Mitochondrial Dysfunction in Alzheimer’s Disease and Mitochondria-Targeted Therapeutics
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe review "Mitochondrial dysfunction in AD and mitochondria-targeted therapeutics" by the authors Jasbir Bisht, Priyanka Rawat, Andrew Shin and Vijay Hegde is a good collection of the bibliography on the hypothesis of mitochondrial dysfunction on Alzheimer's disease and possible treatments. I have some minor comments, except for one that it is the use of Photobiomodulation (that it is not considered in the paper) as a possible treatment for mitochondrial dysfunction, since the main hypothesis for Photobiomodulation is that red and infra-red light would enhance mitochondrial cytochrome c oxidase activity and ATP production, that it is on the same line of vision of the authors for treating AD. Of course, PBM is still an arguable topic, but I think the paper would be enriched including this possible treatment.
Other than that, as I said, there are minor issues, I would tune down a bit some phrases (even if I understand the point of view of the authors) as the one starting the Conclusion "Mitochondrial dysfunction has emerged as a central mechanism...". Even if they have shown several papers pointing this direction, there are many other hypotheses about the aetiology of AD (backed by many other papers).
Many of the sections end up saying "... this accumulation increases synaptic dysfunction" or "downstream of mitochondrial impairment, .... and compromises synaptic function", since it an interconnected pathway, yes affecting one affects the others, and the link with the synaptic function is never clear or straight. I understand it is for clearness/understanding on each section individually, but on the whole paper is a bit repetitive...
The figures are quite clear and easy to understand but I would change a few things to not lead to misunderstandings. On Fig 1, there is a panel called "Genetic integrity...". With this title I thought about nuclear DNA, but on the panel (and paper) they talk about mtDNA, which makes more sense (and again I would tune down "Principal contributor..."). Could they make it more explicit on the panel title?
On figure 3, lower panel (Path Dysr), instead of putting an arrow between APP accumulation and Tau aggregation, I would use a broken line arrow, to show that this connection could imply several other actors.
Finally, along the text there are several double space typos, that I guess there would be corrected.
Author Response
Comments 1: The review "Mitochondrial dysfunction in AD and mitochondria-targeted therapeutics" by the authors Jasbir Bisht, Priyanka Rawat, Andrew Shin and Vijay Hegde is a good collection of the bibliography on the hypothesis of mitochondrial dysfunction on Alzheimer's disease and possible treatments. I have some minor comments, except for one that it is the use of Photobiomodulation (that it is not considered in the paper) as a possible treatment for mitochondrial dysfunction, since the main hypothesis for Photobiomodulation is that red and infra-red light would enhance mitochondrial cytochrome c oxidase activity and ATP production, that it is on the same line of vision of the authors for treating AD. Of course, PBM is still an arguable topic, but I think the paper would be enriched including this possible treatment.
Response 1: Thank you for pointing this out. We agree with this comment. Therefore, we have added the Photobiomodulation section to the manuscript; it can be found on page 17, section 3.10 (highlighted in yellow).
Comments 2: Other than that, as I said, there are minor issues, I would tune down a bit some phrases (even if I understand the point of view of the authors) as the one starting the Conclusion "Mitochondrial dysfunction has emerged as a central mechanism...". Even if they have shown several papers pointing this direction, there are many other hypotheses about the etiology of AD (backed by many other papers).
Response 2: We sincerely thank the reviewer for the insightful comment. We have revised the opening of the conclusion and related statement throughout the manuscript (highlighted in yellow).
Comments 3: Many of the sections end up saying "... this accumulation increases synaptic dysfunction" or "downstream of mitochondrial impairment, .... and compromises synaptic function", since it an interconnected pathway, yes affecting one affects the others, and the link with the synaptic function is never clear or straight. I understand it is for clearness/understanding on each section individually, but on the whole paper is a bit repetitive...
Response 3: We thank the reviewer for this observation. We agree that repeated references to synaptic dysfunction at the ends of multiple sections made the manuscript read as repetitive. We have revised each section (sections 2.2 to 2.6) to reduce these redundant statements (highlighted in yellow).
Comments 4: The figures are quite clear and easy to understand but I would change a few things to not lead to misunderstandings. On Fig 1, there is a panel called "Genetic integrity...". With this title I thought about nuclear DNA, but on the panel (and paper) they talk about mtDNA, which makes more sense (and again I would tune down "Principal contributor..."). Could they make it more explicit on the panel title?
Response 4: We thank the reviewer for this helpful suggestion. We have revised the panel title in Figure 1 from "genetic integrity" to "mtDNA integrity" to avoid confusion with nuclear DNA. The phrase "principal contributor" within the same panel has also been softened to "key contributor". The caption for Figure 1 has been updated accordingly to reflect these changes.
Comments 5: On figure 3, lower panel (Path Dysr), instead of putting an arrow between APP accumulation and Tau aggregation, I would use a broken line arrow, to show that this connection could imply several other actors.
Response 5: Thank you for your feedback. The solid arrow between APP accumulation and TAU aggregation in the lower panel of Figure 3 has been replaced with a dashed arrow to indicate this indirect multistep relationship.
Comments 6: Finally, along the text there are several double space typos, that I guess there would be corrected.
Response 6: We thank the reviewer for noting that the manuscript has been carefully reviewed, and all double-spaced typos have been corrected throughout the text.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript dealing with mitochondrial dysfunction in AD and mitochondria-targeted therapeutics is well written, and only a few minor issues require correction.
Page 2: The expression “extreme reactive production of ROS” likely requires revision.
Figure 1: The statement “ATP for Synaptic Transmission” in the upper left panel of Figure 1 (“Bioenergetics & Redox Regulation”) is somewhat misleading or incomplete, as ATP is important for many more aspects of neuronal physiology than only synaptic transmission. I would recommend modifying this statement accordingly.
Figure 3: The meaning of the abbreviation “APP-CTFβ” is not explained in the figure legend, nor is it mentioned in the main text of the manuscript. The meaning of “CTFβ” and its biological role should also be explained in the main text.
Figure 4: The meaning of the abbreviation “VDAC” is not explained in the figure legend, nor is its mitochondrial function described. This information should be provided, together with a discussion of its relationship to the MPTP in the main text.
There is no reference to Table 1 in the main text of the manuscript, and this should be added.
Author Response
The manuscript dealing with mitochondrial dysfunction in AD and mitochondria-targeted therapeutics is well written, and only a few minor issues require correction.
Comments 1: Page 2: The expression “extreme reactive production of ROS” likely requires revision.
Response 1: We thank the reviewer for pointing this out. The phrase "extreme reactive production of ROS" has been revised to "excessive ROS production" for clarity and grammatical accuracy. (highlighted in yellow).
Comments 2: Figure 1: The statement “ATP for Synaptic Transmission” in the upper left panel of Figure 1 (“Bioenergetics & Redox Regulation”) is somewhat misleading or incomplete, as ATP is important for many more aspects of neuronal physiology than only synaptic transmission. I would recommend modifying this statement accordingly.
Response 2: We thank the reviewer for this valuable observation. We agree with the suggestion. The statement in Figure 1 has been revised from ATP for synaptic transmission to ATP production for synaptic transmission and neuronal homeostasis.
Comments 3: Figure 3: The meaning of the abbreviation “APP-CTFβ” is not explained in the figure legend, nor is it mentioned in the main text of the manuscript. The meaning of “CTFβ” and its biological role should also be explained in the main text.
Response 3: We thank the reviewer for this helpful observation. A new paragraph has been added to section 2.5 to explain its biological role with supporting references. The figure 3 legend has also been updated to include the definition of APP-CTFβ (highlighted in yellow).
Comments 4: Figure 4: The meaning of the abbreviation “VDAC” is not explained in the figure legend, nor is its mitochondrial function described. This information should be provided, together with a discussion of its relationship to the MPTP in the main text.
Response 4: We thank the reviewer for this suggestion. A new paragraph has been added to section 2.7 describing VDAC’s structure, function, and its relationship to the MPTP. The figure 4 legend has been updated to include definitions of abbreviations for VDAC, MPTP, BAX, ROS, and Δψm (highlighted in yellow).
Comments 5: There is no reference to Table 1 in the main text of the manuscript, and this should be added.
Response 5: We thank the reviewer for noting this. A citation to table 1 has now been added at the beginning of section 3. (highlighted in yellow).
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsThe article examines the role of mitochondrial dysfunction in the pathogenesis of Alzheimer’s disease, highlighting how alterations in energy metabolism, oxidative stress, defects in mitophagy, and calcium dysregulation contribute to neurodegeneration. The manuscript also discusses key mitochondria-targeted therapeutic strategies, including antioxidant molecules, modulators of mitochondrial dynamics, gene therapy, and mitotherapy. The topic is timely and of significant scientific interest. The manuscript is generally well structured and clearly written; however, a more thorough revision would be beneficial to further improve clarity, consistency, and overall readability.
Minor comments
- It is recommended to replace the abbreviation “AD” with the full term “Alzheimer’s disease” in the title to improve clarity, readability, and indexing of the manuscript.
- The abstract contains partial conceptual repetition in the following sentences: “Mitochondrial impairments play a central role in AD pathogenesis by disrupting cellular homeostasis, promoting oxidative stress, and contributing to progressive neuronal death. Increasing evidence suggests that mitochondrial impairment plays a significant role in the development and progression of AD.” A revised formulation is suggested to avoid redundancy and improve fluency.
- The use of abbreviations should be carefully checked for consistency throughout the manuscript (e.g., “AD” vs “Alzheimer’s disease”), including the highlights and main text. In addition, protein abbreviations should be defined at first mention.
- Some typographical errors and spacing issues are present and require careful proofreading of the text.
- References should be formatted according to the journal style, including the use of abbreviated journal name, as specified in the guidelines: “Author 1, A.B.; Author 2, C.D. Title of the article. Abbreviated Journal Name Year, Volume, page range.”
- Figure captions are not fully consistent throughout the manuscript. A more concise and uniform style is suggested for all captions (e.g., “Schematic representation of…” instead of “This figure illustrates…”).
- Table 1 should be explicitly cited in the text before its appearance. Additionally, the abbreviation “NCA” in the table should be checked, as it is likely intended to be “NAC”.
Author Response
The article examines the role of mitochondrial dysfunction in the pathogenesis of Alzheimer’s disease, highlighting how alterations in energy metabolism, oxidative stress, defects in mitophagy, and calcium dysregulation contribute to neurodegeneration. The manuscript also discusses key mitochondria-targeted therapeutic strategies, including antioxidant molecules, modulators of mitochondrial dynamics, gene therapy, and mitotherapy. The topic is timely and of significant scientific interest. The manuscript is generally well structured and clearly written; however, a more thorough revision would be beneficial to further improve clarity, consistency, and overall readability.
Minor comments
Comment 1: It is recommended to replace the abbreviation “AD” with the full term “Alzheimer’s disease” in the title to improve clarity, readability, and indexing of the manuscript.
Response 1: We thank the reviewer for this suggestion. The abbreviation of AD has been replaced with the full-term Alzheimer’s disease. (highlighted in yellow).
Comment 2: The abstract contains partial conceptual repetition in the following sentences: “Mitochondrial impairments play a central role in AD pathogenesis by disrupting cellular homeostasis, promoting oxidative stress, and contributing to progressive neuronal death. Increasing evidence suggests that mitochondrial impairment plays a significant role in the development and progression of AD.” A revised formulation is suggested to avoid redundancy and improve fluency.
Response 2: We thank the reviewer for this helpful suggestion. The two repetitive sentences in the abstract have been combined into a single, clearer statement. (highlighted in yellow).
Comment 3: The use of abbreviations should be carefully checked for consistency throughout the manuscript (e.g., “AD” vs “Alzheimer’s disease”), including the highlights and main text. In addition, protein abbreviations should be defined at first mention.
Response 3: We thank the reviewer for this observation. The abbreviations were carefully checked and updated throughout the manuscript (highlighted in yellow).
Comment 4: Some typographical errors and spacing issues are present and require careful proofreading of the text.
Response 4: We thank the reviewer for this helpful observation. The manuscript has been thoroughly checked for spacing issues.
Comment 5: References should be formatted according to the journal style, including the use of abbreviated journal name, as specified in the guidelines: “Author 1, A.B.; Author 2, C.D. Title of the article. Abbreviated Journal Name Year, Volume, page range.”
Response 5: We thank the reviewer for this important note. All references in the manuscript have been carefully reformatted to follow the journal’s required style.
Comment 6: Figure captions are not fully consistent throughout the manuscript. A more concise and uniform style is suggested for all captions (e.g., “Schematic representation of…” instead of “This figure illustrates…”).
Response 6: We thank the reviewer for this suggestion. All figure captions have been revised to follow a consistent and concise style (highlighted in yellow).
Comment 7: Table 1 should be explicitly cited in the text before its appearance. Additionally, the abbreviation “NCA” in the table should be checked, as it is likely intended to be “NAC”.
Response 7: We thank the reviewer for this observation. A citation to Table 1 has been added at the beginning of Section 3. The abbreviation NCA in Table 1 has been corrected to NAC. (highlighted in yellow).
Author Response File: Author Response.pdf
