Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults
Sensory hair cells receive near constant stimulation by omnipresent auditory and vestibular stimuli. To detect and encode these stimuli, hair cells require steady ATP production, which can be accompanied by a buildup of mitochondrial byproducts called reactive oxygen species (ROS). ROS buildup is th...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/77775 |
| _version_ | 1828381246729748480 |
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| author | Daria Lukasz Alisha Beirl Katie Kindt |
| author_facet | Daria Lukasz Alisha Beirl Katie Kindt |
| author_sort | Daria Lukasz |
| collection | DOAJ |
| description | Sensory hair cells receive near constant stimulation by omnipresent auditory and vestibular stimuli. To detect and encode these stimuli, hair cells require steady ATP production, which can be accompanied by a buildup of mitochondrial byproducts called reactive oxygen species (ROS). ROS buildup is thought to sensitize hair cells to ototoxic insults, including the antibiotic neomycin. Work in neurons has shown that neurotransmission is a major driver of ATP production and ROS buildup. Therefore, we tested whether neurotransmission is a significant contributor to ROS buildup in hair cells. Using genetics and pharmacology, we disrupted two key aspects of neurotransmission in zebrafish hair cells: presynaptic calcium influx and the fusion of synaptic vesicles. We find that chronic block of neurotransmission enhances hair-cell survival when challenged with the ototoxin neomycin. This reduction in ototoxin susceptibility is accompanied by reduced mitochondrial activity, likely due to a reduced ATP demand. In addition, we show that mitochondrial oxidation and ROS buildup are reduced when neurotransmission is blocked. Mechanistically, we find that it is the synaptic vesicle cycle rather than presynaptic- or mitochondrial-calcium influx that contributes most significantly to this metabolic stress. Our results comprehensively indicate that, over time, neurotransmission causes ROS buildup that increases the susceptibility of hair cells to ototoxins. |
| first_indexed | 2024-12-10T04:12:11Z |
| format | Article |
| id | doaj.art-3d5b58c2095f46eaaea48a8ad65d2811 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:12:11Z |
| publishDate | 2022-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3d5b58c2095f46eaaea48a8ad65d28112022-12-22T02:02:42ZengeLife Sciences Publications LtdeLife2050-084X2022-09-011110.7554/eLife.77775Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insultsDaria Lukasz0https://orcid.org/0000-0002-8220-7712Alisha Beirl1Katie Kindt2https://orcid.org/0000-0002-1065-8215Section on Sensory Cell Development and Function, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, United States; Department of Biology, Johns Hopkins University, Baltimore, United StatesSection on Sensory Cell Development and Function, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, United StatesSection on Sensory Cell Development and Function, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, United StatesSensory hair cells receive near constant stimulation by omnipresent auditory and vestibular stimuli. To detect and encode these stimuli, hair cells require steady ATP production, which can be accompanied by a buildup of mitochondrial byproducts called reactive oxygen species (ROS). ROS buildup is thought to sensitize hair cells to ototoxic insults, including the antibiotic neomycin. Work in neurons has shown that neurotransmission is a major driver of ATP production and ROS buildup. Therefore, we tested whether neurotransmission is a significant contributor to ROS buildup in hair cells. Using genetics and pharmacology, we disrupted two key aspects of neurotransmission in zebrafish hair cells: presynaptic calcium influx and the fusion of synaptic vesicles. We find that chronic block of neurotransmission enhances hair-cell survival when challenged with the ototoxin neomycin. This reduction in ototoxin susceptibility is accompanied by reduced mitochondrial activity, likely due to a reduced ATP demand. In addition, we show that mitochondrial oxidation and ROS buildup are reduced when neurotransmission is blocked. Mechanistically, we find that it is the synaptic vesicle cycle rather than presynaptic- or mitochondrial-calcium influx that contributes most significantly to this metabolic stress. Our results comprehensively indicate that, over time, neurotransmission causes ROS buildup that increases the susceptibility of hair cells to ototoxins.https://elifesciences.org/articles/77775hair cellneurotransmissionototoxicitylateral linecalciummitochondria |
| spellingShingle | Daria Lukasz Alisha Beirl Katie Kindt Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults eLife hair cell neurotransmission ototoxicity lateral line calcium mitochondria |
| title | Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults |
| title_full | Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults |
| title_fullStr | Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults |
| title_full_unstemmed | Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults |
| title_short | Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults |
| title_sort | chronic neurotransmission increases the susceptibility of lateral line hair cells to ototoxic insults |
| topic | hair cell neurotransmission ototoxicity lateral line calcium mitochondria |
| url | https://elifesciences.org/articles/77775 |
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