Talk:Gnaiger 2019 MitoFit Preprints: Difference between revisions

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== Phase 3.1: Discussion ==
== Phase 3.1: Discussion ==
* 2018-02-21 [[Borutaite V]]
::::* The manuscript is excellent and solid work. Great work!
::::: This time I did just a few small comments.
::::: Thank you for including me as a coauthor. Indeed, I fully support this publication and will use recommendations in future works and teaching materials.


* 2018-02-21 [[Chinopoulos C]]
* 2018-02-21 [[Chinopoulos C]]

Revision as of 15:47, 21 February 2018

Bioblast wiki
» MitoEAGLE preprint 2018-02-08

Phase 3: MitoEAGLE preprint 2018-02-08

Fig. 9. Mitochondrial recovery, YmtE, in preparation of isolated mitochondria.
Towards a shorter version: Old Fig. 9 was removed.
  • 2018-02-08 Gnaiger E Version 22. Change of title: Mitochondrial respiratory states and rates: Building blocks of mitochondrial physiology. Part 1.
Dear co-authors and MitoEAGLE Network Members:
  • New manuscript version 22: www.mitoeagle.org/index.php/M
  • Change of title: Mitochondrial respiratory states and rates
  • Section 3 removed
  • Your feedback will be appreciated until Feb 20
Our MitoEAGLE position statement originally entitled 'The protonmotive force and respiratory control' has been discussed in many meetings and working groups. Many opinions and concerns have been raised about: (1) the exploding length; (2) the heterogeneity from respiratory states, to protonmotive force, to normalization of respiratory flow and flux; (3) the complex thermodynamic treatment in Section 3 of compartmental systems, power and entropy production, exergy, forces, electric and chemical advancement, fluxes, molecular-molar-electrical formats, and motive units; and (4) corresponding concerns about the meaning of co-authorship, if an entire section of the manuscript remains a challenge rather than becoming a familiar piece of collaborative work for most participants.
In the attempt to give a more detailed introduction and provide clarification of some basic principles related to the protonmotive force, I tried to stick to the conventional presentations of electric potential differences, ΔΨ, and chemical potential differences, ΔμH+, up to the point of recognizing a physicochemical incompleteness in the formal representation of potential differences. I am highly motivated to share a very simple but fundamental solution of this generally unrecognized problem with you, and want to talk about this at EBEC2018. The physicochemical formalism of potential differences is incomplete and terminologically inconsistent. The protonmotive force is not an electrochemical potential difference, but a difference of 'stoichiometric potentials'. A generalized concept of 'isomorphic forces' is suggested to describe the incomplete although mathematically correct equation defining the protonmotive force more properly. Since this discussion appears to be presently beyond the scope of a MitoEAGLE position statement, Section 3 (The protonmotive force, proton flux, and respiratory control) was removed from the new Version 22, the manuscript was updated (see improved Figure 8; extended Table 5), and the title was changed to 'Mitochondrial respiratory states and rates'.
Many co-authors asked about the state of submission and possibilities to further contribute and improve our MitoEAGLE position statement. In this phase 3 towards journal submission, we are asking you and a wider range of experts in the field for input preferentially with corresponding references. This should allow us without too much further delay (deadline: Feb 20) to incorporate your feedback and contact relevant journal editors for their opinion on implementing our recommendations into their journal policy. We want to proceed with submission to a preprint server and final journal submission. BBA was discussed at MiP2017 as a potentially suitable journal, and we are open for further suggestions.
With many thanks for your collaboration, Erich


  • 2018-02-06 Gnaiger E Version 21: Note: Subscript ‘§’ indicates throughout the text those parts, where potential differences provide a mathematically correct but physicochemically incomplete description and should be replaced by stoichiometric potential differences (Gnaiger 1993b). A unified concept on vectorial motive transformations and scalar chemical reactions will be derived elsewhere (Gnaiger, in prep.). Appreciation of the fundamental distinction between differences of potential versus differences of stoichiometric potential may be considered a key to critically evaluate the arguments presented in Section 3 on the protonmotive force. Since this discussion appears to be presently beyond the scope of a MitoEAGLE position statement, Section 3 will be removed from the next version and final manuscript. This section should become a topic of discussion within Working Group 1 of the MitoEAGLE consortium, following a primary peer-reviewed publication of the concept of stoichiometric potential differences.

