title: Radiation-induced signaling results in mitochondrial impairment in mouse heart at 4 weeks after exposure to X-rays.
abstract: BACKGROUND
  Radiation therapy treatment of breast cancer, Hodgkin's disease or childhood cancers expose the heart to high local radiation doses, causing an increased risk of cardiovascular disease in the survivors decades after the treatment. The mechanisms that underlie the radiation damage remain poorly understood so far. Previous data show that impairment of mitochondrial oxidative metabolism is directly linked to the development of cardiovascular disease.
  
  
  RESULTS
  In this study, the radiation-induced in vivo effects on cardiac mitochondrial proteome and function were investigated. C57BL/6N mice were exposed to local irradiation of the heart with doses of 0.2 Gy or 2 Gy (X-ray, 200 kV) at the age of eight weeks, the control mice were sham-irradiated. After four weeks the cardiac mitochondria were isolated and tested for proteomic and functional alterations. Two complementary proteomics approaches using both peptide and protein quantification strategies showed radiation-induced deregulation of 25 proteins in total. Three main biological categories were affected: the oxidative phophorylation, the pyruvate metabolism, and the cytoskeletal structure. The mitochondria exposed to high-dose irradiation showed functional impairment reflected as partial deactivation of Complex I (32%) and Complex III (11%), decreased succinate-driven respiratory capacity (13%), increased level of reactive oxygen species and enhanced oxidation of mitochondrial proteins. The changes in the pyruvate metabolism and structural proteins were seen with both low and high radiation doses.
  
  
  CONCLUSIONS
  This is the first study showing the biological alterations in the murine heart mitochondria several weeks after the exposure to low- and high-dose of ionizing radiation. Our results show that doses, equivalent to a single dose in radiotherapy, cause long-lasting changes in mitochondrial oxidative metabolism and mitochondria-associated cytoskeleton. This prompts us to propose that these first pathological changes lead to an increased risk of cardiovascular disease after radiation exposure.
authors.affiliation: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. zarko.barjaktarovic@helmholtz-muenchen.de
authors.forename: Zarko
authors.initials: Z
authors.lastname: Barjaktarovic
authors.forename: Dominik
authors.initials: D
authors.lastname: Schmaltz
authors.forename: Alena
authors.initials: A
authors.lastname: Shyla
authors.forename: Omid
authors.initials: O
authors.lastname: Azimzadeh
authors.forename: Sabine
authors.initials: S
authors.lastname: Schulz
authors.forename: Julia
authors.initials: J
authors.lastname: Haagen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dörr
authors.forename: Hakan
authors.initials: H
authors.lastname: Sarioglu
authors.forename: Alexander
authors.initials: A
authors.lastname: Schäfer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Atkinson
authors.forename: Hans
authors.initials: H
authors.lastname: Zischka
authors.forename: Soile
authors.initials: S
authors.lastname: Tapio
mesh_terms: D000818:Animals; D019295:Computational Biology; D003575:Cytochromes c1 / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D042967:Electron Transport Complex I / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects / Q000528:radiation effects; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D040901:Proteomics; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects*; D019802:Succinic Acid / Q000494:pharmacology; D014965:X-Rays
chemical_list: D024101:Mitochondrial Proteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D003575:Cytochromes c1; D019802:Succinic Acid; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III