Differential bioenergetic profile of human glioblastoma following transplantation of myocyte-derived mitochondria

Kent L. Marshall; Ethan Meadows; Alan Mizener; John M. Hollander; Christopher P. Cifarelli

doi:10.1371/journal.pone.0330322

Peer Review History

Original SubmissionJuly 30, 2025
25 Aug 2025 Decision Letter - Xiaosheng Tan, Editor Dear Dr. Cifarelli, 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 respond to reviewers' comments individually. Please submit your revised manuscript by Oct 09 2025 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. 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 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, Xiaosheng Tan Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for stating the following financial disclosure: “NIGMS P20GM121322 and NIH U54GM104942 to CPC. R01 HL-168290 and R01 ES-034628 to JMH. Community Foundation for the Ohio Valley Whipkey Trust to JMH” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. We note that “STR_3035_3046_PCS.pdf” in your submission contain copyrighted images. All PLOS content is published under the Creative Commons Attribution License (CC BY 4.0), which means that the manuscript, images, and Supporting Information files will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. For more information, see our copyright guidelines: http://journals.plos.org/plosone/s/licenses-and-copyright. We require you to either (1) present written permission from the copyright holder to publish these figures specifically under the CC BY 4.0 license, or (2) remove the figures from your submission: 1. You may seek permission from the original copyright holder of “STR_3035_3046_PCS.pdf” to publish the content specifically under the CC BY 4.0 license. We recommend that you contact the original copyright holder with the Content Permission Form (http://journals.plos.org/plosone/s/file?id=7c09/content-permission-form.pdf) and the following text: “I request permission for the open-access journal PLOS ONE to publish XXX under the Creative Commons Attribution License (CCAL) CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/). Please be aware that this license allows unrestricted use and distribution, even commercially, by third parties. Please reply and provide explicit written permission to publish XXX under a CC BY license and complete the attached form.” Please upload the completed Content Permission Form or other proof of granted permissions as an "Other" file with your submission. In the figure caption of the copyrighted figure, please include the following text: “Reprinted from [ref] under a CC BY license, with permission from [name of publisher], original copyright [original copyright year].” 2. If you are unable to obtain permission from the original copyright holder to publish these figures under the CC BY 4.0 license or if the copyright holder’s requirements are incompatible with the CC BY 4.0 license, please either i) remove the figure or ii) supply a replacement figure that complies with the CC BY 4.0 license. Please check copyright information on all replacement figures and update the figure caption with source information. If applicable, please specify in the figure caption text when a figure is similar but not identical to the original image and is therefore for illustrative purposes only. 4. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 5. 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: 1.The resolution of all figures need to be improved. 2. The signal of Figure 1-B is weak, seems like background, please improve the quality of picture. 3. For Figure 3A, please show the conducting statistics. Reviewer #2: The well written and coherent work describes research on mitochondrial transplantation using non-neoplastic, human myocyte-derived mitochondria into two mesenchymal subtype glioblastoma cell lines. The study investigates the impact on metabolic architecture and response to ionizing radiation, combining functional bioenergetic assays and transcriptomic profiling. The work is well presented, conceptualized and scientifically sound. I have several points that could help to improve the already great study. Questions: Can the authors comment on the purity and integrity of the isolated mitochondria after transplantation? A possible limitation is the short post-translation effect (48 hours), could long-term studies improve the understanding of therapeutic durability? In addition, the observation that U3046 cells show higher mitochondrial uptake but less functional augmentation raises questions about mitochondrial turnover, integration, or degradation in different subtypes. There is minimal discussion on whether mitochondrial transplantation could inadvertently support tumor growth in some contexts or induce off-target effects. The use of the cell-penetrating peptide Pep-1 is described, but the efficiency, potential toxicity, and specificity of this delivery mechanism are not deeply discussed. Clarification on statistical methods and whether all replicates are biological or technical would clarify the validity of the findings. The authors should address how the findings of the work could translate into in vivo models Minor comments: In methods, the composition of mitochondrial isolation buffer should be given Beginning of discussion: “granualr" is mistyped The picture depicted in fig 6a was created de novo by authors, or adopted from different work? If the latter is true, it should be referenced. The same applies for 6b. ****** 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 https://doi.org/10.1371/journal.pone.0330322.r001
Revision 1