Further references


Contacted editors

Updated 2018-02-12
  • Biochem J
  • Cell Metabolism: J. Estrompa, N. Emambokus
  • Chemico-Biological Interactions: D. Dietrich
  • Elsevier
Life Sciences: L. Wold
BBA Bioenergetics - Journal: A. Ruban and S. Arnold
Platelets: P. Harrison, S.P. Watson
Pharmacological Research: E. Clementi
Journal of Physiology and Biochemistry: M.J. Moreno Aliaga
  • FEBS Journal
  • FEBS Lett
  • Int. J. Biol. Macromol.: A. Dong
  • JIMD
  • Journal of Experimental Biology: I. Sokolova, H. Hoppeler, A.A. Biewener, R. Suarez, [email protected]
  • J Physiol: M.C. Hogan,
  • Mitochondrion: K.Singh, C. Thorn
  • Mitochondrial Research: P. Bernardi
  • PLOSOne: J. Heber
  • Redox Biology: S. Lamas

Phase 3.1: Discussion

  • The manuscript is excellent and solid work. Great work!
This time I did just a few small comments.
Thank you for including me as a coauthor. Indeed, I fully support this publication and will use recommendations in future works and teaching materials.
  • In page 10, line 429, please remove “hexokinase”, as this enzyme does not perform a transphosphorylation, it performs only a phosphorylation reaction.
Otherwise, I confirm to have read the newest version of the manuscript and agree to implement the recommendations into my future manuscripts, presentations and teaching materials.
Good luck with the submission!
  • I have given a thorough read to the latest version of the manuscript as downloaded from the MitoEAGLE webpage.
Please find attached my feedback (you will see a series, not many, of comments, or words typed in RED font, to attract your attention to what I have changed/suggested to change).

It is very polished at this stage and it has come a long way from the first version I reviewed back in summer 2017.

With this in mind; "I confirm that I read the latest version of the manuscript, and that I have provided feedback/improvements by sending a .pdf revised copy to the corresponding author (Prof. Erich Gnaiger), and that I agree to implement the recommendations into future manuscripts, presentations and teaching materials"
I would be extremely happy and grateful if I could be upgraded as a "contributing co-author".
  • I have read the manuscript. Again, congratulations for the good job, in my opinion everything is quite clear.
Just couple of small things, it could be interesting to mention that cardiolipin/phospholipids are necessary for the activity and stability of respiratory complexes and interact with subunits in all of them (i.e. PMID: 25038566; 16388600; 26300339). Also, I have noticed that in the manuscript is on UK english and on page 11 (line 480) the word “channeling” is in US english.
  • I am very much honored to be an author of this historical paper. I firmly believe this paper will be a base of new mitochondria based medicine. I had suggested a little for this paper early on and read most of the paper, while I did not grasp some part of it.
  • Thank you for your message and your work in finalizing this review.
I am happy to confirm that I have read the newest version of the manuscript, I am happy to be contributing co-author on the paper and I am happy to implement the recommendations in my future manuscripts presentations and teaching materials.
I have a few minor comments on the manuscript, please see below.
Line 237: ‘exerts’ instead of ‘exters’
Line 388: ‘processes’ instead of ‘process’
Line 388-390: This sentence is confusing; needs to be rephrased. ‘The amount of these chemicals…. being sought.’
Line 393-394: ‘are applied’ should go at the end of the phrase; comma may be needed after the paranthesis ‘…TMRM),’.
Line 738-739: Should be rephrased: ‘Cyanide and azide inhibit CIV and several additional peroxidases involved in Rox.’
Line 959: ‘optimized’ or ‘undergo optimization’ instead of ‘optimization’
Table 5: ‘Mtprep’ should this be with capital letter? Should it acctualy be ‘mt-prep’ or ‘mtprep’ ?
Also in the text we have ‘mt-markers’ and in the table ‘mt-Markers’
I guess we need to have them written in the same way.
General note: We use ‘z’ rather than ‘s’ in various situations like ‘normalization/ optimization’. I guess it needs to be checked with the editor.
  • Stupendous piece of work. It ill be for sure a reference in the field.
I am sending the file with some comments and corrections. Please follow them only if you agree.
  • I will look over the manuscript by the designated deadline.
Thank you very much
  • It is my great honor to be a co-author of MitoEAGLE manuscript.
I like the sections of metabolic state of mitochondria and coupling state. I wondered how to and what portion of protonmotive force generate heat for a long time. If you can explain or comment this on section 2.2, it would be great.
Thank you for your effort and dedication to mitochondria research.
  • I totally agree with the last version of the maniuscript. I have read it carefully.
  • Congratulations on the profound and necessary work in our field.
I read a manuscript versioon 22.
I totally agree with the removal of the chapter about thermodynamics,as we dscussed it at the Mip2017 meeting in Czech Republic.
I have only minor notes. First, Figure 1 shows also AOX. This is correct, but i think that comment or remark that AOX is absent in mammals should be added to the legend of the figure.
Chapter 3 about normalization is proportionally too comprehensive and i see possibilities for shortering paper mainly in this chapter. Table 6 can be excluded, if nessesery.
  • I would like to confirm that I have read the most recent version of the manuscript and I agree to the submission.
I agree to participate as a contributing co-author.
  • Many thanks for your note. I confirm that I read and approve the ms. for submission. Thanks for the great and important work.
  • The revised version is definitively clearer for non-experts, and my previous comments on the manuscript have been addressed. I’ll implement the recommendations detailed in this paper into future publications and teaching material.
Therefore I am happy to be listed as co-author for the submission to Cell Metab.
  • First of all, I think that the manuscript gains a lot after splitting it into the two parts. Reader of the text is more focused and do not get tired before the end .
There are some suggestions and thoughts, when reading the article.
In Figure 1 - maybe it is worth to mention that AOX is not present in mammalian cells ?
Table 2 explains very well terms of different coupled states in Figure 3, which are maybe otherwise difficult to distinguish for people who are not familiar with them. I do not know how it appears in the journal but maybe it is better to sum Table 1 and Table 2 so that when you look Figure 3, it is easier to find definition of the a/un/Dys/de-coupled respiration?
It is great news that the editor-in-chief of Cell Metabolism considered our article to be suitable for his journal. If it is necessary to make the article even shorter, 3.6 may be the part in my opinion. Maybe Table 7 is not so necessary as the texts already explains the basic concept.
In general I think the article is with a great importance to have all the basic concepts and definitions in one article and I am honored to be part of it.
  • Many thanks for the note and well done for the choice to submit to CELL METABOLISM.
I confirm that I read the newest version of the paper and have no further additions.
Please let me know if anything else is needed.
  • I confirm to have read the almost final version of the preprint publication, and agree to implement these recommendations.


