Review A research perspective on sphingolipid metabolism and myalgic encephalomyelitis/chronic fatigue syndrome, 2025, Xiao, Junhua

Thanks for posting! A paper here about sphingolipid metabolism disorders is a bit beyond my understanding but I think may be relevant here.

Does this mean ME could be a lysomal storage disorder or would it ‘just’ overlap?

 

The abstract says that most of those are often fatal. It doesn’t really fit with how people can live with ME/CFS for decades.

 

Thanks @Utsikt I agree, it doesn’t sound like it from that, but I wonder if it’s possible ME could be an as-yet unidentified form of lysosomal storage disease – perhaps so because it isn’t fatal and doesn’t show in infancy? Or maybe ME is overlapping somehow… or maybe neither!

I just used ChatGPT (so of course pinch of salt needed!) to try and see whether there was any link to fatty acid oxidation disorders since there have been studies showing dysfunctional fatty acid oxidation in ME. I wondered if the sphingolipid dysfunction could be a product of another issue rather than ground zero. ChatGPT said:

Some studies suggest that lipid imbalances in FAODs can contribute to changes in ceramide and sphingolipid levels, potentially exacerbating cellular stress.​

Some sphingolipids are metabolized in lysosomes, while FAODs primarily affect mitochondria. However, there is crosstalk between peroxisomes (which handle very-long-chain fatty acids) and mitochondrial β-oxidation.

Deficiencies in one pathway may disrupt lipid homeostasis, indirectly influencing the other.
​

… I thought the mention of peroxisomes was interesting since Lipkin reported finding peroxisome dysfunction.

Here are some links to articles regarding this and FAOD-related findings here and here.

I’m nowhere near as up on the science as so many on s4me are so apologies if this isn’t a good train of thought – I just like to let my brain go down a track to see if there could be something in it but there may not be!

 

Disorders that cause complete shutdown of a function don't mean that there can't be less severe disorders. My ME has responded to changes in fatty acid intake, so I have wondered whether the ratio of the different fatty acids might affect membrane production in ways that affect cellular function. Maybe a vesicle made with a 17/8 ratio of palmitic and butyric acid molecules functions differently than one with a 15/7 ratio, or membrane pores with different ratios are more or less effective at transporting molecules.

 

The basis for this paper seems to be the paper in this thread
Metabolic features of chronic fatigue syndrome, 2016, Naviaux et al

I do remember lipids more generally cropping up in a couple of other papers though so maybe there’s something here?
Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity, 2024, Beentjes, Ponting et al
and
Developing a blood cell-based diagnostic test for ME/CFS using peripheral blood mononuclear cells, 2023, Xu, Morten et al

And now I’ve remembered the tags work so I needn’t have searched!

I did find this on a potential role for the pathways in PD
Clinical Sphingolipids Pathway in Parkinson’s Disease: From GCase to Integrated-Biomarker Discovery
But it seems to be another speculative thing rather like this paper

 

Sphingolipid metabolism has popped up a few times (including in some unpublished analysis that I've done on a long Covid cohort). Iirc it was downregulated in at least two ME/CFS studies I saw, but upregulated in another. Naviaux was one of them, I believe armstrong and germain et al. were the others. You'd have to have an explanatory mechanism that can explain transient up and down-regulation of sphingolipids without leading to lethality. My educated guess is that it is likely mediated by serine metabolism which immediately precedes sphingolipid production and is itself limited by NAD+ availability. There's a cycle involving serine and formate across the mitochondrial membrane that can be used as a "backup" source of regenerating mitochondrial NAD(P)H--differing utilization of this shuttle in response to other signals could potentially explain this strong but directionally inconsistent trend.

All this is just speculation at this point. But considering other circumstantial evidence of impaired mitochondrial NAD(P)H-dependent steroidgenesis (also in germain et al), it seems like sphingolipids are at least one additional piece of evidence towards inability to correctly regulate redox balance.

 

general comment

some things, particularly lipid metabolic pathways, are very variable between tissues (whether relevant enzymes are even expressed or whole processes even occur varies massively with the tissue or cell type)

so studies done in eg circulating blood will have to kind of be interpreted in view of this - hard to generalise some things or attribute to systemic issues, but if only one tissue is capable of doing the particular thing that you are seeing disturbed then that's much easier to make specific interpretations about

 

that’s a good point! In the case of sphingolipids, I believe every cell does have the machinery to generate them since sphingolipid rafts are pretty ubiquitous in cell membranes afaik. But it might be certain cell types that are more likely to upregulate or downregulate sphingolipid production—they’re particularly relevant in neurons, though a neuron-specific signal might be unlikely to appear in blood plasma to begin with.

 

a useful tool if looking at specific enzymes is protein atlas. If you have specific lipids in mind and can trace back to a protein of interest, that's one way to make sense of things. one example for a relevant enzyme: https://www.proteinatlas.org/ENSG00000100596-SPTLC2/tissue

In this example you can see that enzymes with ubiquitous expression will still vary greatly in the magnitude of that expression between tissues (as one would expect)

I expect that you probably know this but trying to keep the broader readership in the loop

 

Thank you both! It’s really useful to have this insight and pointers to more information.

 

Not proposing this as a strong hypothesis, but my ME provided evidence implying that my brain cells were overproducing quinolinic acid during my "worse" phase, which I think would mean less local production of NAD+, which would then reduce local sphingolipid production. However, I don't see why this would measurably change blood level of sphingolipids.

 

That’s interesting, thanks for sharing! I’m also basing some of this off of personal experience with supplements that would directly affect NAD/NADH and FAD/FADH2 ratios.

I think there’s also additional complexity at play here that precludes a simple “there’s a global lack of NAD+” explanation. You could end up with a temporary “lack” of NAD+ within a specific cell both by failure to produce NAD+ via the kynurenine pathway or just by failure to adequately shuttle H- across the mitochondrial membrane, leading to the majority of NAD staying in the reduced NADH form in the cytosol without proper turnover. Plus there’s the fact that redox balance and the kynurenine pathway regulate each other and also tie into other tightly controlled pathways. If there was something wrong in any of these interconnected pathways, it would more likely result in inconsistent oscillations that would be difficult to see clearly by sampling blood at one time point.

And as previously noted, it’s very hard to interpret exact mechanisms from a plasma or urine metabolomics assay especially if the pathway is not exclusive to a cell type. My speculation here is more in the category of “There are a couple semi-consistent findings in ME/CFS metabolomics and mitochondrial function studies and it sure is interesting how so many of them can be directly tied back to redox balance across different organs/tissues.” I think it was even explicitly mentioned in Naviaux et al. that nearly all the differential pathways were reliant on NAD(P)H availability in some way.

But as my old PI used to say: theories are cheap, data is gold. I’m hoping I’ll be able to get more concrete answers sometime soon.