Autophagy in Sensorineural Hearing Loss: Jekyll or Hyde?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this manuscript, Dr. Duran-Alonso summarized the research progresses on autophagy in sensorineural hearing loss. This manuscript includes key research milestones and provides an up-to-date overview of the  functional and pathological roles of autophagy in hair cell development, age-related hearing loss and ototoxic drugs induced hearing loss. One suggestion is to add some diagram(s) to improve the readability of this manuscript.

Author Response

In this manuscript, Dr. Duran-Alonso summarized the research progresses on autophagy in sensorineural hearing loss. This manuscript includes key research milestones and provides an up-to-date overview of the  functional and pathological roles of autophagy in hair cell development, age-related hearing loss and ototoxic drugs induced hearing loss. One suggestion is to add some diagram(s) to improve the readability of this manuscript.

I do thank the reviewer for their suggestion to add a diagram to improve the readability of the manuscript. Following their directions, I have now added a diagram that summarizes key aspects discussed in the manuscript, which I have labeled as Figure 1 (Lines 61-62; Figure 1. Regulation and roles of autophagy in the auditory organ).

Thank you.

Reviewer 2 Report

Comments and Suggestions for Authors

This is an interesting, comprehensive, and well-written review that addresses the role of autophagy in the development, homeostasis, and pathological vulnerability of cochlear hair cells in the organ of Corti. The authors provide a thorough synthesis of current evidence linking dysregulation of autophagic and mitophagic pathways to cochlear damage induced by aging, ototoxic drugs, noise exposure, and genetic mutations. In particular, the manuscript effectively discusses how mitochondrial dysfunction and oxidative stress contribute to auditory cell degeneration under these conditions.

 

A major strength of the review is its balanced presentation of the dual role of autophagy, highlighting its protective function in maintaining cochlear cell homeostasis while also acknowledging that excessive or dysregulated autophagic activation may promote apoptotic pathways and exacerbate hair-cell loss. The authors appropriately emphasize the highly context-dependent nature of autophagic responses, which vary according to cochlear cell type, the nature and intensity of the damaging stimulus, and the timing and duration of exposure, as well as additional influences such as epigenetic regulation and genetic variability.

 

Overall, the article is of high scientific value, as it elucidates autophagy as a central molecular process and a promising therapeutic target for otoprotection. At the same time, the discussion appropriately recognizes the challenges associated with therapeutic modulation of autophagy, including the need for reliable biomarkers to monitor autophagic dynamics and the development of selective, non-toxic autophagy modulators.

 

I suggest that the authors further strengthen the manuscript by incorporating a recent relevant study (doi: 10.1007/s12035-025-05165-0) and expanding the discussion on the role of autophagy in noise-induced and glutamate-mediated synaptopathy. In particular, it would be valuable to address evidence indicating that autophagic processes may compromise the postsynaptic membrane of spiral ganglion neurons under these conditions, thereby extending the discussion beyond hair-cell survival to synaptic integrity.

Author Response

This is an interesting, comprehensive, and well-written review that addresses the role of autophagy in the development, homeostasis, and pathological vulnerability of cochlear hair cells in the organ of Corti. The authors provide a thorough synthesis of current evidence linking dysregulation of autophagic and mitophagic pathways to cochlear damage induced by aging, ototoxic drugs, noise exposure, and genetic mutations. In particular, the manuscript effectively discusses how mitochondrial dysfunction and oxidative stress contribute to auditory cell degeneration under these conditions.

A major strength of the review is its balanced presentation of the dual role of autophagy, highlighting its protective function in maintaining cochlear cell homeostasis while also acknowledging that excessive or dysregulated autophagic activation may promote apoptotic pathways and exacerbate hair-cell loss. The authors appropriately emphasize the highly context-dependent nature of autophagic responses, which vary according to cochlear cell type, the nature and intensity of the damaging stimulus, and the timing and duration of exposure, as well as additional influences such as epigenetic regulation and genetic variability.

Overall, the article is of high scientific value, as it elucidates autophagy as a central molecular process and a promising therapeutic target for otoprotection. At the same time, the discussion appropriately recognizes the challenges associated with therapeutic modulation of autophagy, including the need for reliable biomarkers to monitor autophagic dynamics and the development of selective, non-toxic autophagy modulators.

I suggest that the authors further strengthen the manuscript by incorporating a recent relevant study (doi: 10.1007/s12035-025-05165-0) and expanding the discussion on the role of autophagy in noise-induced and glutamate-mediated synaptopathy. In particular, it would be valuable to address evidence indicating that autophagic processes may compromise the postsynaptic membrane of spiral ganglion neurons under these conditions, thereby extending the discussion beyond hair-cell survival to synaptic integrity.

I would like to thank the reviewer for their positive evaluation of the manuscript and for pointing out the publication by Wang et al. to me. Indeed, I have introduced the results of this publication in the manuscript (pg. 18; lines 497-501) and in Table 3 (pg. 19).

I have also introduced a paragraph in pg. 18 (lines 493-502) expanding on noise exposure, glutamate excitotoxicity, autophagy and ribbon synapses. The newly added publications have been incorporated in the bibliography.

Thank you.