Step by step Lipkin’s metabolomic study produces a coherent picture of mitochondrial dysfunction
The really neat thing about Ian Lipkin’s latest work on ME/CFS is how well all the results fit together. Health Rising reported on the preprint of this paper earlier, but the final version that recently came out has fleshed out some things.
This big NIH-funded Ian Lipkin study had several things going for it. It was larger, and assessed more metabolites than any other study; it used patients diagnosed by ME/CFS experts, and employed, in its words, “complete and cautious statistical approaches”; i.e. it’s a rigorous and trustworthy metabolomic study.
In short, it’s a major paper – and boy, were its findings interesting – not just because they fingered a potential new player – peroxisomes – but because of how well they all fit together – and that’s what this blog will focus on.
All Together Now
Metabolism is a big deal. In some ways, it’s the big deal. It’s concerned with nothing less than the “chemical processes that occur within a living organism in order to maintain life”. Breaking down foods to provide energy, proteins, or fats, etc. is metabolism. So is protein, carbohydrate, and fat synthesis. Any chemical reaction that transforms one compound into something else comes under the rubric of metabolism.
It’s metabolism that produces the sometimes huge, head-spinning diagrams of metabolic pathways. If some part of a pathway gets blocked – the upstream portions of the pathway build up – and the downstream parts of the pathway decline. Or, if a particular pathway is getting hit hard by something (infection, toxin, etc.) that will show up. It’s these kinds of abnormalities metabolomic studies are looking for.
Basically, with metabolomic studies, we’re looking for problems in the chemical reactions that sustain life. Since chemical reactions require energy, problems with energy production can show up big time in these studies – and in this study they did.
Fatty Acid Breakdown – Reductions in plasmalogens that protect the phospholipids which, in turn, support the all-important cellular membranes (the “skin” surrounding the cell) pointed an arrow at the peroxisomes – small organelles in the cells which manufacture them.
Peroxisomes do a lot more than produce plasmalogens, though. They also break down very long-chain fatty acids into the shorter chain fatty acids that our mitochondria use to produce energy. If those fatty acids aren’t broken down, the mitochondria become starved of an important energy source.
That’s precisely what this study suggests may be happening in ME/CFS. The authors believe the peroxisome-fatty acid-mitochondria connection has been cut.
“We posit that this crosstalk between mitochondria and peroxisomes plays an important role in maintaining energy homeostasis and that dysregulation contributes to the fatigue and cognitive dysfunction that are hallmarks of ME/CFS.”
That wasn’t all. The study also found reduced levels of carnitines. Carnitines play a key role in the transport of, yes, long-chain fatty acids from the cytoplasm of the cell to the mitochondria. This study already suggests that two processes involved in getting long chain fatty acids into the mitochondria have taken a hit in ME/CFS.
That’s not all carnitines do, though. Because carnitines also help to maintain cellular membranes, the low levels of carnitines found also threaten the stability of the all-important cellular membranes – leaving them more easily crippled by things like inflammation and oxidative stress.
- We’re back for round 2 as we dig into the same paper twice – kind of. The formal publication of Ian Lipkin’s NIH-funded metabolomic study fleshed out the earlier preprint version of the same study.
- What was so striking about this study was its coherence. Step by step by step – the study results seemed to build on each other to an extraordinary degree – presenting, in the end, a picture of potentially damaged mitochondria struggling to get resources.
- First, we see signs that the peroxisomes – little organelles in the cell – are not working well. Peroxisomes do two very important things: they break down long chain fatty acids into components the mitochondria can use – and they produce the compounds called phospholipids that protect the cellular membranes.
- The low levels of carnitines also found simply amplified those very same problems because carnitines transport fatty acids into the mitochondria and they also play a key role in the cellular membranes.
- Low levels of carnitines may turn out to be a big deal as they can also flip a switch that tells the peroxisomes to start producing carnitine – thus presumably inhibiting their ability to break down long chain fatty acids.
- Because peroxisomes also regulate the mopping up of free radicals (reactive oxygen species (ROS) the impaired peroxisome functioning could also contribute to a hot mess of inflammation.
- That brings us back to the membranes that protect the cells – including the mitochondria. Low levels of a major membranal component – phosphatidylcholine (PC) – potentially spell yet more trouble for the mitochondrial membranes and mitochondrial functioning.
- Plus, the low PC levels may also impair another transport mechanism into the mitochondria. Low PC’s can interrupt the transport of proteins into the mitochondria – further inhibiting mitochondrial production.
- Thus far we have evidence of starved mitochondria that are getting pummeled by free radicals.
- The authors weren’t done yet, though. Next came low levels of several compounds indicative of mitochondrial damage and/or damaged membranes.
- Finally, a not quite statistically significant decline in choline levels could contribute to autonomic nervous system dysfunction.
- The findings seemed pretty compelling given the rigorous nature of the study, and similar findings regarding problems with long chain fatty acids in ME/CFS and fibromyalgia. The authors cautioned, though, that it’s “imperative that the validity of novel findings reported here be independently tested in other cohorts” and that larger studies with more ME/CFS patients be done.”
- Let’s hope that’s done and Lipkin and others get a chance to study both ME/CFS and long COVID patients in bigger studies. With few long COVID studies exploring the mitochondria or the metabolome let’s also hope long COVID researchers – particularly the NIH’s RECOVER Initiative- are keeping an eye on ME/CFS studies.
- Meanwhile, the NIH is still somehow spending over a billion dollars on long COVID while spending virtually nothing on its sister disease ME/CFS. While it’s renewing the ME/CFS research centers, they’re being funded at the same paltry levels as they were five years ago. Hopefully, at some point that will change.
Low levels of carnitines may turn out to be a big deal as they can also flip a switch that tells the peroxisomes to start producing carnitine – thus presumably inhibiting their ability to break down long chain fatty acids.
Because peroxisomes also regulate the mopping up of free radicals (reactive oxygen species (ROS)), the impaired peroxisome functioning could also contribute to a hot mess of inflammation.
That brings us back to the cellular membranes that protect the cell – a prime target of free radicals. Thus far, we’ve two potential hits to them (low plasmologen and carnitine levels), and now comes a third: low levels of an important membranal component – phosphatidylcholine (PC).
The PC depletion suggests that yet another important transport mechanism into the mitochondria has been disturbed in ME/CFS. Low PCs can interrupt the transport of proteins into the mitochondria – further inhibiting mitochondrial production.
That’s not all. Low PC levels can also impair the ability of protein translocases which shuttle proteins through the various membranes in the mitochondria and direct them to their proper place. Problems with these protein translocases have been directly shown to impact the ability of the mitochondria to produce ATP or energy.
Look how quickly a potential suite of hits to the mitochondria have shown up:
- Problems breaking down long chain fatty acids so that the mitochondria can use them,
- Problems transporting the fatty acids into the mitochondria,
- Damage to the cellular membranes that protect the mitochondria (and other cells) from damage,
- Problems shuttling crucial proteins into the various compartments of the mitochondria.
More was coming, though.
The authors reported that the low levels of lysophosphatidylcholines, phospholipid ethers, and prostaglandins (D2, F2α) have been associated with mitochondrial damage and/or increased oxidative stress which, given the poor state the mitochondrial membranes appear to be in, is not a happy situation.
About those membranes… the low levels of PCs, ceramides, sphingomyelins, and phospholipid ethers provide further evidence of membrane damage, as they all play important roles found in the membranes as well. Cells get their marching orders through receptors found in their membranes. Because ceramides play an important role in the propagation of signals through the membranes, the low ceramide levels found could render a cell dead in the water unable to respond to the signals it’s getting.
Next came low levels of choline – essential for the production of phosphatidylcholines (PC) – which, as was previously noted, were low. The low levels of choline did not meet the statistical criteria needed for significance – but it was getting close.
Because choline also enhances the functioning of the G-protein coupled receptors that regulate autonomic nervous system (ANS) functioning and play a role in the production of epinephrine, as well, the authors proposed that the lower choline levels might be impacting ANS functioning, resulting in problems with blood flows and oxygen supply to the tissues.
It was the coherence of its findings that made this study so intriguing – every major finding seemed to fit together in some way. What we really want out of a study is the ability to tell a biological tale, and this one certainly did regarding the mitochondria.
Of course, we must remember that correlation is not causation, and that the body is very complex and can and does frequently fool us. The authors said so in so many words. While noting the strengths of the study (rigorously defined patients, a “complete and cautious statistical approach”, etc.), the authors stated that it was “imperative that the validity of novel findings reported here be independently tested in other cohorts”, and that larger studies with more ME/CFS patients be done.
Still, the emergence of such a coherent pattern of dysfunction is nothing if not encouraging, particularly since one of the central findings – problems with long chain fatty acid metabolism – was also found by the Fisher research group in Australia, and has popped up in fibromyalgia as well.
The funding for the NIH-funded ME/CFS research centers has been renewed – at the same pitiful levels they began with – and which caused some researchers to shy away.
I don’t know how much longer the NIH can keep up the farce of spending a billion-plus dollars on long COVID while ignoring ME/CFS, but let’s hope that studies like this one from Lipkin and those from Maureen Hanson’s NIH-funded centers will change its mind, and Lipkin will be able to get the funding to do a larger study containing both ME/CFS and long-COVID patients, one which is able to get definitive results.
The ME/CFS field, after all, is way ahead of the pack regarding the mitochondria and metabolomics. ME/CFS researchers latched onto metabolomics about six years ago, and since then many studies have been done, yet few metabolomic studies have been done in long COVID, and none that approaches the sophistication of this one. Nor have the mitochondria received much study in long COVID. One hopes that long COVID and RECOVER Initiative researchers are keeping an eye on the mitochondrial and metabolomic findings in ME/CFS.
The long-COVID studies that have been done suggest the mitochondria have been impacted, and a recent hypothesis paper proposed that “NAD+ metabolome disruption” plays a central role in the condition, suggesting that intravenous NAD+ trials begin.
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