Peroxisome Carrier SLC25A17: Potential Biomarker for Peroxisome Dysfunction and Human Disease

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is a review dedicated to the SLC25A17 (PMP34) protein, a unique member of the SLC25 transporter family localized in peroxisomes. The authors explore the structure, proposed functions, and potential roles of the protein in various diseases, including cancer, neurodegenerative disorders, and mental illnesses. This topic is relevant as peroxisomal transporters remain understudied, and their dysfunction is associated with a wide range of pathologies. However, despite the importance of the topic under consideration, the manuscript contains a number of significant shortcomings in terms of structure, depth of analysis, and scientific rigor, which need to be addressed before the presentation.

Main comments:

1. Inconsistency between the stated aim and content: In the abstract and introduction, the authors state that the review aims to elucidate the physiological role of SLC25A17, however, the text is dominated by a simple enumeration of known facts, and critical controversies in the literature (e.g. regarding the transport of ATP, NAD⁺ and the effect on fatty acid oxidation) remain unresolved. The discussion is superficial and does not offer a clear concept that would explain the difference in phenotypes between the models (mice, zebrafish, and yeast).

2. There are errors in the numbering in Section 3 ("Functions of SLC25A17").

3. The role of SLC25A17 in peroxisome biogenesis is unclear. The text mentions that in yeast, PMP47 affects the number of organelles, but not in mice or fish (section 3.3.4). The authors miss the opportunity to discuss the possible reasons for this difference, such as the different roles of cofactors or the presence of compensatory mechanisms in higher eukaryotes.

4. The relationship between SLC25A17 and autophagy and the JAK/STAT3 signaling pathway is only briefly mentioned, although it is a key mechanism that needs to be deciphered in the cancer section.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Peroxisome-localizing SLC25A17 is proposed to transport metabolites and cofactors required for peroxisomal function. Although its substrate specificity remains elusive, recent studies employing gene knockout approaches have provided important insights into physiological roles of SLC25A17 in yeast, zebrafish, mice, and human cultured cells. In addition, gene expression analyses and genome-wide association studies have revealed associations between SLC25A17 and various cancers, as well as bipolar disorder. This manuscript provides a timely and well-organized review of these findings and in principle, suitable for publication.

However, in several sections, the logic and conclusions do not appear to be sufficiently supported, which may lead to confusions for readers. These issues should be carefully address as outlined below. Furthermore, section 5 “Discussion” is partially redundant. The topics discussed there should be appropriately integrated into 3 “Functions of SLC25A17”. Finally, all references should be carefully checked and appropriately cited in the relevant parts of the text.

 

Specific comments

• Throughout the manuscript, two terms SLC25A17 and PMP34 are used interchangeably and should be standardized to SLC25A17.
• Line 10-12: These two sentences present contradictory information regarding localization to mitochondria versus peroxisomes, and should therefore be revised.
• Line 46-48: The punctuation may be inappropriate and should be revised.
• Line 67-72: The second sentence appears partially redundant and should be revised.
• Line 83: “… orthologue of PMP47 in C. boidinii (?)”
• Title of Figure 1 should be revised.
• In Figure 2, sequences should be arranged in one column rather than 2 columns.
• Line 111-113: Please explain this experiment. To where were these cofactors preloaded?
• Line 113-114: Please consider revising the conjunctions or sentence structure.
• Line 115-116: Please add more explanations regarding experiments using Zebrafish.
• Line 118: What is not produced in peroxisomes?
• Line 123-125: The first part of the sentence appears to be redundant and should be revised.
• Line 136-141: Please specify the cited reference.
• Line 153-156: These sentences appear redundant and may be removed.
• Line 152: The citation of [15] appears incorrect.
• Line 157-158: Why was this conclusion drawn? The study using SLC25A17-KO mice provides strong evidence and should be appropriately introduced.
• Line 164: A period appears to be missing.
• Line 172-173: It may be inappropriate to generalize to “cofactors transporter”, since VLCFA is discussed here.
• Line 175: … influence VLCFA oxidation in mammalian cells (?)
• Line 175-176: Why was this statement made here?
• Line 178-187: It should be carefully considered how SLC25A17 is involved in MCFA oxidation. Based on the description human SLC25A17 appears to exhibit MCFA transport activity in S cerevisiae.
• Line 202-204: This sentence is somewhat difficult to read, and should be revised.
• Line 239-244: It remains unclear how progesterone-induced decidual protein and PPARs are regulated by SLC25A17 and how they influence tumor activity. Additional explanations would improve clarity.
• Line 250-252: This conclusion does not appear to follow from the preceding sentences, and additional explanations is required.
• Line 257-263: How is the SLC25A17 expression in those immune cells related to the cancer activity? Why is the statement of “Additionally ….” meaningful? The reference number [23] appears to be incorrect.
• Line 278-284: These sentences are difficult to follow and should be revised for clarity.
• Line 296-304: The study of [55] reports that familial risk for bipolar I disorder is not associated with impaired peroxisomal function, and that DHA deficits associated with familial bipolar disorder are not attributed to heritable defects in peroxisomal function. In light of this, how do the authors interpret the reported genetic association of SLC25A17 and bipolar disorder?
• Line 322: “in SLC25A17 (KO mice?)”

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I am satisfied with the authors' responses to my comments, as they have improved their work significantly. The article is ready for publication!

Author Response

Thank you very much for reviewing our manuscript. Thanks to reviewer’s insightful feedback, we were able to further improve our manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The revised manuscript has been improved by addressing most of my comments. However, one major concern regarding the Discussion section remains unsolved. It appears that newly added text has further increased redundancy. Given that a standard discussion is uncommon in review articles, parts of this section should be integrated into the relevant sections or reorganized into more specific sections with appropriate subheadings.

Newly added section “4.1 TNBC” describes findings based on SLC25A17-depleted breast cancer cell lines. However, the observed effects appear to be mediated primarily through ROS production, and more direct evidence linking SLC25A17 to TNBC, such as mechanistic insight or clinicopathological correlations is lacking.

In addition, the statement in Line 237 is apparently incorrect, and the following comments have not been fully addressed.

- Throughout the manuscript, two terms SLC25A17 and PMP34 are used interchangeably and should be standardized to SLC25A17. => Please see the line 133.

- Line 10-12: These two sentences present contradictory information regarding localization to mitochondria versus peroxisomes, and should therefore be revised.

=> The contradiction remained in this revision. How about including “peroxisome” in the first sentence.

 

Overall, although this review compiles many recent findings, the manuscript is not well organized, and some statements may be misleading to readers. I recommend that authors carefully reassess the literatures and ensure that each statement is accurate and well supported by appropriate references.

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf