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A deletion of mitochondrial DNA in murine doxorubicin-induced cardiotoxicity
K Adachi1, Y Fujiura, F Mayumi
1Institute of Cardiovascular Diseases, Kurume University School of Medicine, Fukuoka, Japan.
Abstract:
A deletion of about 4 kb has been determined in the mutated mitochondrial DNA (mtDNA) in cardiomyocytes with chronic doxorubicin (DOX)-induced cardiotoxicity in mouse. The incidence of the mtDNA deletion increased with the dosage and with the duration of the DOX administration. Coenzyme Q10 administration prevented the mtDNA deletion and decreased the thiobarbituric acid reactive substance content in the heart mitochondria, suggesting some free radical involvement in this mtDNA deletion. This mtDNA deletion may be involved in cardiomyopathy, which is known to be dosage-dependently induced by DOX administration.
Insights
Mitochondrial DNA (mtDNA) deletions in heart cells increase with doxorubicin (DOX) dosage and duration. Coenzyme Q10 prevents these deletions, suggesting a role in DOX-induced cardiotoxicity.
Area of Science:
- Cardiology
- Mitochondrial Biology
- Toxicology
Background:
- Doxorubicin (DOX) is a widely used chemotherapy agent.
- DOX administration can lead to cardiotoxicity, a serious side effect.
- The precise mechanisms underlying DOX-induced cardiotoxicity are not fully understood.
Purpose of the Study:
- To investigate the role of mitochondrial DNA (mtDNA) deletions in doxorubicin (DOX)-induced cardiotoxicity.
- To examine the effect of Coenzyme Q10 on DOX-induced mtDNA alterations.
Main Methods:
- Mice were treated with chronic doxorubicin (DOX) to induce cardiotoxicity.
- Mitochondrial DNA (mtDNA) deletions in cardiomyocytes were analyzed.
- Thiobarbituric acid reactive substance (TBARS) content in heart mitochondria was measured.
- The effect of Coenzyme Q10 administration was evaluated.
Main Results:
- A significant deletion of approximately 4 kb was identified in the mitochondrial DNA (mtDNA) of cardiomyocytes from DOX-treated mice.
- The incidence of this mtDNA deletion correlated positively with DOX dosage and duration of administration.
- Coenzyme Q10 treatment effectively prevented the occurrence of mtDNA deletions.
- Coenzyme Q10 also reduced the levels of thiobarbituric acid reactive substances (TBARS) in heart mitochondria.
Conclusions:
- A specific 4 kb mitochondrial DNA (mtDNA) deletion in cardiomyocytes is associated with chronic doxorubicin (DOX)-induced cardiotoxicity.
- The findings suggest that free radical involvement plays a role in the pathogenesis of DOX-induced mtDNA deletions.
- Coenzyme Q10 demonstrates a protective effect against DOX-induced cardiotoxicity, potentially by mitigating mtDNA damage.