Respiratory chain deficiency precedes the disrupted calcium homeostasis in chronic doxorubicin cardiomyopathy.
BACKGROUND
Doxorubicin causes a chronic cardiomyopathy in which genetic and functional lesions of mitochondria accumulate in the long-term. A disrupted Ca2+ homeostasis is also implicated in doxorubicin cardiotoxicity. We investigated if the alterations in myocellular Ca2+ are primary or secondary to the respiratory chain dysfunction in chronic doxorubicin cardiomyopathy.


RESULTS
A "long-observation group" of rats was treated with intravenous doxorubicin (1 mg/kg per week) for 7 weeks, starting at 11 weeks of age. Controls received equivalents of saline. A "short-observation group" received seven injections of doxorubicin, starting at 41 weeks of age. All rats were euthanized at 48 weeks of age. Only the long-observation rats developed a significant clinical, macroscopic, histological, and ultrastructural cardiomyopathy. Their intramyocardial cytochrome c oxidase (COX) activity was lowest; they had the highest loss of mitochondrial DNA (mtDNA) and its encoded respiratory chain subunit COX I, and the highest amount of ultrastructural and intracellular calcium accumulation resembling hydroxyapatite. The short-term-group hearts had fewer alterations of the cardiomyopathy score, COX-activity, and mtDNA-content than the long-observation group. Despite a measurable loss of mtDNA and its encoded respiratory chain activity, however, there was virtually no detectable calcium accumulation in the hearts of the short-term group.


CONCLUSIONS
mtDNA depletion and secondary respiratory chain dysfunction precedes the precipitation of mitochondrial calcium deposits in chronic doxorubicin cardiotoxicity.
Lebrecht
Dirk
D
Department of Rheumatology and Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany.
Kirschner
Janbernd
J
Geist
Andrea
A
Haberstroh
Jörg
J
Walker
Ulrich A
UA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004272:DNA, Mitochondrial / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D004579:Electron Transport / Q000187:drug effects*; D003576:Electron Transport Complex IV / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar
D000903:Antibiotics, Antineoplastic; D004272:DNA, Mitochondrial; D004317:Doxorubicin; D003576:Electron Transport Complex IV; D002118:Calcium