  • I confirm that I have read the newest version of the manuscript and agree to implement the recommendations into my future manuscripts, presentations and teaching materials.
Thank you very much
  • Everything looks and sounds for me.
  • In figure 1A. I believe there are typos in the protons pumped at complex III and IV.
What ends up on the innermembrane side of complex III is 4H+ (or for molecular oxygen 8H+). Some of which comes from UQH2 and some from the matrix.
What ends up on the innermembrane side of complex IV is 2H+ (or for molecular oxygen 4H+). Half the protons from the matrix side combine with O2 to form water and don’t make it into the innermembrane space. Please see the attached edit. Plus a Figure 4.2 from the Brand and Nicholson Text.
If this is not correct, please clarify this issue for me.
Otherwise I agree with the manuscript and to be a co-author. Thank you.
  • I'm happy with this version of the manuscript. I confirm to have read the newest version of the manuscript and i agree to implement the recommendations into my future manuscripts, presentations and teaching materials.
  • It is great to hear that Cell Metabolism is interested. This work is a masterpiece of gentile science with rigorous attention to detail, and is sure to be broadly cited wherever it ends up. I am honored to have contributed as a co-author.
Best of luck with submission!
  • I am working at a couple of new short comments that I would like to submit to your attention as my additional contribution to the improvement of the current version of the manuscript. I hope that I will be able to send you my notes within a few days.
Meanwhile, as a contributing co-author, I confirm "to have read the newest version of the manuscript and to have made additions or suggestions for improvement". I also agree to implement the recommendations into my future manuscripts, presentations and teaching materials.
  • No further suggestions. I confirm to have read the newest version of the manuscript and to have made a suggestion for improvement
  • I have had an opportunity to review the contents of the manuscript and agree to implement the recommendations into our future manuscripts, presentations and teaching materials.
I am excited at the opportunity to present this article to the broader community and hope this gets accepted in ‘Cell Metabolism’. I once again thank you for your leadership in this regard, and look forward to our next meeting.
  • Thank-you for listing me. Happy to help in any other way
  • I´ve read the latest version and everything is to my satisfaction, my suggestion have been considered. I will implement this in my future papers, presentations and lectures. Best wishes and good luck with the submission.
  • I herby confirm that I have read the last version of the manuscript. I think the manuscript give a clear introduction to terms related to mitocondrial respiratory and I confirm to include them in my lab and in teaching.
  • Thanks for your letter re the manuscript. I’d be happy to be included as a co-author and will have a detailed read of it and get back to you in the next few days if i have any comments/suggestions.
...thanks for all the hard work.
  • I have read the newest version of the manuscript which it is far over my actual knowledge in the field. I have learned during the reading, and consequently I will be implement the concepts into our manuscripts, presentations, as well as teaching materials.
  • I am happy to be upgraded as contributing co-author and I will have a careful read over the current manuscript by Monday.
  • Thank you once more for the opportunity to participate in introducing concepts for the broad scientific community. I have read the newest version of the manuscript and I fully agree with nomenclature of mitochondrial respiratory states and rates. Also, I will try the best to implement the nomencalture in my (or my students) future papers, presentations and materials as I have been trying to do up to now.
  • I have read through the latest version of the manuscript. I do not have any additional suggestions for revision. Thank you for including me as a co-author.
I agree to implement the recommendations into my future manuscripts, presentations, and teaching materials. Please let me know if anything additional is needed.
  • This is fantastic to see the end of this first manuscript.
I hope this will go through.
  • Thank you for your note and update. I’ve been reading thoroughly and with great interest the latest version (#22) of the manuscript. I do not expect to have any further comments, but in case I have them you will receive them within the deadline
  • I have read the paper, it is very comprehensive. It struck me it might be perhaps informative to make a more head-on comparison of the new (leak, ET, ROX ) and old (state 1, 2 etc) definitions of the respiratory states, for example in one of the tables, or an addition table.
  • I am glad to have this opportunity and happy for selecting me as a Joint collaborator.
However, I go through the manuscript of all the concept of mitochondrial physiology, and previously that book I have already, also helps me a to understand the concept of Mitochondrial Physiology. Here, I am sending you a three answer of your question, I am bit unfit for reviewing all that concepts in this short span period. Here, I am sending all the explanations which I think, as per my understanding. If any feedback please let me know.
I will also share with my Supervisors and Colleague in further.
Gnaiger E: Do you recognize a general need for a consensus on nomenclature and standards of reporting in the field of mitochondrial respiratory physiology?
Sharma V: Respiratory rates and states would be possible to develop a researchers need to choose which effect size provides the best summary and specify which effect size they report. In the end, the choice of an Proton motive force, ETS, ET has play a significant role in effect size calculation depends on the research question and the experimental design. It is important to explicitly stated that which effect size is calculated, and to make a motivated choice about which effect sizes to report. With the current overview, The manuscript have provided a practical concept and consistency to assist researchers in choosing and calculating effect sizes by establishing the link between vectorial and scalar energy transformation and coupling in oxidative phosphorylation in both states.
Gnaiger E: Can you provide comments and suggestions for the ‘MitoEAGLE preprint: Mitochondrial respiratory states and rates’ from your point of view as an editor?
Sharma V: As per my suggestion the manuscript explained very well about to do the mechanisms behind observed oxygen consumption, and factors affecting the oxygen consumption rates and consequence of different electron pathway.
However, I would suggest the elaborate of any kind of procedure which will conduct as in vivo method determination of mitochondrial respiratory chain. I am not aware about how to perform such measurements in tissue does anybody have any experience in this topic kindly mentioned.
  • Short Classification of Mitochondrial biomarkers with respect to disorders in Respiratory states and Rates. (Healthy and Diseases States)
  • Emphasize the abnormal mitochondrial function and positioning alters multiple components of the specific organ physiological system.
Gnaiger E: Which further steps do you suggest towards implementing a harmonized terminology on mitochondrial states and rates in your editorial policy?
Sharma V:
  • Metabolic programming of immune cell differentiation and proliferation into anti and pro-inflammatory phenotypes, driven by the balance of oxidative phosphorylation (OXPHOS) vs. glycolysis and mitochondrial reactive oxygen species (mtROS).[1]
  • Mitochondrial epidemiological studies with reference to particular disease states and rates. [2]
  • Modulating the mitochondrial quality with diseases transmission with respect to mitochondrial biomarkers.[3][4]
  • Development of simulation studies, based on experimental method for predicting the future perspective of specific mitochondrial disorder.
  • Designing of multi-omics experiments and applying on large data sets to develop a precise medicine approach in mitochondrial dysfunction and also helps us to understand the physiological mechanism in different aspects. [3][4]
Reference
1. Picard, M., D.C. Wallace, and Y. Burelle, The rise of mitochondria in medicine. Mitochondrion, 2016. 30: p. 105-116.
2. Diot, A., et al., Modulating mitochondrial quality in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children. Biochemical Society Transactions, 2016. 44(4): p. 1091-1100.
3. Haas, R., et al., Designing and interpreting ‘multi-omic’experiments that may change our understanding of biology. Current Opinion in Systems Biology, 2017. 6: p. 37-45.
4. Meng, C., et al., A multivariate approach to the integration of multi-omics datasets. BMC bioinformatics, 2014. 15(1): p. 162.
  • I have read the manuscript and have no suggestions for further improvements. Let me know if you need any more information from me. I accept the upgrade to contributing co-author.
  • I read the last version and my group are all studying the manuscript to use it as a “bible” of mitochondria.
I am ok with the submission to a journal
  • I have not yet congratulated and thanked you for putting together this impressive document and for coordinating this whole effort, and I am doing so now. I attach the manuscript with a few comments, all minor and editorial. Good luck with the submission and thanks for involving me in the project!
  • Thank you. I have gone through the last version and will go through the latest version and get back asap.
I have read the manuscript again. It’s very solid. This time I only have a couple suggestions which may be implemented:
Page 11, line 480-482:
“…(4) mitochondrial density (enzyme concentrations and membrane area) and morphology (cristae folding, fission and fusion).”
Suggested reference to support this sentence: PMID: 24606803
Page 23, line 1018-1019:

