Add export of succinate from cells and mitochondria

[johan-gson]

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Description of the issue:

We should add export of succinate from cells and mitochondria. There is some evidence for that, for example: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273505/ Also, that complex II can be run in reverse, which I assume implicitly says that succinate is exported: https://www.science.org/doi/10.1126/science.abi7495 This is important in hypoxia, since fumarate turned into succinate will accept electrons as an alternative to oxygen.

Expected feature/value/output:

Succinate can be exported out of the cell, I guess first from mitochondria to cytosol, and then out of the cell, and then an exchange rxn.

I hereby confirm that I have:

• [X] Tested my code on my own computer for running the model
• [X] Done this analysis in the main branch of the repository
• [X] Checked that a similar issue does not exist already

[johan-gson]

I think we should add this. The following evidence from retina shows that MCT1 (i.e., the SLC16A1 gene) or MCT4 (i.e., the SLC16A3 gene) can both mediate the succinate export out of cells: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8976921/
I'm guessing there are more ways, but this is a start.

The export mechanism from mitochondria to the cytosol is governed by dicarboxylate transporters, for example Slc26a6 - see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090288/. In addition, https://www.sciencedirect.com/topics/neuroscience/dicarboxylate-transporter suggests SLC25A10. There are probably more genes that could fill this function, but "SLC26A6 OR SLC25A10" is a start.

I'm not totally sure what the reactions should look like, if any H+ should follow in the transportation mechanism. So, something like this:

succinate[m] <=> succinate[c] GPR: SLC26A6 OR SLC25A10
succinate[c] => succinate[e] GPR: SLC16A1 OR SLC16A3 - maybe the GPR can be copied from lactate

This page: http://www.informatics.jax.org/go/term/GO:0071422 suggests more genes, and that "SLC13A2 OR SLC13A3" can be responsible for import.

So, succinate import/export seems rather complicated, but this could be a start. Any comments?

[haowang-bioinfo]

@johan-gson sounds good

what specific changes do you suggest to start?

[feiranl]

There is a reaction for Succinate import/export which is co-transport with Sodium in Recon with gene annotation of "SLC13A2" or "SLC13A3", but not sure whether we should add sodium too. http://bigg.ucsd.edu/models/Recon3D/reactions/HMR_9610 http://bigg.ucsd.edu/models/Recon3D/reactions/SUCCt4_2 http://bigg.ucsd.edu/models/Recon3D/reactions/SUCCt4_2

[mihai-sysbio]

@feiranl this is still available in the latest version of the model, see https://metabolicatlas.org/explore/Human-GEM/gem-browser/reaction/MAR09610

[feiranl]

Yes. It is just import. I think Johan wants an export rxn. Recon has three rxns with both import and export.

[johan-gson]

Hi, yeah sorry, I didn't focus so much on import, that seems to already exist. Good sign that the genes are the same. The export is the important thing for cases like hypoxia, although import of course also needs to be there as well since other cells need to take this up. I looked a bit at transport in/out of mitochondria, there are a lot of antiporters in the model for this. I did however have to explicitly add an export reaction to make my simulations work, and I think the sodium-dependent reactions should be added. An alternative is to make this (http://bigg.ucsd.edu/universal/reactions/SUCCtm) reversible, it is not now (see below).

I think the sodium should be added to the reactions, the recon3D reactions are probably right, so 2 Na ions in the reaction as well.

Transport reactions today:

MAR04854		fumarate[c] + succinate[m] <=> fumarate[m] + succinate[c]		ENSG00000183048
MAR04862		Pi[m] + succinate[c] => Pi[c] + succinate[m]		ENSG00000183048
MAR04863		succinate[c] + sulfate[m] <=> succinate[m] + sulfate[c]
MAR04864		succinate[c] + sulfite[m] <=> succinate[m] + sulfite[c]
MAR06287		citrate[c] + H+[c] + succinate[m] => citrate[m] + H+[m] + succinate[c]		ENSG00000100075
MAR06290		H+[c] + isocitrate[c] + succinate[m] => H+[m] + isocitrate[m] + succinate[c]		ENSG00000100075
MAR06294		cis-aconitate[c] + H+[c] + succinate[m] => cis-aconitate[m] + H+[m] + succinate[c]		ENSG00000100075
MAR02220		citrate[c] + succinate[m] <=> citrate[m] + succinate[c]		ENSG00000100075
MAR02413		isocitrate[m] + succinate[c] <=> isocitrate[c] + succinate[m]		ENSG00000100075
MAR02418		cis-aconitate[m] + succinate[c] <=> cis-aconitate[c] + succinate[m]		ENSG00000100075

[johan-gson]

I think then that this will be solved automatically when Human2 imports changes from Recon3D, correct? Let's check if the GPRs match when that is done, and after that we can close this issue.