The Impact of Krebs Cycle Intermediates on the Endocrine System and Immune System: A Comparison

Round 1

Reviewer 1 Report

This review is well written and concise. There is good use of tables to summarise the manuscripts that have been reviewed as well as the main impact of Krebs cycle intermediates their reported mode of action. The overall topic is of interest to a wide audience. 

General 

It is a common misuse of terminology in this field to use words such as ‘production’ and ‘generation’ when referring to energy and mitochondrial oxidative phosphorylation, e.g energy production or energy generation. However, energy is NOT produced or generated in humans, energy comes from our external environment by eating energy rich foods such as protein, carbohydrates, and fats. It is only through processes within the body that this energy is converted into an energy source that our bodies use for energy utilisation. Thus mitochondria are energy converters and not energy producers. Moreover, given that ATP is the product of a biological reaction, the correct terminology to describe this is ATP synthesis, instead of ATP production or ATP generation.  

There is no reference to table 1 or 2 in the main body of the text. 

Specific

Line 54 – check grammar 

Lines 112-114 – Not clear why some of the intermediates are in BOLD

Section on impacts of Krebs cycle on the endocrine system: 

Energy metabolism in most cells of the human body is controlled by ATP demand and thus the phosphorylation potential (ATP/ADP ratio), it would be interesting to know to what extent the ATP/ADP ratio controls ATP synthesis in cells making up tissues and organs of the endocrine system such as the adrenal and thyroid glands. It is well known that metabolic control in pancreatic beta-cells occurs through both ATP supply and ATP demand. Therefore, to some extent, increased substrate supply and consequent oxidation in pancreatic beta-cells can increase mitochondrial oxidative phosphorylation independent of significant changes in ATP demand. Given that the author refers to the electron transfer complex as setting the oxidation pace and thus ATP synthesis rate on line 140, in what cell types are you referring specifically, as in most cell types the phosphorylation potential controls substrate oxidation and downstream reactions that lead to ATP synthesis. 

Line 148-149 – electrons are passed through the respiratory complexes to the final electron acceptor, oxygen. ATP is only synthesised when protons pass back through the ATP synthase into the mitochondrial matrix. Correct basic knowledge of ETC and ATP synthesis. 

Line 154-155 – I was unable to find evidence in the manuscripts referenced here to support this sentence, please check references and or provide more evidence on this. For example, do these papers show evidence to support changes in total ATP synthesis or just mitochondrial ATP synthesis. 

Author Response

Dear Reviewer,

thanks a lot for your comment. Your comments have been considered in the revised version of the manuscript.

In more Detail:

Reviewers Comment:

This review is well written and concise. There is good use of tables to summarise the manuscripts that have been reviewed as well as the main impact of Krebs cycle intermediates their reported mode of action. The overall topic is of interest to a wide audience. 

Answer: Thanks a lot for this positive comment.

General 

Comment:

It is a common misuse of terminology in this field to use words such as ‘production’ and ‘generation’ when referring to energy and mitochondrial oxidative phosphorylation, e.g energy production or energy generation. However, energy is NOT produced or generated in humans, energy comes from our external environment by eating energy rich foods such as protein, carbohydrates, and fats. It is only through processes within the body that this energy is converted into an energy source that our bodies use for energy utilisation. Thus mitochondria are energy converters and not energy producers. Moreover, given that ATP is the product of a biological reaction, the correct terminology to describe this is ATP synthesis, instead of ATP production or ATP generation.  

Answer: Thanks a lot for these corrections. In the revised version of the manuscript these points have been addressed and corrected.

Comment

There is no reference to table 1 or 2 in the main body of the text. 

A: These references have been included into the revised version.

Specific

Line 54 – check grammar 

A: Thanks grammar has been checked and the manuscript has been copy-edited.

Lines 112-114 – Not clear why some of the intermediates are in BOLD

A. This has been corrected.

Section on impacts of Krebs cycle on the endocrine system: 

Energy metabolism in most cells of the human body is controlled by ATP demand and thus the phosphorylation potential (ATP/ADP ratio), it would be interesting to know to what extent the ATP/ADP ratio controls ATP synthesis in cells making up tissues and organs of the endocrine system such as the adrenal and thyroid glands. It is well known that metabolic control in pancreatic beta-cells occurs through both ATP supply and ATP demand. Therefore, to some extent, increased substrate supply and consequent oxidation in pancreatic beta-cells can increase mitochondrial oxidative phosphorylation independent of significant changes in ATP demand. Given that the author refers to the electron transfer complex as setting the oxidation pace and thus ATP synthesis rate on line 140, in what cell types are you referring specifically, as in most cell types the phosphorylation potential controls substrate oxidation and downstream reactions that lead to ATP synthesis. 

A. Answer: Thanks a lot for these corrections. In the revised version of the manuscript these points have been addressed and corrected.

Line 148-149 – electrons are passed through the respiratory complexes to the final electron acceptor, oxygen. ATP is only synthesised when protons pass back through the ATP synthase into the mitochondrial matrix. Correct basic knowledge of ETC and ATP synthesis. 

A. Answer: Thanks a lot for these corrections. In the revised version of the manuscript these points have been addressed and corrected.

Line 154-155 – I was unable to find evidence in the manuscripts referenced here to support this sentence, please check references and or provide more evidence on this. For example, do these papers show evidence to support changes in total ATP synthesis or just mitochondrial ATP synthesis. 

A. Answer: Thanks a lot for these corrections. In the revised version of the manuscript these points have been addressed and corrected.

Reviewer 2 Report

A timely chosen topic no doubt, as the energy imbalances becoming more and more important with the rise of Obesity and linked diabetes around the world. Mitochondrial dysfunctions is key, where the Krebs cycle plays big role as mention and derived from the referral studies. A well written article no doubt, but have the limitation in the following sections and must be revised.

SPECIFICS ARE:

Page 3 Flow Diagram (Figure 1):  Must be more compacted and make it much smarter to make it more attractive so that it won’t take that space. If the color printing is not an issue, fill the boxes with different shade.

In Discussion: After all being said in the results on findings and the importance in the endocrine system and immune system, author must have presented the pathways (diagrammatic) they act and causing the disease mechanism in a gene -Disease interaction in a cellular or molecular principle should have been given for the ease of the readers and the researchers.  More inclusion of medical importance of such information and future views are to be mentioned taking most chronic disease as an example.

Author Response

Dear reviewer,

thanks a lot for the positive comments. Your comments have been considered and the manuscript was improved according to your comments.

I more detail:

Comment:

A timely chosen topic no doubt, as the energy imbalances becoming more and more important with the rise of Obesity and linked diabetes around the world. Mitochondrial dysfunctions is key, where the Krebs cycle plays big role as mention and derived from the referral studies. A well written article no doubt, but have the limitation in the following sections and must be revised.

A. Thanks a lot for the positive comment.

SPECIFICS ARE:

Page 3 Flow Diagram (Figure 1): Must be more compacted and make it much smarter to make it more attractive so that it won’t take that space. If the color printing is not an issue, fill the boxes with different shade.

A. A better/improved version of the figure has been added to the manuscript.

In Discussion: After all being said in the results on findings and the importance in the endocrine system and immune system, author must have presented the pathways (diagrammatic) they act and causing the disease mechanism in a gene -Disease interaction in a cellular or molecular principle should have been given for the ease of the readers and the researchers. More inclusion of medical importance of such information and future views are to be mentioned taking most chronic disease as an example.

A: A chapter to the pathways has been added to the manuscript.

Round 2

Reviewer 2 Report

Thanks for taking care of the manuscript well with the desired changes , and now acceptable.