Some weeks ago, I had what I think was a viral infection, and it made my ME symptoms worse after high-protein meals. After the infection was gone, I remained sensitive to proteins. After much experimentation, I determined that I was sensitive to proline. If I consume ~1400 mg of proline, I'll get a noticeable increase in ME symptoms, most noticeably brainfog and muscle aches (I assume neuropathic). Larger doses of proline makes the severity much worse. The time for the decrease in symptoms depends on the dose: just past the threshold may take hours; much larger doses can take days. My response to proline seems a lot like PEM, which in turn seems a lot like an increase in my usual ME symptoms, so this might provide an insight into the core dysfunction of ME and/ or PEM.
Why might proline be involved in ME? Well, proline is critical for mitochondrial function. This paper explains it: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752965/
"Proline dehydrogenase (PRODH), a.k.a. proline oxidase (POX), is a mitochondrial inner membrane protein. Oxidation of proline to pyrroline-5-carboxylate (P5C) mediates the proline cycle that shuttles NADP(H)/NADP(+) redox equivalents between mitochondria and cytosol and forms a metabolic interlock with the pentose phosphate pathway"
"Proline dehydrogenase/oxidase (PRODH/POX) is a mitochondrial protein critical to multiple stress pathways."
"We found that PRODH/POX binds directly to CoQ1 and that CoQ1-dependent PRODH/POX activity required functional Complex III and Complex IV. PRODH/POX supported respiration in living cells during nutrient stress; however, expression of PRODH/POX resulted in an overall decrease in respiratory fitness. Effects on respiratory fitness were inhibited by DHP and NAC, indicating that these effects were mediated by PRODH/POX-dependent reactive oxygen species (ROS) generation. PRODH/POX expression resulted in a dose-dependent down-regulation of Complexes I–IV of the ETC, and this effect was also mitigated by the addition of DHP and NAC."
To me, it certainly seems like it's possible for proline to be involved in the cellular dysfunction found in ME. I came across a couple of papers that showed that excess proline can reduce mitochondrial function in the brain, an effect that can be reduced by pre-treatment with antioxidants. I'll have to experiment with that to see if it reduces my sensitivity.
Abnormal proline metabolism might explain the collagen problems some PWME report, since proline is critical for collagen formation. Alternatively, maybe a problem with maintaining collagen worsens ME by releasing more proline to muck up mitochondria.
There's a human brain-specific high affinity L-proline transporter (hPROT). "These findings warrant the consideration of a synaptic regulatory role for this transporter and its presumed natural substrate, L-proline, in the mammalian central nervous system." That sounds like it could be one of those biological mechanisms that no one notices when doing ordinary medical testing, but whose subtle dysfunction could result in significant symptoms.
I assume that my present sensitivity to proline is unusual, so I don't think that ME is proline sensitivity. However, this link between proline and ME/PEM symptoms might be worth investigating further, so I'm posting this to see if it triggers some ideas in other people, or makes some researcher evaluate test results from a new perspective.
Also, for people who are wondering why some foods make them feel worse, you could check to see if they're proline-rich. Wheat is very high in protein (there goes another staple from my diet
). Peanuts are too, and of course, meats. Proline sensitivity is very annoying, diet-wise. 
One suggestion for a simple test for researchers: do the nanoneedle test with extra proline added to the fluid. Doing it with extra antioxidants and extra proline might be worthwhile too.
Why might proline be involved in ME? Well, proline is critical for mitochondrial function. This paper explains it: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752965/
"Proline dehydrogenase (PRODH), a.k.a. proline oxidase (POX), is a mitochondrial inner membrane protein. Oxidation of proline to pyrroline-5-carboxylate (P5C) mediates the proline cycle that shuttles NADP(H)/NADP(+) redox equivalents between mitochondria and cytosol and forms a metabolic interlock with the pentose phosphate pathway"
"Proline dehydrogenase/oxidase (PRODH/POX) is a mitochondrial protein critical to multiple stress pathways."
"We found that PRODH/POX binds directly to CoQ1 and that CoQ1-dependent PRODH/POX activity required functional Complex III and Complex IV. PRODH/POX supported respiration in living cells during nutrient stress; however, expression of PRODH/POX resulted in an overall decrease in respiratory fitness. Effects on respiratory fitness were inhibited by DHP and NAC, indicating that these effects were mediated by PRODH/POX-dependent reactive oxygen species (ROS) generation. PRODH/POX expression resulted in a dose-dependent down-regulation of Complexes I–IV of the ETC, and this effect was also mitigated by the addition of DHP and NAC."
To me, it certainly seems like it's possible for proline to be involved in the cellular dysfunction found in ME. I came across a couple of papers that showed that excess proline can reduce mitochondrial function in the brain, an effect that can be reduced by pre-treatment with antioxidants. I'll have to experiment with that to see if it reduces my sensitivity.
Abnormal proline metabolism might explain the collagen problems some PWME report, since proline is critical for collagen formation. Alternatively, maybe a problem with maintaining collagen worsens ME by releasing more proline to muck up mitochondria.
There's a human brain-specific high affinity L-proline transporter (hPROT). "These findings warrant the consideration of a synaptic regulatory role for this transporter and its presumed natural substrate, L-proline, in the mammalian central nervous system." That sounds like it could be one of those biological mechanisms that no one notices when doing ordinary medical testing, but whose subtle dysfunction could result in significant symptoms.
I assume that my present sensitivity to proline is unusual, so I don't think that ME is proline sensitivity. However, this link between proline and ME/PEM symptoms might be worth investigating further, so I'm posting this to see if it triggers some ideas in other people, or makes some researcher evaluate test results from a new perspective.
Also, for people who are wondering why some foods make them feel worse, you could check to see if they're proline-rich. Wheat is very high in protein (there goes another staple from my diet
One suggestion for a simple test for researchers: do the nanoneedle test with extra proline added to the fluid. Doing it with extra antioxidants and extra proline might be worthwhile too.