Inhibition of Mitochondrial Division Attenuates Cisplatin-Induced Toxicity in the Neuromast Hair Cells

Abstract

Cisplatin and other related platinum antineoplastic drugs are commonly used in the treatment of a variety of cancers in both adults and children but are often associated with severe side effects, including hearing loss. Cisplatin’s ototoxic effects are multifaceted, culminating in irreversible damage to the mechanosensory hair cells in the inner ear. Platinum drugs act on cancerous cells by forming nuclear DNA adducts, which may initiate signaling leading to cell cycle arrest or apoptosis. Moreover, it was reported that cisplatin may induce mitochondrial DNA damage in non-cancerous cells. Therefore, protecting mitochondria may alleviate cisplatin-induced insult to non-proliferating cells. Thus, it is important to identify agents that shield the mitochondria from cisplatin-induced insult without compromising the anti-tumor actions of the platinum-based drugs. In this study we tested the protective properties of mitochondrial division inhibitor, mdivi-1, a derivative of quinazolinone and a regulator of mitochondrial fission. Interestingly, it has been reported that mdivi-1 increases the apoptosis of cells that are resistant to cisplatin. The ability of mdivi-1 to protect hair cells against cisplatin-induced toxicity was evaluated in a fish model. Wild-type (Tübingen strain), cdh23 mutant, and transgenic pvalb3b::GFP zebrafish stably expressing GFP in the hair cells were used in this study. Larvae at 5–6 days post fertilization were placed in varying concentrations of cisplatin (50–200 μM) and/or mdivi-1 (1–10 μM) for 16 h. To evaluate hair cell’s viability the number of hair bundles per neuromast were counted. To assess hair cell function, we used the FM1-43 uptake assay and recordings of neuromast microphonic potentials. The results showed that mdivi-1 protected hair cells of lateral line neuromasts when they were challenged by 50 μM of cisplatin: viability of hair cells increased almost twice from 19% ± 1.8% to 36% ± 2.0% (p < 0.001). No protection was observed when higher concentrations of cisplatin were used. In addition, our data were in accord with previously reported results that functional mechanotransduction strongly potentiates cisplatin-induced hair cell toxicity. Together, our results suggest that mitochondrial protection may prevent cisplatin-induced damage to hair cells.

ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity

“…Together, these results are consistent with the hypothesis that protection against AGs can be conferred by a direct competitive block of the channel, reducing intracellular accumulation, as has been suggested for gentamicin with both berbamine and d-tubocurarine (29). In the absence of direct evidence of whether or not cisplatin can enter mammalian hair cells through the MET channel (65), these data are at least consistent with prevention of MET-dependent toxicity as found in lateral line hair cells (26, 61).…”

“…Although zebrafish lateral line hair cells require functional MET channels for cisplatin-induced cell death to occur (26), there is currently no evidence that cisplatin actually enters lateral line hair cells through the MET channels in this species. The hair cells might instead be less metabolically stressed when the MET current is absent, e.g., due to a reduced Ca 2+ influx, thus increasing their resistance to ototoxic drugs (61). Whether or not the MET channels contribute to entry of cisplatin in mammalian hair cells remains uncertain.…”

Water Waves to Sound Waves: Using Zebrafish to Explore Hair Cell Biology

“…In support of this avenue, a recent study found that the cumulative history of mitochondrial activity correlated with susceptibility to death from neomycin exposure (Pickett et al 2018). Application of mdivi-1-a mitochondrial fission inhibitor-protected hair cells from cisplatin-induced hair cell toxicity (Vargo et al 2017), suggesting that mitochondrial function may broadly influence susceptibility of hair cells to damage. This suggests that mitochondrial dynamics may play a role in hair cell viability.…”

Genomic non-redundancy of the mir-183/96/182 cluster and its requirement for hair cell maintenance

“…Recordings of microphonic potentials 50,74 were conducted as previously described 75 . Zebrafish larvae were anesthetized using ethyl 3-aminobenzoate methanesulfonic acid (Sigma-Aldrich) dissolved in a bath solution (120 mM NaCl, 2 mM KCl, 10 mM HEPES, 2 mM CaCl 2 , 0.7 mM NaH 2 PO 4 and adjusted to pH 7.3).…”