“Mitochondria undergo dynamic fission and fusion cycles, and can exist in multiple stages and sizes which may be altered by a range of factors.”

I suggest to add something like this after the quoted sentence: “Changes in mitochondrial morphology is often associated with alterations in mitochondrial function, and In cultured cells this can be evaluated by quantitative analysis of mitochondrial shape using fluorescence microscopy and image analysis in 2 or 3 dimensions (Ref PMID: 24988307)”
Thanks.
  • Thank you for the opportunity to join as a co-author on the manuscript "Mitochondrial respiratory states and rates: Building blocks of mitochondrial physiology". I have taken the time to read the latest version, and am favourably impressed with the clarity of the writing and the content. This will be a most useful publication for many different research groups and teachers world-wide.
I did detect one typographical error: Box 1. Line 236/237 Membrane fluidity “exters”…, should I think read “extends”.
  • I have read the newest version of the manuscript and I think the manuscript looks excellent and I have no more further suggestions.


  • I'm glad to take part in the discussion of the MitoEAGLE preprint. The new version of the manuscript provides a significant step forward for the approach to mitochondrial metabolism concepts and the terminology harmonization, especially for the young scientists. For my purposes, I found very important the section on the Flux Normalization methods and principles; this point is crucial for the interpretation of the final outcomes and for the results comparison between different labs. The endeavour to find standard protocols and normalization requires time; nonetheless a statistical evaluation of the best mitochondrial marker for different mitochondrial preparation and tissues is needed. This issue is well pointed out in the conclusion section.
In Classical terminology for isolated mitochondria, the “classical states” of mitochondrial respiration are well presented; I have personally started the study of mitochondrial bioenergetic using the mitochondrial States as references for evaluating my respirometry experiments. Must we consider this terminology out of date or rather a co-existing complementary terminology?
  • please find attached our position statement manuscript - with one comment from me, right at the beginning (highlighted yellowed text).
Overall, the text is still not easy to digest. I had to read mnay sections two or three times to understand their intention. Maybe, a professional science writer should work on in to smoothen the tex as much as possible.
  • Thank you very much for inviting me to be a coauthor of your masterpiece of mitochondrial history! I will try my best to be qualified for being a contributing co-author
Gnaiger E: I would be very thankful for receiving your comments and critical evaluation of the present version of our manuscript.
  • Dear Anthony, Pushpa did a great job. Here is a first-level promising answer (see here).
Molina AJ: That is fantastic! I have worked with that editor before. A positive response from her is a promising sign.
  • I read the MitoEAGLE paper, and you've done a lot of work with it! It is more compact now, and it's much easier to read. The part of thermodynamics might be a separate article, this would be very important for young scientists and for the education in general in the field of bioenergetics.
May be you could advise me? I have problem with terminology, but I´m not sure, is it the topic of our paper (Mitochondrial respiratory states and rates: Building blocks of mitochondrial physiology). It is not clear at all, when the mitochondrial preparations are in vivo, in situ, ex vivo or in vitro. With isolated mitochondria no problem, this mitochondrial preparation is always described as in vitro. But with mitochondria in cell cultures the terminology is very messy. I met various variants like in vivo, in situ and ex vivo in different papers. The story is not better also with permebilized samples and tissue homogenates.
Gnaiger E: Thank you for your positive feedback. I agree that the thermodynamics part is important. I was reluctant to remove it, but the arguments to reduce the complexity of the present MS were valid.
You make a good point on the terminology of in vivo, in situ, ex vivo, .. I suggest that we ‘make it’ a topic of our paper, since we start with the definition of mitochondrial preparations. I suggest: all mitochondrial preparations are ‘in vitro’ (then we do not need ‘ex vivo’). In contrast to isolated mitochondrial and homogenate preparations, mitochondria can be considered as ‘in situ’ relative to the plasma membrane in permeabilized fibers and permeabilized cells. Do you think that everybody can agree on that? The text is included in the new version as a suggestion:
“Mitochondrial preparations are defined as either isolated mitochondria, or tissue and cellular preparations in which the barrier function of the plasma membrane is disrupted. Since this entails the loss of cell viability, mitochondrial preparations are not studied in vivo. In contrast to isolated mitochondria and tissue homogenate preparations, mitochondria in permeabilized tissues and cells are in situ relative to the plasma membrane.” (I will upload the new version in a few minutes)
Now we were invited by CELL METABOLISM to submit our manuscript for in-depth editorial evaluation.
  • Dear Prof. Liu Shusen, I would be very thankful for receiving your comments and critical evaluation of the present version of our manuscript. Below is the link to our updated version.
Liu SS: I will give my response as much as possible to you after my finishment of reading it. but, I am not sure every point I could agree with that noted in the manuscript, although, it is very good totally and generally! My main consideration is that biomembrane bioenergetics ,the study on mitochondrial oxidative phosphorylation is still in the rapid period of development and refinement, not only technically, but also theoritically/conceptionally. So, I need get time to learn and to read more recent scientific research achievements and progresses, including your manuscript!
  • I have received a response from "CELL METABOLISM". Looks like they are interested in our manuscript. Please read their response and advise me what to do next.
Gnaiger E: Thank you so much for your correspondence with CELL METABOLISM. This sounds like the door is not closed. I propose that I will add the Executive summar into the present pdf file and send the whole manuscript to Nikla Emambokus, Editor-in-Chief, Cell Metabolism. In any case, it will be interesting to receive his response.
Sharma P: Excellent idea to polish the manuscript and submit to CELL METABOLISM ASAP before editor changes his mind.
Gnaiger E: Dear Dr. Emambokus, we thank you for your interest in evaluating our manuscript ‘Mitochondrial respiratory states and rates: Building blocks of mitochondrial physiology’ in your in-house editorial review system.
A pdf file of the full manuscript is attached. A Task Group of the COST Action MitoEAGLE has been working on this manuscript with Open Access as a ‘MitoEAGLE preprint’ and the ultimate aim of peer-reviewed publication: » http://www.mitoeagle.org/index.php/MitoEAGLE_preprint_2018-02-08
The global MitoEAGLE network made it possible to collaborate with more than 250 co-authors to reach consensus on the present manuscript. Nevertheless, we do not consider scientific progress to be supported by ‘declaration’ statements (other than on ethical or political issues). Our manuscript aims at providing arguments for further debate rather than pushing opinions. We hope to initiate a much broader process of discussion and want to raise the awareness on the importance of a consistent terminology for the reporting of scientific data in the field of bioenergetics, mitochondrial physiology and pathology. Quality of research requires quality of communication. Some established researchers in the field may not want to re-consider the use of jargon which has become established despite deficiencies of accuracy and meaning. In the long run, superior standards will become accepted. We hope to contribute to this evolutionary process, with an emphasis on harmonization rather than standardization.
The manuscript has not yet been formatted for a specific journal. We will be glad to ensure that-before submission-an updated version conforms to the format guidelines for your journal, should you encourage us to proceed with submission at your EM site.
We are looking forward to hearing your opinion about the timeliness and potential impact of our manuscript, and possibly your suggestions for improvement.
With many thanks for your consideration, and kind regards, Erich Gnaiger
  • I have sent the enlosed letter to several jpournals, in which we published during the last 5 years, and which may have something in common with mitochondrial physiology. I have included you as the “to your information” addressee.
Gnaiger E: Many thanks for your great efforts!
  • Dr. Gnaiger, here are some suggestions or items that might need to be double checked. Most of the items are minor. The manuscript looks great
Thank you for your effort. This manuscript is timely, informative, and clearly sets forth the future: highly educational as well. No single author or smaller group could do what’s been accomplished here. Again, I must Thank you for orchestrating it so well!
I found a couple of things in the manuscript where some items need to be double checked, clarified, or verified that they are not typos or missing characters as posted (Version 22_2018-02-08 ). Hopefully, the below listed comments will aid in the final manuscript and publication. and editing.
Lines 210-211: might be better as “enzymes of the tricarboxylic acid and fatty acid oxidation”.
Lines 219-223: Possible to many “and’s, not sure if this is a run on sentence or not.
Line 404: (10 ug•10-6 cells) is this 10-6 cells or 106 cells, also is the dot the best way to separate the 2 different normalization values?
464, 524-525, Figure 3 Note 5 and through the whole manuscript: “superoxide anion radical” could be simply “superoxide” unless the intent is to educate people unfamiliar with this molecule and highlight that it’s a radical and an anion.
Line 741: is (CHNO; 2[H]) correct or a typo or missing a character?
Gnaiger E: Dear Brett, many thanks for your excellent comments and (already earlier) contributions. We have an interesting reply from CELL METABOLISM (see here). We will send them the MS.


  • Here are a few additinal comments on the review (pages 6, 13, 25). I'm still a little bit under the impression that it is very complex for general users to apply properly all the nomenclature.
About the editors, nobody comes into my mind but I will look if I can find some to send the letter of information too.
  • I think, the letter to the editor you sent is it's really nicely written, with all needed information.
  • Thank you very much for your collaboration adn invitation. I think that it is a very nice article.
I will send it to the editors.
In fact, this afternoon I have a meeting with Santiago Lamas who is an associate editor of redox Biology,and I can talk about the article.
Gnaiger E:May I ask you to send a letter with the information contained in the template (feel free to modify) to relevant editors whom you know.
  • Thanks, Erich. I will do so.
  • I deeply appreciate your efforts to make the text more affordable also for not-experts in the field: I agree with you and I am convinced that this help to better widespread the message inside and to gain much more visibility and an enhanced number of potential reader will be reached.
BTW, I am preparing to send the letter you suggested to some EiC but I think it would be useful to avoid any overlapping in this task: therefore I am suggesting you make available a list of EiC/journals already contacted in order it could be easier to resend the same letter to the same EiC.
Moreover, before sending the letter, the sender should advise you for a continuous update of the list.
You can also prepare a doodle/surveymonkey or similar where each contributor could add by his/her own the journal contacted.
  • I offer some suggestions.
Gnaiger E: Many thanks for your excellent comments and (already earlier) contributions. We have an interesting reply from CELL METABOLISM (see Dr.Sharma). We will send them the MS.
Buettner GR: This manuscript has had a rigorous “internal” review. Thus, a journal’s review would not be expected to add too much.
I think you are in the driver’s seat, as many journals would welcome this work. I would not bend too much to a specific journal’s demands. Bargain hard if the editor(s) want changes in format, length etc.
To ensure the work gets into PubMed Central (12 mo from publication), I assume an author(s) must have NIH grant support. I have such support. Others may as well. Thus, this may need consideration.  ::::: I have done this for other collaborative works; obviously it helps me justify my grant -- showing productively and progress, but most important it assists with long-term accessibility.
The goal is to get easy and wide distribution to all researchers whose research touches on this area.
Stocker R: I completely agree with Garry. Accessibility is going to be a key determinator whether this project will be a success and result in broad adherence to the guidelines provided.
  • Dear Erich, thanks a lot. I think this is a great idea. I sent the message contained in the attachment to three editors I’ve been in contact with and their colleagues.
  • I would suggest you to contact Prof. Liu Shusen for his comments. I copy this message to him so that he may be helpful.
Gnaiger E: Many thanks for reaching out to Prof. Liu Shusen. I have gladly added you to the list of co-authors of our MitoEAGLE Position Statement.
We recieved an interesting reply from CELL METABOLISM (see preprints main page). We will send them the MS.
  • 2018-02-12 Jadiya P
  • I have gone through the preprint version and its really nice compilation of our current understanding of the mitochondrial physiology as well as related terminology. In the Box1, Line 229, it would be great to add one sentence for the endoplasmic reticulum and mitochondrial contacts as these contact sites involved in metabolites transfer as well as mitochondrial dynamics regulation.
"The crosstalk between mitochondria and endoplasmic reticulum are involved in the regulation of various cellular functions, such as calcium homeostasis, cell division, autophagy, differentiation, anti-viral signaling, and others (Murley and Nunnari 2016)".
Ref: Murley A, Nunnari J (2016) The Emerging Network of Mitochondria-Organelle Contacts. Mol Cell 61(5):648-653.
Gnaiger E: Many thanks for your contribution, which I added according to your suggestion (line 217). Thanks for joining our initiative as a co-author.
  • I has become a balanced and high quality document. Nevertheless still some comments. Please find these attached (written in the scan and I added only the pages with comments). Please find also an alternative abstract, which is slightly altered (improved) over the one pasted in the scan.
Gnaiger E: Thank you very much, your input is much appreciated and largely included in the new ms version. We have an interesting reply from CELL METABOLISM (see here). We will send them the MS.
  • I believe there is strong need for such armonization procedure.
A detail regarding it. I would personally propose to redefine the electron transfer capacity as ETC rather than ETS –it is less confusing.
  • Thank you for the email and the attached paper.
I found the paper really very informative and as discussed before the initiative is very much needed and timely.
At this point I have no further input; we do have some papers in Revision and if we get them through I will send the citations for adding in this Review paper.
Gnaiger E: On ET- versus ETS-capacity. I also like ETS better. BUT: There is the OXPHOS system, and we do not say ‘OXPHOS system capacity’. There is the ET system – we should say ET-capacity.
  • It's a pleasure to participate in such interesting project for me, thank You for invitation!
  • A suggestion is to post something similar to relevant sections at the American Physiological Society. (http://connect.the-aps.org/home). You could probably sent this to all sections, but I’m pretty sure there would be interest from members of the endocrinology and metabolism and exercise physiology sections.
  • I would send it to the editor in Chief of Mitochondrion. Is it OK?
Gnaiger E:Excellent – thanks
  • the demand specifies to send the information to Editors of Journals that I know. I could do that for J. Cellular Physiology but do not you expect a higher and more poweful journal to publish this excellent paper ? In addition, the timing....would be bfore you submit or after...
  • I want to congratulate you and all the co-authors for the excellent work. The manuscript has highly improved since my last reading. I am sending some minor suggestions annotated in the attached pdf file. Thank you very much for the collaboration,
Gnaiger E: Thank you for your kind feedback and for the careful reading with excellent improvements – obviously you are a professional science writer. I have incorportated your suggestions in the new version 24.
  • I think Cell Metabolism is hardly possible. Did you consider JBC (with John Demu as editor for mitochondria) or Nature Communications? Maybe also Molecular Metabolism, but that may be too little physiological.
  • Will have a look.
  • Off course! I can prepare a letter and forward this message to actual editors whom I know.
  • Sure Erich. I will send it to a couple of editors. I will keep you informed.
  • OK- I sent the letter to an editor of JIMD
  • The manuscript looks fantastic and I am very excited about it. Just a couple of comments. In the section on standardization. It is well outlined how proper standardization should be conducted; however in the manuscript we do not say, which method of standardization to use. For instance, flux can be normalized to wet weight or dry weight of the tissue (for permeabilized fibers) but we do not say which to use and the flux per mass values are very different depending on which you use. There is a lot more variability in weight wet measurements due to how much drying researcher does. Also, most scales are not accurate enough for measuring 1-2mg pieces of tissue and weighing the sample three times can give much more consistent values. If measurements are off by just one or even less than one mg when weighing a 1mg piece of muscle, then values can have double or half the respiration rates when normalizing to mass. Also, I recommend in the paper suggesting all raw data should be published in a supplemental table. This way anyone can access and compare values. Also, while the limitations of the normalizing factors are discussed in detail, we should specify which marker of mitochondrial content (CS activity mtDNA copy number) to use for normalizing. It may be important to explain that when phosphorylation is not limiting oxygen consumption such as in mouse permeabilized muscle fibers the addition of uncouplers does not increase oxygen flux; therefore, when generating flux control ratios using CI+CII_E to normalize to becomes confusing because CI+CII_P will also equal 1.
As far as journals go, I think that diabetes would be a good journal to submit to if cell metabolism does not work out. Although it is limited to this one metabolic disorder nearly every researcher studying mitochondrial physiology have published in this journal.
Another possible journal is EMBO as the word mitochondria turns up over 1500 articles and is a well read journal.
Gnaiger E: Thank you for your valuable comments. I agree with you, that recommendations on wet weight versus dry weight should be given. In fact, a MitoEAGLE Task Group is working on this to provide a comparative experimental basis for evaluation and a corresponding recommendation. This will be summarized in a separate MitoEAGLE position paper. Similarly, a recommendation on the ‘best’ mt-marker would be helpful, if such a best marker does exist. The present MS may contribute to make us more aware on the importance of paying critical attention to mt-markers. A insufficiently substantiated recommendation, however, would not help and weaken the impact of our manuscript.
Ps: We are working on nomenclature of the pathway states. I regret to have introduced the CI+II nomenclature (but CI+CII is different), hence we replaced it with a less difficult terminology:
  • Lemieux H, Blier PU, Gnaiger E (2017) Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers. Sci Rep 7:2840, DOI:10.1038/s41598-017-02789-8. - http://www.bioblast.at/index.php/Lemieux_2017_Sci_Rep
Valentine JM: I agree and I am excited to contribute to this critical work in any way possible. Please let me know what I can do!!! Thank you for the reference paper.
Garcia-Roves P Most of your comments are being addressed in different tasks coordinated by Working Group 2 (MitoEAGLE data repository on muscle tissues): http://www.mitoeagle.org/index.php/MitoEAGLE_data:_muscle
We are currently interested on OXPHOS capacity in permeabilized myofibers, addressing the effect of oxygen, ADP and blebbistatin in MiR05Cr and Buffer Z; where wet and dry weight is also being discussed. Moreover, we are performing a study to supply mitochondrial respirometry reference values using permeabilized mouse soleus muscle fibers from C57Bl6J mice and same experimental procedures.
Valentine JM: This is very exciting!!!
Especially about the reference values for C57/BL6J mice. I am sure that you have seen the paper below, but incase you have not there seems to be a pretty substantial difference in respiration rates between C57BL/6J and C57/BL6N mice depending on the substrates used. It may be worth highlighting the differences in the two mouse lines at the working group2 because often times people do not mention or even know which C57/BL6 mouse they are using.(https://www.ncbi.nlm.nih.gov/pubmed/27495226)
  • I am happy to send a letter to editors. I came up with four editors from their Cell Metab website. They are Martin Brand, Michael Murphy, Nils-Goran Larsson, and Varnsi Mootha. I wanted to see if you suggest anyone else who I might include in the email as this will have an impact on our paper. I am happy with your template and will send it as is. I would also like to confirm that you want me to use the email address of [email protected] instead of individual emails of relevant editors.
  • I'll do it with pleasure
  • Of course that I will send the letter to the known editors. I would appreciate if you would confirm if the idea is to send to Cell Metabolism or any journal that you know that includes studies of mitochondria such as Sci report, Hepatology, BBA, etc.
  • As you requested, I will think of possible Journal Editors (e.g. I am familiar with U. Brandt-BBA bioenergetis, but I suppose that you already asked him; if not, please let me know). Meanwhile, I wonder if you would like to consider also the possibility of submitting the same inquiry to the "Scientific Committee of the World Mitochondria Society", whose annual conference will be held as usual in Berlin (next date: October 2018 - https://www.targeting-mitochondria.com/)
  • I have just looked at the preprint very quickly and I see many changes 😊 Wow! Very, very good job! During next days I will be reading it carefully. Now I am thinking about the journal where this review could be sent. So, in my opinion, this manuscript is excellent and you may consider to send it i.e. here ? :) ... Nature Methods, IF >25; of course earlier writing to editor
  • Will do and send to other editors. I am the editor of experimental gerontology. Have you considered to publish this in a methods journal?
  • Thank you very much, I will send the input of the editors.
  • Great initiative. I will send the letter to the editors I know and will come back to you. Again thanks again for your efforts
  • Many thanks for the information. I will disseminate the information.
sent to : [email protected]
  • I know Keshav K Singh, Editor-in-chief of “Mitochondrion”, but I guess he might have been contacted already?
  • Id be happy to forward the letter to Editors
  • Thank you very much for your great effort in revising the manuscript and for sending me the revised version of this article that we have co-authored last year! It has been greatly improved!
  • Yes, thanks for this and the preprint earlier. I will try to get it done by early next week.


  • MitoEAGLE preprint 2018-02-08 Version 22
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