Author response: Cumulative mitochondrial activity correlates with ototoxin susceptibility in zebrafish mechanosensory hair cells

Mitochondria play a prominent role in mechanosensory hair cell damage and death. Although hair cells are thought to be energetically demanding cells, how mitochondria respond to these demands and how this might relate to cell death is largely unexplored. Using genetically encoded indicators, we found that mitochondrial calcium flux and oxidation are regulated by mechanotransduction and demonstrate that hair cell activity has both acute and long-term consequences on mitochondrial function. We tested whether variation in mitochondrial activity reflected differences in the vulnerability of hair cells to the toxic drug neomycin. We observed that susceptibility did not correspond to the acute level of mitochondrial activity but rather to the cumulative history of that activity.

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Using the Zebrafish Lateral Line to Understand the Roles of Mitochondria in Sensorineural Hearing Loss

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.628712 ◽

2021 ◽

Vol 8 ◽

Cited By ~ 1

Author(s):

Melanie Holmgren ◽

Lavinia Sheets

Keyword(s):

Cell Death ◽

Hearing Loss ◽

Hair Cell ◽

Sensorineural Hearing Loss ◽

Lateral Line ◽

Hair Cells ◽

High Energy ◽

Sensorineural Hearing ◽

Mitochondrial Activity ◽

Ototoxic Drugs

Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model in which to study hair-cell mitochondrial activity. Moreover, the ease of genetic manipulation of zebrafish embryos allows for the study of mutations implicated in human deafness, as well as the generation of transgenic models to visualize mitochondrial calcium transients and mitochondrial activity in live organisms. Studies of the zebrafish lateral line have shown that variations in mitochondrial activity can predict hair-cell susceptibility to damage by aminoglycosides or noise exposure. In addition, antioxidants have been shown to protect against noise trauma and ototoxic drug–induced hair-cell death. In this review, we discuss the tools and findings of recent investigations into zebrafish hair-cell mitochondria and their involvement in cellular processes, both under homeostatic conditions and in response to noise or ototoxic drugs. The zebrafish lateral line is a valuable model in which to study the roles of mitochondria in hair-cell pathologies and to develop therapeutic strategies to prevent sensorineural hearing loss in humans.

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Axodendritic versus axosomatic cochlear efferent termination is determined by afferent type in a hierarchical logic of circuit formation

Science Advances ◽

10.1126/sciadv.abd8637 ◽

2021 ◽

Vol 7 (4) ◽

pp. eabd8637

Author(s):

Jemma L. Webber ◽

John C. Clancy ◽

Yingjie Zhou ◽

Natalia Yraola ◽

Kazuaki Homma ◽

...

Keyword(s):

Hair Cells ◽

Fiber Type ◽

Afferent Fiber ◽

Outer Hair Cells ◽

Type I ◽

Type Ii ◽

Efferent Neurons ◽

Distinct Pair ◽

Mechanosensory Hair Cells ◽

Circuit Formation

Hearing involves a stereotyped neural network communicating cochlea and brain. How this sensorineural circuit assembles is largely unknown. The cochlea houses two types of mechanosensory hair cells differing in function (sound transmission versus amplification) and location (inner versus outer compartments). Inner (IHCs) and outer hair cells (OHCs) are each innervated by a distinct pair of afferent and efferent neurons: IHCs are contacted by type I afferents receiving axodendritic efferent contacts; OHCs are contacted by type II afferents and axosomatically terminating efferents. Using an Insm1 mouse mutant with IHCs in the position of OHCs, we discover a hierarchical sequence of instructions in which first IHCs attract, and OHCs repel, type I afferents; second, type II afferents innervate hair cells not contacted by type I afferents; and last, afferent fiber type determines if and how efferents innervate, whether axodendritically on the afferent, axosomatically on the hair cell, or not at all.

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Delta-Notch signalling and the patterning of sensory cell differentiation in the zebrafish ear: evidence from the mind bomb mutant

Development ◽

10.1242/dev.125.23.4637 ◽

1998 ◽

Vol 125 (23) ◽

pp. 4637-4644 ◽

Cited By ~ 22

Author(s):

C. Haddon ◽

Y.J. Jiang ◽

L. Smithers ◽

J. Lewis

Keyword(s):

