Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy.
BACKGROUND
Doxorubicin causes a chronic cardiomyopathy of unknown pathogenesis. We investigated whether acquired defects in mitochondrial DNA (mtDNA) and interconnected respiratory chain dysfunction may represent a molecular mechanism for its late onset.


RESULTS
Rats were treated weekly with intravenous doxorubicin (1 mg/kg) for 7 weeks, starting at 11 weeks of age (group B). Controls received saline. Group C received doxorubicin identically to group B, but the course was started at 41 weeks of age. All rats were killed at week 48. Doxorubicin was also injected once, either 6 days (group D) or 2 hours (group E) before euthanasia. Heart and skeletal muscle were examined. Only group B rats developed a significant clinical, macroscopic, histological, and ultrastructural cardiomyopathy. Group B hearts had the lowest cytochrome c oxidase (COX) activity (24% of controls; P=0.003), the highest citrate synthase activity (135% of controls; P=0.005), and the highest production of superoxide. In group B, the respiratory subunit COXI, which is encoded by mtDNA, was reduced (P<0.001), as was mtDNA (49% of controls, P<0.001). Group C hearts differed from group B in their lower cardiomyopathy score (P=0.006), higher COX activity (P=0.02), and higher mtDNA content (P=0.04). Group B and to a lesser extent group C hearts contained deleted mtDNA. There was no detectable mitochondrial toxicity in group D and E hearts or in skeletal muscle.


CONCLUSIONS
In doxorubicin cardiomyopathy, mtDNA alterations, superoxide, and respiratory chain dysfunction accumulate long-term in the absence of the drug and are associated with a late onset.
Medizinische Universitätsklinik, Departments of Rheumatology and Clinical Immunology, Freiburg, Germany.
Dirk
D
Lebrecht
Bernhard
B
Setzer
Uwe-Peter
UP
Ketelsen
Jörg
J
Haberstroh
Ulrich A
UA
Walker
D000367:Age Factors; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics*; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D004579:Electron Transport / Q000187:drug effects*; D003576:Electron Transport Complex IV / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D013481:Superoxides; D004317:Doxorubicin; D003576:Electron Transport Complex IV