10 Sep 2025 Author Response Responses to Reviewers (PONE-D-25-41544) Reviewer #1: 1.The resolution of all figures need to be improved. Thank you for bringing the resolution to our attention. All figures have been formatted according to the publisher’s requirements using TIFF format and 600 dpi. 2. The signal of Figure 1-B is weak, seems like background, please improve the quality of picture. This figure has been formatted to 600 dpi and the mitochondrial dye is more clearly visible. Once again, this figure represents the baseline mitochondrial content of the cells prior to mitochondrial transplant from the myocyte donor cells, so we anticipated that the intensity of staining would be less than the red tracker dye (myocyte only) and the overlay (native; green and donor; red). 3. For Figure 3A, please show the conducting statistics. A table has been inserted into this figure with the time specific values and standard deviations for both the OCR and ECAR data. Reviewer #2: The well written and coherent work describes research on mitochondrial transplantation using non-neoplastic, human myocyte-derived mitochondria into two mesenchymal subtype glioblastoma cell lines. The study investigates the impact on metabolic architecture and response to ionizing radiation, combining functional bioenergetic assays and transcriptomic profiling. The work is well presented, conceptualized and scientifically sound. I have several points that could help to improve the already great study. Questions: Can the authors comment on the purity and integrity of the isolated mitochondria after transplantation? The mitochondrial isolation was performed using a commercially available kit with manufacturer provided technical references. Although we performed the JC-1 assay on the transplants under stress and non-stress conditions, no additional test of mitochondrial function or membrane integrity was performed. We can assume that the response in the U3035 cells indicates that functional mitochondria and the U3046 cells received the same complement of donor mitochondria from the same extractions. We have mentioned this limitation to the process in our revised discussion: Discussion Page 15, Line 23: “Our work also indicates that transplanted mitochondria maintain polarization even under nutrient-limited or hypoxic conditions and reduced radiation-induced depolarization, suggesting a stabilizing effect on mitochondrial integrity under metabolic stress.” A possible limitation is the short post-translation effect (48 hours), could long-term studies improve the understanding of therapeutic durability? In our previous work on this topic, we employed the strategy of mitochondrial transplantation from one distinct glioblastoma cell line to another, using the same donor: recipient dye combinations (Marshall et al, 2025). In that study, we assayed for the retention of donor mtDNA in recipient cells up to 14 days post-transplantation. Within the revised discussion, we review the potential applications for mitochondrial transplantation largely encompassing adjuvant therapy to the standard of care given in a relatively short interval. We have mentioned the need for “long-term” studies in the discussion and how these would benefit translational potential: Discussion Page 17 Line 14: “Rather than a direct cytotoxic strategy, mitochondrial augmentation may represent a precision therapeutic approach to unmask latent metabolic liabilities in adaptable GBM subtypes. Stratification based on baseline metabolic engagement and radiation transcriptional profiles may help identify patients most likely to benefit from metabolism- and redox-directed combination strategies. This builds on our prior work that significant heterogeneity in response exists among glioblastoma cell lines, even those that share mesenchymal gene expression profiles [24]. Further in vivo studies will aid in elucidating the impact that mitochondrial transplantation could have in optimizing standard of care treatment for glioblastoma as a therapeutic adjunct.” In addition, the observation that U3046 cells show higher mitochondrial uptake but less functional augmentation raises questions about mitochondrial turnover, integration, or degradation in different subtypes. Thank you for addressing this phenomenon. One of our central conclusions to this study is the potential variable response to mitochondrial transplantation based on the recipient cell line. This underscores the heterogeneity of glioblastoma that becomes apparent when standard treatments, such as radiotherapy, are undertaken. We have discussed this in one of our other previous studies (Cifarelli et al, 2021) and have incorporated it into the revision: Discussion: Page 15, Line 22: “Notably, U3046 cells exhibited more persistent mitochondrial signal post-transplantation, possibly reflecting enhanced uptake or reduced turnover. Our work also indicates that transplanted mitochondria maintain polarization even under nutrient-limited or hypoxic conditions and reduced radiation-induced depolarization, suggesting a stabilizing effect on mitochondrial integrity under metabolic stress.” Discussion: Page 17, Line 16: “Stratification based on baseline metabolic engagement and radiation transcriptional profiles may help identify patients most likely to benefit from metabolism- and redox-directed combination strategies. This builds on our prior work that significant heterogeneity in response exists among glioblastoma cell lines, even those that share mesenchymal gene expression profiles [24].” There is minimal discussion on whether mitochondrial transplantation could inadvertently support tumor growth in some contexts or induce off-target effects. This was an initial concern of ours as well and emphasizes the need for further in vivo studies. We have discussed this in the limitations section: Discussion Page 17 Line 3: “While promising, this study has important limitations. Chief among them is the absence of in vivo outcome data and the lack of assessment regarding how mitochondrial transplantation may influence the long-term proliferative capacity of GBM cells. Addressing the former would require rodent model testing, which is complicated by the challenge of selecting a representative cell line—especially given the significant functional differences we observed between just two human GBM lines. Moreover, the increasing recognition of immune system involvement in GBM response would necessitate either the use of rodent glioma lines or humanized models, both of which may limit translatability. Regarding the potential impact on proliferation, our prior study using neoplastic donor and recipient cells did not demonstrate any increase in proliferative index [7]. However, future investigations—particularly those involving different donor:recipient combinations—will need to closely evaluate this possibility.” The use of the cell-penetrating peptide Pep-1 is described, but the efficiency, potential toxicity, and specificity of this delivery mechanism are not deeply