Cisplatin exposure acutely disrupts mitochondrial bioenergetics in the zebrafish lateral-line organ

Lee, David S.; Schrader, Angela; Warchol, Mark E.; Sheets, Lavinia

doi:10.1016/j.heares.2022.108513

Cited by 13 publications

(11 citation statements)

References 46 publications

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“…Hair cell damage was first assessed in wildtype * AB larvae. Prior to drug treatment, fish were incubated in DAPI (catalog # MBD0015, Sigma-Aldrich, St. Louis, MO, United States; diluted to 1 µg/ml in EM) for 10 min at 28 • C. In live larvae, DAPI specifically labels lateral line hair cells and the label is retained after euthanasia (Uribe et al, 2018;Coffin et al, 2021;Holmgren et al, 2021;Lee et al, 2022; also see Supplementary Figure 1). Fish were then rinsed twice in EM and incubated for 24 h with variable concentrations (0.01-50 µM) in one of the following drugs (obtained from Sigma-Aldrich unless specified): remdesivir (catalog # 7226, Bio-Techne, Minneapolis, MN, United States), lopinavir, ritonavir, imatinib (catalog # S1380, S1185, S2475, respectively; Selleckchem, Houston, TX, United States), dexamethasone, azithromycin, or ivermectin (catalog # D1756, PHR1088, I8898, respectively).…”

Section: Drug Treatments and Hair Cell Assessmentmentioning

confidence: 99%

Putative COVID-19 therapies imatinib, lopinavir, ritonavir, and ivermectin cause hair cell damage: A targeted screen in the zebrafish lateral line

Coffin

Dale

Doppenberg

et al. 2022

Front. Cell. Neurosci.

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The biomedical community is rapidly developing COVID-19 drugs to bring much-need therapies to market, with over 900 drugs and drug combinations currently in clinical trials. While this pace of drug development is necessary, the risk of producing therapies with significant side-effects is also increased. One likely side-effect of some COVID-19 drugs is hearing loss, yet hearing is not assessed during preclinical development or clinical trials. We used the zebrafish lateral line, an established model for drug-induced sensory hair cell damage, to assess the ototoxic potential of seven drugs in clinical trials for treatment of COVID-19. We found that ivermectin, lopinavir, imatinib, and ritonavir were significantly toxic to lateral line hair cells. By contrast, the approved COVID-19 therapies dexamethasone and remdesivir did not cause damage. We also did not observe damage from the antibiotic azithromycin. Neither lopinavir nor ritonavir altered the number of pre-synaptic ribbons per surviving hair cell, while there was an increase in ribbons following imatinib or ivermectin exposure. Damage from lopinavir, imatinib, and ivermectin was specific to hair cells, with no overall cytotoxicity noted following TUNEL labeling. Ritonavir may be generally cytotoxic, as determined by an increase in the number of TUNEL-positive non-hair cells following ritonavir exposure. Pharmacological inhibition of the mechanotransduction (MET) channel attenuated damage caused by lopinavir and ritonavir but did not alter imatinib or ivermectin toxicity. These results suggest that lopinavir and ritonavir may enter hair cells through the MET channel, similar to known ototoxins such as aminoglycoside antibiotics. Finally, we asked if ivermectin was ototoxic to rats in vivo. While ivermectin is not recommended by the FDA for treating COVID-19, many people have chosen to take ivermectin without a doctor’s guidance, often with serious side-effects. Rats received daily subcutaneous injections for 10 days with a clinically relevant ivermectin dose (0.2 mg/kg). In contrast to our zebrafish assays, ivermectin did not cause ototoxicity in rats. Our research suggests that some drugs in clinical trials for COVID-19 may be ototoxic. This work can help identify drugs with the fewest side-effects and determine which therapies warrant audiometric monitoring.

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Section: Drug Treatments and Hair Cell Assessmentmentioning

confidence: 99%

Putative COVID-19 therapies imatinib, lopinavir, ritonavir, and ivermectin cause hair cell damage: A targeted screen in the zebrafish lateral line

Coffin

Dale

Doppenberg

et al. 2022

Front. Cell. Neurosci.

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“…We have previously shown that cisplatin induces Caspase-3-mediated apoptosis in conjunction with disruption of hair cell mitochondrial bioenergetics, suggesting a mitochondrially driven cell death pathway (18). To evaluate the onset and pattern of Caspase-3 activation, we exposed wildtype larvae at 6 dpf to either media exchange or 1 mM cisplatin for 2 hours, then allowed recovery in EM for an additional 2 hours.…”

Section: Cisplatin Treatment Leads To Progressive Activation Of Caspa...mentioning

confidence: 99%

“…Cisplatin exposure and fixation with activated Caspase-3 antibodies were performed as previously described with a few modifications (18). Briefly, groups of wildtype larvae (AB*) at 6 dpf were incubated for 2 hours in 30 mL EM with or without 1 mM cisplatin (Abcam) at 28˚C.…”

Section: Whole-mount Immunohistochemistry Imaging and Analysis Of Cas...mentioning

confidence: 99%

Cisplatin drives mitochondrial dysregulation in sensory hair cells

Lee,

Schrader,

Zou

et al. 2024

Preprint

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Cisplatin is a commonly used chemotherapy that causes permanent hearing loss by injuring cochlear hair cells. The underlying mechanisms that drive hair cell loss remain unknown, but mitochondria have emerged as potential mediators of cisplatin ototoxicity. Direct observation of changes in hair cell mitochondrial function are challenging because the mammalian inner ear is optically inaccessible. Here, we perform live in vivo imaging of hair cells within the zebrafish lateral-line organ to evaluate the role of mitochondria in cisplatin ototoxicity. Using a genetically encoded biosensor that measures cumulative mitochondrial activity in hair cells, we demonstrate that greater redox history increases susceptibility to cisplatin. Next, we conduct time-lapse imaging of individual hair cells to understand dynamic changes in mitochondrial homeostasis. We observe spikes in mitochondrial calcium and cytosolic calcium immediately prior to hair cell death. Furthermore, we use a mitochondrially-localized probe that fluoresces in the presence of cisplatin to show that cisplatin accumulates in hair cell mitochondria. Lastly, we demonstrate that this accumulation occurs before mitochondrial dysregulation, Caspase-3 activation, and ultimately, hair cell death. Our findings provide additional evidence that suggest mitochondria are integral to cisplatin ototoxicity and cisplatin directly targets hair cell mitochondria.

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“…Using genetic reporters to monitor cytosolic and mitochondrial dynamics in zebrafish during AA exposure, it has been possible to decode the signalling between mitochondrial, ER and the cytosolic compartments during HC death ( Esterberg et al, 2016( Esterberg et al, , 2014( Esterberg et al, , 2013Lee et al, 2022 ;Pickett et al, 2018 ). Like AA-induced signalling in mammalian HCs, exposure of lateral line HCs to neomycin or cisplatin causes rapid collapse of m, followed shortly by elevations in cytosolic Ca 2 + .…”

Section: Mitochondrial Ca 2 + Dysregulation and Activation Of The Ptp...mentioning

confidence: 99%

Mitochondrial form and function in hair cells

2023

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Cisplatin exposure acutely disrupts mitochondrial bioenergetics in the zebrafish lateral-line organ

Cited by 13 publications

References 46 publications

Putative COVID-19 therapies imatinib, lopinavir, ritonavir, and ivermectin cause hair cell damage: A targeted screen in the zebrafish lateral line

Putative COVID-19 therapies imatinib, lopinavir, ritonavir, and ivermectin cause hair cell damage: A targeted screen in the zebrafish lateral line

Cisplatin drives mitochondrial dysregulation in sensory hair cells

Mitochondrial form and function in hair cells

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