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Add export of succinate from cells and mitochondria #424
Description
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:
- Tested my code on my own computer for running the model
- Done this analysis in the
mainbranch of the repository - Checked that a similar issue does not exist already
Activity
[-]Should we add export of succinate from cells (and mitochondria)?[/-][+]Add export of succinate from cells and mitochondria[/+]johan-gson commentedon Nov 9, 2022
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 commentedon Nov 9, 2022
@johan-gson sounds good
what specific changes do you suggest to start?
feiranl commentedon Nov 9, 2022
There is a reaction for Succinate import/export which is co-transport with Sodium in
Reconwith 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 commentedon Nov 9, 2022
@feiranl this is still available in the latest version of the model, see https://metabolicatlas.org/explore/Human-GEM/gem-browser/reaction/MAR09610
feiranl commentedon Nov 9, 2022
Yes. It is just import. I think Johan wants an export rxn. Recon has three rxns with both import and export.
johan-gson commentedon Nov 9, 2022
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:
johan-gson commentedon Nov 19, 2022
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.
edkerk commentedon Jul 11, 2026
The mitochondrial side is already covered: succinate can leave the mitochondria through the reversible SLC25A10 and SLC25A1 antiporters (exchange with malate, fumarate, sulfate, sulfite, or citrate). But you were right that cellular export was missing: the three plasma-membrane succinate transporters (MAR09610, MAR04939, MAR04938) are all Na-coupled and import-only (irreversible), so cytosolic succinate had no way out, and the Recon3D import did not add an export.
Added a cellular export reaction,
MAR20192:succinate[c] + H+[c] <=> succinate[e] + H+[e], GPRSLC16A1 or SLC16A3, reversible, modelled on the existing lactate MCT reaction and based on the MCT-mediated succinate export you cited (PMID:35363247). Import via SLC13A2/SLC13A3 already existed, so the pair is now complete and succinate can be secreted through the existing exchange reaction MAR09415.feat: add cellular succinate export via MCT proton symport (#1039)
edkerk commentedon Sep 27, 2026
#1105 corrects the succinate export reaction added in #1039:
succinate[c] + 2 H+[c] => succinate[e] + 2 H+[e]SLC16A1 or SLC16A3->SLC16A1The reaction stays export-only. MCT1 can move succinate in both directions in oocytes (PMID:32946811), so this is a modelling choice: import of succinate is already covered by the Na+-coupled SLC13A2/SLC13A3 reactions (MAR09610, MAR04938, MAR04939).
Implemented in #1105.
edkerk commentedon Oct 5, 2026
Fixed in Human 2.1.0.