Cell Differentiation ◽

Lateral Inhibition ◽

Hair Cells ◽

Sensory Cell ◽

Cell Types ◽

Notch Signalling ◽

Supporting Cells ◽

Fine Grained ◽

Mechanosensory Hair Cells ◽

The Mind

Mechanosensory hair cells in the sensory patches of the vertebrate ear are interspersed among supporting cells, forming a fine-grained pattern of alternating cell types. Analogies with Drosophila mechanosensory bristle development suggest that this pattern could be generated through lateral inhibition mediated by Notch signalling. In the zebrafish ear rudiment, homologues of Notch are widely expressed, while the Delta homologues deltaA, deltaB and deltaD, coding for Notch ligands, are expressed in small numbers of cells in regions where hair cells are soon to differentiate. This suggests that the delta-expressing cells are nascent hair cells, in agreement with findings for Delta1 in the chick. According to the lateral inhibition hypothesis, the nascent hair cells, by expressing Delta protein, would inhibit their neighbours from becoming hair cells, forcing them to be supporting cells instead. The zebrafish mind bomb mutant has abnormalities in the central nervous system, somites, and elsewhere, diagnostic of a failure of Delta-Notch signalling: in the CNS, it shows a neurogenic phenotype accompanied by misregulated delta gene expression. Similar misregulation of delta; genes is seen in the ear, along with misregulation of a Serrate homologue, serrateB, coding for an alternative Notch ligand. Most dramatically, the sensory patches in the mind bomb ear consist solely of hair cells, which are produced in great excess and prematurely; at 36 hours post fertilization, there are more than ten times as many as normal, while supporting cells are absent. A twofold increase is seen in the number of otic neurons also. The findings are strong evidence that lateral inhibition mediated by Delta-Notch signalling controls the pattern of sensory cell differentiation in the ear.

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Rheotaxis in Larval Zebrafish Is Mediated by Lateral Line Mechanosensory Hair Cells

PLoS ONE ◽

10.1371/journal.pone.0029727 ◽

2012 ◽

Vol 7 (2) ◽

pp. e29727 ◽

Cited By ~ 87

Author(s):

Arminda Suli ◽

Glen M. Watson ◽

Edwin W. Rubel ◽

David W. Raible

Keyword(s):

Lateral Line ◽

Hair Cells ◽

Larval Zebrafish ◽

Mechanosensory Hair Cells

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Larval zebrafish rapidly sense the water flow of a predator's strike

Biology Letters ◽

10.1098/rsbl.2009.0048 ◽

2009 ◽

Vol 5 (4) ◽

pp. 477-479 ◽

Cited By ~ 93

Author(s):

M.J. McHenry ◽

K.E. Feitl ◽

J.A. Strother ◽

W.J. Van Trump

Keyword(s):

Water Flow ◽

Lateral Line ◽

Hair Cells ◽

Escape Response ◽

Neuromuscular Control ◽

Lateral Line System ◽

Line System ◽

Novel Device ◽

Larval Fishes ◽

Mechanosensory Hair Cells

Larval fishes have a remarkable ability to sense and evade the feeding strike of a predator fish with a rapid escape manoeuvre. Although the neuromuscular control of this behaviour is well studied, it is not clear what stimulus allows a larva to sense a predator. Here we show that this escape response is triggered by the water flow created during a predator's strike. Using a novel device, the impulse chamber, zebrafish ( Danio rerio ) larvae were exposed to this accelerating flow with high repeatability. Larvae responded to this stimulus with an escape response having a latency (mode=13–15 ms) that was fast enough to respond to predators. This flow was detected by the lateral line system, which includes mechanosensory hair cells within the skin. Pharmacologically ablating these cells caused the escape response to diminish, but then recover as the hair cells regenerated. These findings demonstrate that the lateral line system plays a role in predator evasion at this vulnerable stage of growth in fishes.

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The cell biology of hearing

The Journal of Cell Biology ◽

10.1083/jcb.201001138 ◽

2010 ◽

Vol 190 (1) ◽

pp. 9-20 ◽

Cited By ~ 166

Author(s):

Martin Schwander ◽

Bechara Kachar ◽

Ulrich Müller

Keyword(s):

Hair Cell ◽

Inner Ear ◽

Hair Cells ◽

Cell Biology ◽

Cell Development ◽

Biological Mechanisms ◽

Electrical Signals ◽

Mechanosensory Hair Cells

Mammals have an astonishing ability to sense and discriminate sounds of different frequencies and intensities. Fundamental for this process are mechanosensory hair cells in the inner ear that convert sound-induced vibrations into electrical signals. The study of genes that are linked to deafness has provided insights into the cell biological mechanisms that control hair cell development and their function as mechanosensors.

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