Doxorubicin treatment of human cardiomyocytes increased mitochondria-lysosome contact frequency approximately seven-fold compared with control (6.6 vs 0.9 contacts per minute).
Does doxorubicin alter mitochondria-lysosome contact dynamics in human cardiomyocytes?
Doxorubicin significantly increases mitochondria-lysosome contact frequency and alters organelle architecture in human cardiomyocytes, suggesting disrupted inter-organelle communication contributes to anthracycline cardiotoxicity.
Absolute Event Rate: 6.6% vs 0.9%
Background: Doxorubicin (DOX) is a highly effective anticancer drug but its clinical use is limited by dose-dependent cardiotoxicity. Emerging evidence implicates lysosomal dysfunction and disrupted mitochondrial homeostasis in this toxicity. Because inter-organelle communication is essential for maintaining cellular balance under stress, we examined whether altered mitochondria–lysosome membrane contact sites (MCS) contribute to DOX-induced cardiotoxicity. Objective: To investigate how DOX affects mitochondria-lysosome membrane contact sites (MCS) dynamics in human cardiomyocytes using high-resolution live-cell imaging. Methods: Human AC16 cardiomyocytes were treated with 1 μM DOX for 16 hours. Mitochondria and lysosomes were simultaneously visualized using MitoTracker Green and LysoTracker Deep Red on a Zeiss LSM 980 Airyscan microscope. MCS events were quantified per cell. Mitochondrial morphology, lysosomal abundance, and protein expression of the lysosomal calcium channel mucolipin-1 (MCOLN1) were also assessed. Results: DOX increased mitochondria-lysosome contact frequency approximately seven-fold compared with control (6.6 ± 0.3 versus 0.9 ± 0.3 contacts per minute, n=3). Treated cells also showed pronounced mitochondrial fragmentation and a marked rise in lysosomal number (49.7±17.6 versus 6.7±1.5 lysosomes per cell). Following DOX withdrawal, contact frequency partially normalized while lysosomal abundance remained elevated, suggesting differential regulation of these stress responses. Western Blotting analysis revealed increased expression of mucolipin-1 (MCOLN1), a lysosomal calcium-release channel that modulates mitochondria-lysosome contact dynamics and mediates contact-dependent calcium transfer to mitochondria. This upregulation suggests a potential compensatory cellular response to DOX-induced stress and altered organellar dynamics.Conclusions: DOX significantly remodels mitochondria–lysosome contact dynamics in human cardiomyocytes, increasing MCS frequency and altering organelle architecture. These changes highlight disruption of inter-organelle communication as a potential contributor to anthracycline cardiotoxicity. Future work assessing contact duration, functional consequences on mitochondrial quality control, and in vivo validation will be essential for determining whether MCS regulation represents a viable therapeutic target. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Kobayashi et al. (Fri,) conducted a other in Doxorubicin-induced cardiotoxicity. Doxorubicin vs. Control was evaluated on Mitochondria-lysosome contact frequency (contacts per minute). Doxorubicin treatment of human cardiomyocytes increased mitochondria-lysosome contact frequency approximately seven-fold compared with control (6.6 vs 0.9 contacts per minute).
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