Aminoglycoside induced ototoxicity associated with mitochondrial DNA mutations

Foster, Joseph; Tekin, Mustafa

doi:10.1016/j.ejmhg.2016.06.001

Cited by 9 publications

(5 citation statements)

References 78 publications

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“…Many studies on aminoglycoside ototoxicity point to mitochondrial involvement as they are thought to be a target of aminoglycosides (reviewed in: Foster and Tekin, 2016 ). Our study highlights how hair-cell neurotransmission impacts mitochondria – promoting cellular metabolism, leading to a buildup of ROS and more oxidized mitochondria ( Figures 5 and 6 ).…”

Section: Discussionmentioning

confidence: 99%

Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults

Lukasz

Beirl

Kindt

2022

eLife

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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.

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Section: Discussionmentioning

confidence: 99%

Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults

Lukasz

Beirl

Kindt

2022

eLife

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“…Many studies on aminoglycoside ototoxicity point to mitochondrial involvement as they are thought to be a target of aminoglycosides (reviewed in: [51]). Our study highlights how hair-cell neurotransmission impacts mitochondria – promoting cellular metabolism, leading to a buildup of ROS and more oxidized mitochondria (Figure 5, 6, 7).…”

Section: Discussionmentioning

confidence: 99%

Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults

Lukasz

Beirl

Kindt

2022

Preprint

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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 is 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.

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“…Mutations in this gene are associated with an increased risk of aminoglycoside-induced hearing loss and maternally inherited non-syndromic hearing loss [54]. Aminoglycosiderelated hearing loss typically occurs shortly after exposure to these antibiotics, and the m.1555A>G variant in MT-RNR1 is strongly linked to this condition [55].…”

Section: A Mt-rnr1 Genementioning

confidence: 99%

Exploring the Heterogeneity of Non-Syndromic Hearing Loss: A Comprehensive Review of Implicated Genes and the Role of Whole Exome Sequencing

Barrak,

Bonyadi,

Hasan Jasim Hami

et al. 2023

UTJsci

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Background: Hereditary hearing loss (HHL) accounts for approximately 50-60% of all hearing loss (HL) cases, highlighting the significant role genetics play in this condition. HHL can be mostly classified into two main forms: syndromic and non-syndromic. Of these, non-syndromic hearing loss (NSHL) is the most prevalent, contributing to over 70% of HHL cases. The hearing process involves a complex interplay of various components inside the ear, working together to convert sound waves into comprehensible signals for the brain. Non-syndromic hearing loss (NSHL) is known for its extraordinary diversity and complexity, influenced by a vast array of genes, with more than 120 identified thus far. These genes can be categorized into distinct functional groups, encompassing cochlear ion homeostasis, hair bundle development and cell adhesion, synaptic transmission, transcriptional regulation, and mitochondrial function. The advent of next-generation sequencing (NGS) technologies has been instrumental in unraveling the genetic underpinnings of NSHL. Among NGS techniques, whole exome sequencing (WES) appeared as a revolutionary advancement, outperforming other approaches like targeted panel sequencing and whole-genome sequencing in terms of cost-effectiveness and efficiency. WES not only aids in deciphering the genetic basis of hearing loss but also offers the potential to revolutionize patient care and diagnosis. It paves the way for a new era for precision medicine in the realm of hearing loss, promising more accurate and tailored treatments for affected individuals. This transformative approach is poised to bring about substantial advancements in our understanding of hereditary hearing loss and its clinical management.

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Aminoglycoside induced ototoxicity associated with mitochondrial DNA mutations

Cited by 9 publications

References 78 publications

Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults

Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults

Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults

Exploring the Heterogeneity of Non-Syndromic Hearing Loss: A Comprehensive Review of Implicated Genes and the Role of Whole Exome Sequencing

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