jnmaciuch
Senior Member (Voting Rights)
Hi all!
I'm a graduate student living with ME/CFS and currently studying ME/CFS and long COVID. I was recently reviewing literature on mitochondrial dysfunction and stumbled onto something very interesting which potentially explains several semi-consistent findings in the literature.
Specifically, I was struck by Lawson et al. (2016)'s findings of no mitochondrial dysfunction in ME/CFS and increased ATP production from glycolysis. Since there's been other evidence of mitochondrial dysfunction, this struck me as odd, so I dove a bit deeper into the referenced methods with the hunch that perhaps something that was in the cell media inadvertently "fixed" mitochondrial function.
Turns out something was added--malate and pyruvate. If my hunch is right, then the most significant effect of adding malate would be restarting the malate-aspartate shuttle--the main mechanism for supplying H+ to mitochondrial NAD+ and maintaining the pool of mitochondrial NADH.
And this explanation would actually explain some other consistent findings since mitochondrial NAD(P)H is a necessary substrate for other reactions, most notably steroid hormone synthesis (found to be decreased in ME/CFS and long COVID, full disclosure the second link is my paper currently in review) and bile acid synthesis (decreased in ME/CFS).
This may also result in reduced cytosolic NAD+, which would impair ethanol breakdown, potentially explaining alcohol intolerance common to ME/CFS (also my paper). Since mitochondrial NAD+/NADH levels also have a bidirectional relationship with circadian rhythm, this could also potentially explain sleep disturbances. It's also known that COVID can impair the oxidative arm of the TCA cycle, so I'm thinking similarities between long COVID and ME/CFS may be due to failure to recover the TCA cycle after infection.
Long story short, I'm currently trying to organize a study to formally test this. But while I'm waiting for logistics to sort themselves out, I figured I could use myself as a lab rat. Since malate in the form of malic acid is present in a lot of fruits (albeit at low concentrations) I tried to see what would happen if I consumed a lot all at once.
Turns out the highest concentration I had available in my kitchen was in the spice sumac, and ingesting ~2 tbsp with water led to my brain fog melting away almost immediately and out of nowhere I had the energy to get up and do some chores. I already take a stimulant which enables me to be in grad school, and this felt like taking double the stimulant without the racing heart or other negative side effects.
The effect lasted for about 2 hours.
Since it's possible that this was due to 1) placebo effect or 2) something else in the sumac, I found a malic acid supplement online to test out my theory further. The supplement happens to look almost identical to a serrapeptase supplement I already take (which has a very mild pain relief effect, but nothing close to what I experienced with the sumac), so I asked a family member to randomize which one they gave me. Huge boost from the malic acid, nothing from the 'placebo.'
I also had another friend with ME/CFS try the sumac and reported almost exactly the same effects and duration without me sharing those details in advance. I'm still trying to work out dosage (the full supplement seems to trigger some low blood sugar/headaches if I don't eat frequently) but I'm still amazed I saw this much of an effect.
In the mean time, if anyone else is willing to try this and report if it has any effect on you, I'd be extremely interested (especially if you're willing to do a placebo control!). Given the heterogeneity in this illness it's likely not everyone's symptoms are caused by the same cellular mechanism, so this may not work for everyone (I especially don't think it'll work if you don't experience PEM). But since it'll take a while to sort logistics for a formal study, I wanted to share on this community forum and see if others could provide some informal data.
I'm a graduate student living with ME/CFS and currently studying ME/CFS and long COVID. I was recently reviewing literature on mitochondrial dysfunction and stumbled onto something very interesting which potentially explains several semi-consistent findings in the literature.
Specifically, I was struck by Lawson et al. (2016)'s findings of no mitochondrial dysfunction in ME/CFS and increased ATP production from glycolysis. Since there's been other evidence of mitochondrial dysfunction, this struck me as odd, so I dove a bit deeper into the referenced methods with the hunch that perhaps something that was in the cell media inadvertently "fixed" mitochondrial function.
Turns out something was added--malate and pyruvate. If my hunch is right, then the most significant effect of adding malate would be restarting the malate-aspartate shuttle--the main mechanism for supplying H+ to mitochondrial NAD+ and maintaining the pool of mitochondrial NADH.
And this explanation would actually explain some other consistent findings since mitochondrial NAD(P)H is a necessary substrate for other reactions, most notably steroid hormone synthesis (found to be decreased in ME/CFS and long COVID, full disclosure the second link is my paper currently in review) and bile acid synthesis (decreased in ME/CFS).
This may also result in reduced cytosolic NAD+, which would impair ethanol breakdown, potentially explaining alcohol intolerance common to ME/CFS (also my paper). Since mitochondrial NAD+/NADH levels also have a bidirectional relationship with circadian rhythm, this could also potentially explain sleep disturbances. It's also known that COVID can impair the oxidative arm of the TCA cycle, so I'm thinking similarities between long COVID and ME/CFS may be due to failure to recover the TCA cycle after infection.
Long story short, I'm currently trying to organize a study to formally test this. But while I'm waiting for logistics to sort themselves out, I figured I could use myself as a lab rat. Since malate in the form of malic acid is present in a lot of fruits (albeit at low concentrations) I tried to see what would happen if I consumed a lot all at once.
Turns out the highest concentration I had available in my kitchen was in the spice sumac, and ingesting ~2 tbsp with water led to my brain fog melting away almost immediately and out of nowhere I had the energy to get up and do some chores. I already take a stimulant which enables me to be in grad school, and this felt like taking double the stimulant without the racing heart or other negative side effects.
The effect lasted for about 2 hours.
Since it's possible that this was due to 1) placebo effect or 2) something else in the sumac, I found a malic acid supplement online to test out my theory further. The supplement happens to look almost identical to a serrapeptase supplement I already take (which has a very mild pain relief effect, but nothing close to what I experienced with the sumac), so I asked a family member to randomize which one they gave me. Huge boost from the malic acid, nothing from the 'placebo.'
I also had another friend with ME/CFS try the sumac and reported almost exactly the same effects and duration without me sharing those details in advance. I'm still trying to work out dosage (the full supplement seems to trigger some low blood sugar/headaches if I don't eat frequently) but I'm still amazed I saw this much of an effect.
In the mean time, if anyone else is willing to try this and report if it has any effect on you, I'd be extremely interested (especially if you're willing to do a placebo control!). Given the heterogeneity in this illness it's likely not everyone's symptoms are caused by the same cellular mechanism, so this may not work for everyone (I especially don't think it'll work if you don't experience PEM). But since it'll take a while to sort logistics for a formal study, I wanted to share on this community forum and see if others could provide some informal data.
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