PUBLICATION
A pH imbalance is linked to autophagic dysregulation of inner ear hair cells in Atp6v1ba-deficient zebrafish
- Authors
- Ikeuchi, M., Inoue, M., Miyahara, H., Sebastian, W.A., Miyazaki, S., Takeno, T., Kiyota, K., Yano, S., Shiraishi, H., Shimizu, N., Hanada, R., Yoshimura, A., Ihara, K., Hanada, T.
- ID
- ZDB-PUB-240128-1
- Date
- 2024
- Source
- Biochemical and Biophysical Research Communications 699: 149551149551 (Journal)
- Registered Authors
- Hanada, Reiko, Hanada, Toshikatsu
- Keywords
- ATP6V1B1, Atp6v1ba, Hearing loss, V-ATPase, Zebrafish, dRTA
- MeSH Terms
-
- Acidosis*
- Acidosis, Renal Tubular*/genetics
- Adenosine Triphosphate
- Animals
- Hair/metabolism
- Hair Cells, Auditory/pathology
- Hearing Loss, Sensorineural*/genetics
- Hearing Loss, Sensorineural*/pathology
- Humans
- Hydrogen-Ion Concentration
- Mutation
- Organometallic Compounds*
- Vacuolar Proton-Translocating ATPases*/genetics
- Vacuolar Proton-Translocating ATPases*/metabolism
- Zebrafish/metabolism
- PubMed
- 38277730 Full text @ Biochem. Biophys. Res. Commun.
Citation
Ikeuchi, M., Inoue, M., Miyahara, H., Sebastian, W.A., Miyazaki, S., Takeno, T., Kiyota, K., Yano, S., Shiraishi, H., Shimizu, N., Hanada, R., Yoshimura, A., Ihara, K., Hanada, T. (2024) A pH imbalance is linked to autophagic dysregulation of inner ear hair cells in Atp6v1ba-deficient zebrafish. Biochemical and Biophysical Research Communications. 699:149551149551.
Abstract
V-ATPase is an ATP hydrolysis-driven proton pump involved in the acidification of intracellular organelles and systemic acid-base homeostasis through H+ secretion in the renal collecting ducts. V-ATPase dysfunction is associated with hereditary distal renal tubular acidosis (dRTA). ATP6V1B1 encodes the B1 subunit of V-ATPase that is integral to ATP hydrolysis and subsequent H+ transport. Patients with pathogenic ATP6V1B1 mutations often exhibit an early onset of sensorineural hearing loss. However, the mechanisms underlying this association remain unclear. We employed morpholino oligonucleotide-mediated knockdown and CRISPR/Cas9 gene editing to generate Atp6v1ba-deficient (atp6v1ba-/-) zebrafish as an ortholog model for ATP6V1B1. The atp6v1ba-/- zebrafish exhibited systemic acidosis and significantly smaller otoliths compared to wild-type siblings. Moreover, deficiency in Atp6v1ba led to degeneration of inner ear hair cells, with ultrastructural changes indicative of autophagy. Our findings indicate a critical role of ATP6V1B1 in regulating lysosomal pH and autophagy in hair cells, and the results provide insights into the pathophysiology of sensorineural hearing loss in dRTA. Furthermore, this study demonstrates that the atp6v1ba-/- zebrafish model is a valuable tool for further investigation into disease mechanisms and potential therapies for acidosis-related hearing impairment.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping