MTOR Signaling in the Inner Ear As Potential Target to Treat Hearing Loss

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jul 2

PMID 34198685

Citations 7

Authors

Maurizio Cortada

Soledad Levano

Daniel Bodmer

Affiliations

Soon will be listed here.

Abstract

Hearing loss affects many people worldwide and occurs often as a result of age, ototoxic drugs and/or excessive noise exposure. With a growing number of elderly people, the number of people suffering from hearing loss will also increase in the future. Despite the high number of affected people, for most patients there is no curative therapy for hearing loss and hearing aids or cochlea implants remain the only option. Important treatment approaches for hearing loss include the development of regenerative therapies or the inhibition of cell death/promotion of cell survival pathways. The mammalian target of rapamycin (mTOR) pathway is a central regulator of cell growth, is involved in cell survival, and has been shown to be implicated in many age-related diseases. In the inner ear, mTOR signaling has also started to gain attention recently. In this review, we will emphasize recent discoveries of mTOR signaling in the inner ear and discuss implications for possible treatments for hearing restoration.

Citing Articles

VASCilia (Vision Analysis StereoCilia): A Napari Plugin for Deep Learning-Based 3D Analysis of Cochlear Hair Cell Stereocilia Bundles.

Kassim Y, Rosenberg D, Das S, Huang Z, Rahman S, Shammaa I bioRxiv. 2024; .

PMID: 38948743 PMC: 11212889. DOI: 10.1101/2024.06.17.599381.

A Low Dose of Rapamycin Promotes Hair Cell Differentiation by Enriching SOX2 Progenitors in the Neonatal Mouse Inner Ear Organoids.

Wu W, Chen P, Yang J, Liu Y J Assoc Res Otolaryngol. 2024; 25(2):149-165.

PMID: 38472516 PMC: 11018585. DOI: 10.1007/s10162-024-00938-1.

mTORC2 regulates auditory hair cell structure and function.

Cortada M, Levano S, Hall M, Bodmer D iScience. 2023; 26(9):107687.

PMID: 37694145 PMC: 10484995. DOI: 10.1016/j.isci.2023.107687.

mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging.

Das A, Reis F Int J Mol Sci. 2023; 24(17).

PMID: 37686434 PMC: 10487471. DOI: 10.3390/ijms241713628.

mTOR Signaling in BDNF-Treated Guinea Pigs after Ototoxic Deafening.

Tisi A, Ramekers D, Flati V, Versnel H, Maccarone R Biomedicines. 2022; 10(11).

PMID: 36428503 PMC: 9687683. DOI: 10.3390/biomedicines10112935.

References

Scaiola A, Mangia F, Imseng S, Boehringer D, Berneiser K, Shimobayashi M . The 3.2-Å resolution structure of human mTORC2. Sci Adv. 2020; 6(45). PMC: 7673708. DOI: 10.1126/sciadv.abc1251. View

Francis S, Katz J, Fanning K, Harris K, Nicholas B, Lacy M . A novel role of cytosolic protein synthesis inhibition in aminoglycoside ototoxicity. J Neurosci. 2013; 33(7):3079-93. PMC: 3711767. DOI: 10.1523/JNEUROSCI.3430-12.2013. View

Sha S, Chen F, Schacht J . PTEN attenuates PIP3/Akt signaling in the cochlea of the aging CBA/J mouse. Hear Res. 2009; 264(1-2):86-92. PMC: 2868099. DOI: 10.1016/j.heares.2009.09.002. View

Corwin J, Cotanche D . Regeneration of sensory hair cells after acoustic trauma. Science. 1988; 240(4860):1772-4. DOI: 10.1126/science.3381100. View

Bar-Peled L, Chantranupong L, Cherniack A, Chen W, Ottina K, Grabiner B . A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013; 340(6136):1100-6. PMC: 3728654. DOI: 10.1126/science.1232044. View

Reiling J, Sabatini D . Stress and mTORture signaling. Oncogene. 2006; 25(48):6373-83. DOI: 10.1038/sj.onc.1209889. View

Fu W, Hall M . Regulation of mTORC2 Signaling. Genes (Basel). 2020; 11(9). PMC: 7564249. DOI: 10.3390/genes11091045. View

Zid B, Rogers A, Katewa S, Vargas M, Kolipinski M, Lu T . 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell. 2009; 139(1):149-60. PMC: 2759400. DOI: 10.1016/j.cell.2009.07.034. View

Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung S . SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006; 127(1):125-37. DOI: 10.1016/j.cell.2006.08.033. View

10.

Wang J, Puel J . Presbycusis: An Update on Cochlear Mechanisms and Therapies. J Clin Med. 2020; 9(1). PMC: 7019248. DOI: 10.3390/jcm9010218. View

11.

Zheng J, Gao W . Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nat Neurosci. 2000; 3(6):580-6. DOI: 10.1038/75753. View

12.

Fang B, Xiao H . Rapamycin alleviates cisplatin-induced ototoxicity in vivo. Biochem Biophys Res Commun. 2014; 448(4):443-7. DOI: 10.1016/j.bbrc.2014.04.123. View

13.

Roczniak-Ferguson A, Petit C, Froehlich F, Qian S, Ky J, Angarola B . The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012; 5(228):ra42. PMC: 3437338. DOI: 10.1126/scisignal.2002790. View

14.

Fujioka M, Akiyama T, Hosoya M, Kikuchi K, Fujiki Y, Saito Y . A phase I/IIa double blind single institute trial of low dose sirolimus for Pendred syndrome/DFNB4. Medicine (Baltimore). 2020; 99(19):e19763. PMC: 7220392. DOI: 10.1097/MD.0000000000019763. View

15.

Kazyken D, Magnuson B, Bodur C, Acosta-Jaquez H, Zhang D, Tong X . AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. Sci Signal. 2019; 12(585). PMC: 6935248. DOI: 10.1126/scisignal.aav3249. View

16.

Bodmer D, Levano-Huaman S . Sesn2/AMPK/mTOR signaling mediates balance between survival and apoptosis in sensory hair cells under stress. Cell Death Dis. 2017; 8(10):e3068. PMC: 5680579. DOI: 10.1038/cddis.2017.457. View

17.

Saito K, Araki Y, Kontani K, Nishina H, Katada T . Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. J Biochem. 2005; 137(3):423-30. DOI: 10.1093/jb/mvi046. View

18.

Hresko R, Mueckler M . mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem. 2005; 280(49):40406-16. DOI: 10.1074/jbc.M508361200. View

19.

Stuttfeld E, Aylett C, Imseng S, Boehringer D, Scaiola A, Sauer E . Architecture of the human mTORC2 core complex. Elife. 2018; 7. PMC: 5837792. DOI: 10.7554/eLife.33101. View

20.

Ganley I, Lam D, Wang J, Ding X, Chen S, Jiang X . ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009; 284(18):12297-305. PMC: 2673298. DOI: 10.1074/jbc.M900573200. View