PONE-D-22-07315Leukocyte mitochondrial DNA copy number is a potential non-invasive biomarker for psoriasisPLOS ONE

Dear Dr. salem,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jun 05 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Tomoyoshi Komiyama, Ph.D

Academic Editor

PLOS ONE

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Additional Editor Comments:

Dear Authors,

The focus of your study was to investigate whether the mtDNA-CN is related to psoriasis and can serve as a disease biomarker.　In the results, the study demonstrated low mtDNA-CN in psoriasis patients compared to controls for the first time. In addition, it found that the reduction in mtDNA-CN was correlated with the disease duration and severity, suggesting that lower mtDNA-CN may be an early abnormality in psoriasis, and is also associated with the disease progression.

If these results become clear, I think your research is important for the future of clinical treatment of patients diagnosed with psoriasis, research on the causes of psoriasis, and clinical researchers who aim to better understand psoriasis characteristics during unconstrained daily activities.

However, I think that it is necessary to strengthen the reliability of the result by adding as much information as possible.

Based on two reviewer’s comments, I believe some major revision may be needed.

I have attached the comments from these reviewers about the manuscript that you might consider.

I think that the points suggested by these reviews will be helpful in the revision.

Tomoyoshi Komiyama

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this study, these authors have investigated that mtDNA-CN is a potential biomarker for psoriasis. This is an important finding in the field of psoriasis. The manuscript is compact and well written. Below are comments aimed at improving this important study even further:

1. All data present bar graph. I recommend to refine bar graph with overlapping dots plot or dot plot (Figure 1-3).

2. These authors described “the first to measure mtDNA-CN in psoriasis patients” in Abstract. I believe that this is true, however this sentence is prone to trouble for Journal (Plos One). I recommend to omit “the first”.

3. I recommend to refine detailed statistical significance in Abstract (page 2 line 12 and 14).

Reviewer #2: The manuscript entitled " Leukocyte mitochondrial DNA copy number is a potential non-invasive biomarker for psoriasis " describes a clinical study aimed to investigate the role of mtDMA in psoriasis. Although the experimental design and methods overall look appropriate, the manuscript requires significant revision.

Q1: Before treatment, there was a significant difference in age between the psoriasis group and the normal group. How to exclude the influence of age in this study?

Q2: This study showed a decrease in mtDNA in the serum of patients with psoriasis and investigated the relationship between mtDNA and the duration and severity of the disease, as well as its potential use as a biomarker for psoriasis. However, the relationship between mtDNA and mitochondrial function has not been directly proved here. It is suggested that the author add other blood examination indicator related to mitochondrial function and compare them with mtDNA to further clarify the influence of mtDAN on mitochondrial function.

Q3: Psoriasis is a chronic immune-mediated inflammatory skin disease, which is closely related to the function of mitochondria. The authors note: “Oxidative damage to mtDNA can result in mutations and alterations in mtDNA replication and/or transcription efficiency and mtDNA-CN, which may subsequently lead to a decline in mitochondrial functionwith more ROS production”. Mitochondria are the main sites of ROS production, and high concentration of ROS can promote oxidative stress response, and the increase of oxidative stress and inflammation will further induce mitochondrial damage, leading to cell apoptosis. However, the author did not detect ROS and inflammation indicators, so it is suggested to add the content of this part to clarify the effects of mtDNA damage on ROS, inflammation and apoptosis, and whether mtDNA changes affect psoriasis by regulating the above pathways?

Q4: Please add the code/number of ethics in the manuscript.

Q5: Statistical analyses require clarification. Were the data normally distributed? Please indicate in the chart notes which data conform to normal distribution and test method used.

Q6: Please provide a statement of interest.

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-22-07315R1Leukocyte mitochondrial DNA copy number is a potential non-invasive biomarker for psoriasisPLOS ONE

Dear Dr. salem,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 25 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tomoyoshi Komiyama, Ph.D

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Dear authors

Your study found that reduction in mtDNA-CN was correlated with disease duration and severity, suggesting that lower mtDNA-CN may be an early abnormality in psoriasis and is associated with disease progression.

I thought your study of the genetic marker for psoriasis was very interesting on a potential. Also, I think that the authors responded appropriately to the comments from the two reviewers. However, please correct some further points as noted below.

1.The purposes and results are slightly inconsistent across the abstract, introduction, discussion, and conclusion sections, please ensure they are the same throughout the manuscript so that they are easy to understand.

2. Please combine the known mitochondrial information that forms the basis of the discussion section with the introduction section.

3. Make the conclusion a little clearer. For limitation, please make a separate limitation section or add it to the discussion section as this needs to be described separately to the conclusion.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this study, these authors have investigated that mtDNA-CN is a potential biomarker for psoriasis.

This is an important finding in the field of psoriasis.

The manuscript is compact and well written.

In addition, I found that the manuscript has been revised well.

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Kazuhito Gotoh

Reviewer #2: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Leukocyte mitochondrial DNA copy number is a potential non-invasive biomarker for psoriasis

PONE-D-22-07315R2

Dear Dr. salem,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Tomoyoshi Komiyama, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear authors,

Thank you for submitting your revised manuscript.

I think it was much easier to understand than the original manuscript.

The authors revised the sentences according to reviewer’s comments.

I am satisfied with the responses and the edits, I am happy to accept this manuscript.

Therefore, I have no further questions.

Tomoyoshi Komiyama

Reviewers' comments: