Dose-dependent increase in sensitivity to calcium-induced mitochondrial dysfunction and cardiomyocyte cell injury by doxorubicin.
We previously reported the induction of calcium-dependent calcium release and depolarization of membrane potential of cardiac mitochondria from rats treated chronically (13 weeks) with doxorubicin. The fact that this was inhibited by cyclosporine A and ruthenium red suggests induction of the mitochondrial permeability transition and calcium cycling. The objective of this investigation was to characterize the cumulative dose-dependent interference with mitochondrial calcium transport by doxorubicin and to assess whether alteration of mitochondrial calcium regulation is manifested as an increased sensitivity to calcium-induced injury to cardiomyocytes isolated from rats exposed in vivo. Mitochondria or cardiomyocytes were isolated from rats treated with 2 mg/kg/week doxorubicin s.c. for 1-9 weeks. Mitochondria isolated from hearts of doxorubicin-treated rats exhibited a dose-dependent increase in sensitivity to calcium-induced calcium release and membrane depolarization, both of which were inhibited by cyclosporine A. Cardiomyocytes isolated from rats treated for 6 weeks with doxorubicin expressed an increased sensitivity to calcium-induced cell killing. The calcium intolerance was prevented by adding either cyclosporine A or ruthenium red to block mitochondrial calcium cycling. These data demonstrate that doxorubicin treatment in vivo causes: (1) a dose-dependent interference with mitochondrial calcium transport and calcium-dependent regulation of membrane potential indicative of induction of the mitochondrial permeability transition, and (2) an increased sensitivity to calcium-induced loss of cell viability. The fact that blocking mitochondrial calcium cycling protected cardiomyocytes from the calcium intolerance suggests that altered regulation of mitochondrial calcium transport may be a critical event in doxorubicin-induced cardiomyopathy.
Solem
L E
LE
Toxicology Graduate Program, University of Minnesota, Duluth 55812-2487, USA.
Heller
L J
LJ
Wallace
K B
KB
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D051381:Rats; D011916:Rats, Inbred F344
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D002118:Calcium