Key result
Exposure to a sublethal dose of doxorubicin reduced the mitochondrial membrane potential red-to-green fluorescence ratio by 40.6% and increased mitophagy to 62.2% in H9c2 cardiomyocytes.
Why the study?
Doxorubicin causes cardiotoxic side effects frequently resulting in irreversible heart failure, but the complexities surrounding this toxicity, particularly at sublethal dosages, remain to be fully elucidated.
Effect estimate: 40.6% decrease
Absolute Event Rate: 1.9% vs 3.2%
p-value: p=<0.01
Sublethal doxorubicin induces early mitochondrial disruption in cardiomyocytes via CaMKII phosphorylation, identifying a potential therapeutic target to prevent anthracycline-induced cardiotoxicity.
Sublethal doxorubicin may flag CaMKII as a target to avert anthracycline cardiotoxicity; hypothesis-generating in animal models.
Background: Doxorubicin (Dox) is effective against different types of cancers, but it poses cardiotoxic side effects, frequently resulting in irreversible heart failure. However, the complexities surrounding this cardiotoxicity, especially at sublethal dosages, remain to be fully elucidated. We investigated early cellular disruptions in response to sublethal Dox, with a specific emphasis on the role of phosphorylated calcium/calmodulin-dependent protein kinase II (CaMKII) in initiating mitochondrial dysfunction. Methods: This study utilized the H9c2 cardiomyocyte model to identify a sublethal concentration of Dox and investigate its impact on mitochondrial health using markers such as mitochondrial membrane potential (MMP), mitophagy initiation, and mitochondrial calcium dynamics. We examined the roles of and interactions between CaMKII, dynamin-related protein 1 (Drp1), and the mitochondrial calcium uniporter (MCU) in Dox-induced mitochondrial disruption using specific inhibitors, such as KN-93, Mdivi-1, and Ru360, respectively. Results: Exposure to a sublethal dose of Dox reduced the MMP red-to-green fluorescence ratio in H9c2 cells by 40.6% compared with vehicle, and increased the proportion of cells undergoing mitophagy from negligible levels compared with vehicle to 62.2%. Mitochondrial calcium levels also increased by 8.7-fold compared with the vehicle group. Notably, the activation of CaMKII, particularly its phosphorylated form, was pivotal in driving these mitochondrial changes, as inhibition using KN-93 restored MMP and decreased mitophagy. However, inhibition of Drp1 and MCU functions had a limited impact on the observed mitochondrial disruptions. Conclusion: Sublethal administration of Dox is closely linked to CaMKII activation through phosphorylation, emphasizing its pivotal role in early mitochondrial disruption. These findings present a promising direction for developing therapeutic strategies that may alleviate the cardiotoxic effects of Dox, potentially increasing its clinical efficacy.
No takes yet. Share an insight, caveat, or question.
Priyono et al. (2024) studied Doxorubicin-induced cardiotoxicity. Doxorubicin vs. Vehicle was evaluated on Mitochondrial membrane potential (R/G ratio) (40.6% decrease, p=<0.01). Exposure to a sublethal dose of doxorubicin reduced the mitochondrial membrane potential red-to-green fluorescence ratio by 40.6% and increased mitophagy to 62.2% in H9c2 cardiomyocytes.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: