title: Cardiac cytochrome c and cardiolipin depletion during anthracycline-induced chronic depression of mitochondrial function.
abstract: It is still unclear why anthracycline treatment results in a cardiac-specific myopathy. We investigated whether selective doxorubicin (DOX) cardiotoxicity involving mitochondrial degeneration is explained by different respiratory complexes reserves between tissues by comparing and contrasting treatment effects in heart vs liver and kidney. Alternatively, we have also explored if the degeneration is due to alterations of mitochondrial thresholds to incompatible states.
  
  
  
  Heart, liver and kidney mitochondria were isolated from male Wistar rats weekly injected with DOX during 7weeks. Global flux and isolated step curves were obtained for Complex I, III, IV, as well as for the adenine nucleotide translocator. We show treatment-related alterations in global flux curve for Complex III in all analyzed tissues and in Complex IV activity curve solely in heart. However, all mitochondrial threshold curves remained unchanged after treatment in the analyzed tissues. No treatment-related differences were detected on transcript or protein analysis of selected respiratory complexes subunits. However, a specific loss of cytochrome c and cardiolipin was measured in heart, but not in other organs, mitochondria from DOX-treated animals.
  
  
  
  Contrary to our hypothesis, impaired mitochondrial respiration could not be explained by intrinsic differences in respiratory complexes reserves among tissues or, by alterations in mitochondrial thresholds after treatment. Instead, we propose that loss of cytochrome c and cardiolipin are responsible for the depressed mitochondrial respiration observed after chronic DOX treatment. Moreover, cardiac cytochrome c and cardiolipin depletion decreases metabolic network buffering, hindering cardiac ability to respond to increased workload, accelerating cardiac aging.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Biocant Park, 3060-197 Cantanhede, Portugal; Department of Life Sciences, School of Sciences and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors.forename: Gonçalo C
authors.initials: GC
authors.lastname: Pereira
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Biocant Park, 3060-197 Cantanhede, Portugal; Department of Life Sciences, School of Sciences and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors.forename: Susana P
authors.initials: SP
authors.lastname: Pereira
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Biocant Park, 3060-197 Cantanhede, Portugal; Department of Life Sciences, School of Sciences and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors.forename: Ludgero C
authors.initials: LC
authors.lastname: Tavares
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Biocant Park, 3060-197 Cantanhede, Portugal; Department of Life Sciences, School of Sciences and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors.forename: Filipa S
authors.initials: FS
authors.lastname: Carvalho
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Biocant Park, 3060-197 Cantanhede, Portugal; Department of Life Sciences, School of Sciences and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors.forename: Silvia
authors.initials: S
authors.lastname: Magalhães-Novais
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Biocant Park, 3060-197 Cantanhede, Portugal; Department of Life Sciences, School of Sciences and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors.forename: Inês A
authors.initials: IA
authors.lastname: Barbosa
authors.affiliation: Department of Life Sciences, School of Sciences and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Santos
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Minnesota Medical School, Duluth, MN 55812, USA.
authors.forename: James
authors.initials: J
authors.lastname: Bjork
authors.affiliation: Department of Life Sciences, School of Sciences and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors.forename: António J
authors.initials: AJ
authors.lastname: Moreno
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Minnesota Medical School, Duluth, MN 55812, USA.
authors.forename: Kendall B
authors.initials: KB
authors.lastname: Wallace
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Biocant Park, 3060-197 Cantanhede, Portugal. Electronic address: pauloliv@cnc.uc.pt.
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Oliveira
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D002308:Cardiolipins / Q000032:analysis*; D045304:Cytochromes c / Q000032:analysis*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D017240:Mitochondrial Myopathies / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D017208:Rats, Wistar
chemical_list: D000903:Antibiotics, Antineoplastic; D002308:Cardiolipins; D004317:Doxorubicin; D045304:Cytochromes c
keywords: Animal model; Anthracycline; Cardiolipin; Cardiotoxicity; Metabolic reserve