discussed. CPPs, including Pep-, have been used in clinical models. We have updated the discussion with additional references: Discussion Page 15, Line 18: “Using a Pep-1 peptide–mediated delivery platform, we achieved efficient mitochondrial transfer from skeletal myocytes, confirmed by fluorescent signal tracking. CPPs, such as Pep-1 have a substantial amount of data supporting the efficiency of transport into a donor cell [18, 19]. Moreover, recent studies have confirmed that this approach can be clinically translatable with no evidence of toxicity[20].” Clarification on statistical methods and whether all replicates are biological or technical would clarify the validity of the findings. These notes are made within the figure captions for each data figure where applicable. The authors should address how the findings of the work could translate into in vivo models Discussion Page 17, Line 14: “Rather than a direct cytotoxic strategy, mitochondrial augmentation may represent a precision therapeutic approach to unmask latent metabolic liabilities in adaptable GBM subtypes. Stratification based on baseline metabolic engagement and radiation transcriptional profiles may help identify patients most likely to benefit from metabolism- and redox-directed combination strategies. This builds on our prior work that significant heterogeneity in response exists among glioblastoma cell lines, even those that share mesenchymal gene expression profiles [24]. Further in vivo studies will aid in elucidating the impact that mitochondrial transplantation could have in optimizing standard of care treatment for glioblastoma as a therapeutic adjunct.” Minor comments: In methods, the composition of mitochondrial isolation buffer should be given The mitochondrial isolation is performed using a commercially-available kit (BioVision; K288-50), now Abcam; ab288084). The manufacturer does not provide the composition of this proprietary buffer. Beginning of discussion: “granualr" is mistyped Corrected The picture depicted in fig 6a was created de novo by authors, or adopted from different work? If the latter is true, it should be referenced. The same applies for 6b. Thank you for identifying this oversight on our behalf. The figures from the KEGG pathways have been granted copyright release from the appropriate owners and documentation Attachments Attachment Submitted filename: PONE-D-25-41544_Response_to_reviewers_v1.pdf https://doi.org/10.1371/journal.pone.0330322.r002
20 Sep 2025 Decision Letter - Xiaosheng Tan, Editor Dear Dr. Cifarelli, 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 respond to reviewer's comments. Please submit your revised manuscript by Nov 04 2025 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. 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 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, Xiaosheng Tan Academic Editor PLOS ONE Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: No Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: 1. The quality of Figure 5 is not good. It is hard to identify the letter. Please improve it. 2. The quality of Figure 4A, 4B are not good. The letter of the top is hard to identify. 3. Please reorganize the order of all figures. Reviewer #2: The authors answered all my questions and addressed the concerns. I recommend the work for publication and congratulate them on the great work. ****** 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 https://doi.org/10.1371/journal.pone.0330322.r003
Revision 2
23 Sep 2025 Author Response Responses to Reviewers (PONE-D-25-41544R1) Reviewer #1: 1. The quality of Figure 5 is not good. It is hard to identify the letter. Please improve it. Figure 5 has been re-uploaded at 1200dpi, which exceeds the requirements of the Journal. 2. The quality of Figure 4A, 4B are not good. The letter of the top is hard to identify. Figures 4A and 4B have been re-uploaded at 1200dpi, which exceeds the requirements of the Journal. 3. Please reorganize the order of all figures. The order has been re-checked and is in accordance with the text. Reviewer #2: The authors answered all my questions and addressed the concerns. I recommend the work for publication and congratulate them on the great work. Thank you for your support. Attachments Attachment Submitted filename: PONE-D-25-41544_Response_to_reviewers_v2.docx https://doi.org/10.1371/journal.pone.0330322.r004
26 Sep 2025 Decision Letter - Xiaosheng Tan, Editor Dear Dr. Cifarelli, 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 Nov 10 2025 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. 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 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, Xiaosheng Tan Academic Editor PLOS ONE Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 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: Please respond to reviewer's comment. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Reviewer #1: It looks fine now. I agree to publish it. But the quality of Figure 5 is not good. It is better to improve the resolution of it. ****** 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: Chunyu WEI ******** [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 https://doi.org/10.1371/journal.pone.0330322.r005
Revision 3
29 Sep 2025 Author Response Responses to Reviewer (PONE-D-25-41544R2) Reviewer #1: Reviewer #1: It looks fine now. I agree to publish it. But the quality of Figure 5 is not good. It is better to improve the resolution of it. Figure 5 has been revised again. Attachments Attachment Submitted filename: PONE-D-25-41544R2_Response_to_reviewers.docx https://doi.org/10.1371/journal.pone.0330322.r006
1 Oct 2025 Decision Letter - Xiaosheng Tan, Editor Differential Bioenergetic Profile of Human Glioblastoma following Transplantation of Myocyte-derived Mitochondria PONE-D-25-41544R3 Dear Dr. Cifarelli, 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. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Xiaosheng Tan Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0330322.r007
Formally Accepted
Acceptance Letter - Xiaosheng Tan, Editor PONE-D-25-41544R3 PLOS ONE Dear Dr. Cifarelli, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Xiaosheng Tan Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0330322.r008

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .