N Torrey Pine Rd, San Diego, CA 92037, USA.
authors: Rolf
authors: R
authors: Bodmer
authors: Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 N Torrey Pine Rd, San Diego, CA 92037, USA, juan.arredondo@uam.es margarita.cervera@uam.es kocorr@sanfordburnham.org.
authors: Karen
authors: K
authors: Ocorr
authors: Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red (CIBERER), c/ Arzobispo Morcillo s/n,Universidad Autónoma de Madrid, Madrid 28029, Spain, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid 28041, Spain juan.arredondo@uam.es margarita.cervera@uam.es kocorr@sanfordburnham.org.
authors: Margarita
authors: M
authors: Cervera
authors: Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red (CIBERER), c/ Arzobispo Morcillo s/n,Universidad Autónoma de Madrid, Madrid 28029, Spain, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid 28041, Spain juan.arredondo@uam.es margarita.cervera@uam.es kocorr@sanfordburnham.org.
authors: Juan J
authors: JJ
authors: Arredondo
mesh_terms: D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004330:Drosophila / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D016159:Tumor Suppressor Protein p53; C474203:p53 protein, Drosophila; D003576:Electron Transport Complex IV