PURPOSE: Doxorubicin is one of the most effective chemotherapeutic agents. 
However, up to 30% of the patients treated with doxorubicin suffer from 
congestive heart failure. The mechanism of doxorubicin cardiotoxicity is likely 
multifactorial and most importantly, the genetic factors predisposing to 
doxorubicin cardiotoxicity are unknown. On the basis of the fact that mtDNA 
lesions and mitochondrial dysfunctions have been found in human hearts exposed 
to doxorubicin and that mitochondrial topoisomerase 1 (Top1mt) specifically 
controls mtDNA homeostasis, we hypothesized that Top1mt knockout (KO) mice might 
exhibit hypersensitivity to doxorubicin.
EXPERIMENTAL DESIGN: Wild-type (WT) and KO Top1mt mice were treated once a week 
with 4 mg/kg doxorubicin for 8 weeks. Heart tissues were analyzed one week after 
the last treatment.
RESULTS: Genetic inactivation of Top1mt in mice accentuates mtDNA copy number 
loss and mtDNA damage in heart tissue following doxorubicin treatment. Top1mt KO 
mice also fail to maintain respiratory chain protein production and 
mitochondrial cristae ultrastructure organization. These mitochondrial defects 
result in decreased O2 consumption, increased reactive oxygen species 
production, and enhanced heart muscle damage in animals treated with 
doxorubicin. Accordingly, Top1mt KO mice die within 45 days after the last 
doxorubicin injection, whereas the WT mice survive.
CONCLUSIONS: Our results provide evidence that Top1mt, which is conserved across 
vertebrates, is critical for cardiac tolerance to doxorubicin and adaptive 
response to doxorubicin cardiotoxicity. They also suggest the potential of 
Top1mt single-nucleotide polymorphisms testing to investigate patient 
susceptibility to doxorubicin-induced cardiotoxicity.