Key result
Doxorubicin drives cardiotoxicity by triggering direct mitochondrial and lysosomal permeabilization and promoting apoptosis.
Why the study?
Doxorubicin poses long-term cardiotoxic risks that increase mortality among cancer patients, but the molecular mechanisms of mitochondria–lysosome crosstalk during apoptosis remain unclear.
Doxorubicin causes cardiotoxicity in part by directly triggering mitochondrial and lysosomal permeabilization and disrupting cardiolipin, suggesting that protecting cardiolipin could serve as a cardioprotective strategy.
Doxorubicin is among the most commonly used chemotherapeutic agents for a wide range of cancers. Despite its effectiveness, it poses long-term cardiotoxic risks that elevate mortality among cancer patients. In this study, doxorubicin-mediated mitochondria–lysosome crosstalk in apoptosis and the underlying molecular mechanism are explored. The interactions between organelle-specific phospholipids and doxorubicin, and their structural basis, are investigated using comprehensive spectroscopy and molecular dynamics simulations. Our results by in situ Raman spectroscopy reveal that doxorubicin can directly trigger mitochondrial and lysosomal permeabilization, facilitating the release of key apoptotic modulators. Besides phospholipids, doxorubicin is found to interact with cytochrome c and boost its proapoptotic effect. Further study indicates that protecting cardiolipin is sufficient to inhibit doxorubicin-induced disruption of CL conformation. Accordingly, the molecular mechanism underlying doxorubicin-mediated mitochondria–lysosome crosstalk in apoptosis is proposed, paving the way for the rational design of cardioprotective agents targeting mitochondria and lysosomes for cancer patients.
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Song et al. (2026) studied Doxorubicin-induced cardiotoxicity. Doxorubicin was evaluated on Mitochondria-lysosome crosstalk and structural basis of organelle-specific interactions. Doxorubicin triggered direct mitochondrial and lysosomal permeabilization and interacted with cytochrome c to boost apoptosis, revealing molecular mechanisms of its cardiotoxicity.
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