Monitoring of Doxorubicin-Mediated Mitochondria–Lysosome Crosstalk by In Situ Raman Spectroscopy: The Molecular Mechanism during Apoptosis and Implications for Cardiotoxicity

Abstract 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.