+100%-

The title of this metabolomic study “Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” made it clear that something new was in the works. Peroxisomal dysfunction had hardly popped up at all in the mitochondrial and metabolomic studies done to date – and yet it was headlining the outcome of a big, meaty NIH-funded study.

The study with the strange title came out of Ian Lipkin’s Center for Solutions for ME/CFS and featured a metabolomic analysis of 888 metabolic analytes in 106 ME/CFS cases and 91 frequency-matched healthy controls.

metabolism

Metabolism involves reactions that break down compounds (catabolic) and reactions that build them up (anabolic).

Metabolomics studies assess the levels of metabolites. A metabolite is the end product of metabolism which refers to the sum total of chemical reactions that keep us alive. We break down molecules (catabolic) or build up (anabolic) compounds to keep the energy flowing, the organs operating correctly, the body repair processes working, etc. Since we know the metabolic pathways in detail, we can use altered levels of metabolites to determine where breakdowns are occurring. Since energy – either the use of it or creation of it – plays a key role in metabolism, metabolomic studies are particularly good at ferreting out problems that occur when energy production is lacking.

The metabolomic studies are particularly interesting because of the ground they cover. If you throw, as this study did, nearly 900 metabolites into the mix, there’s no telling what might pop up. If studies of that breadth show a consistent signature –  you’ve probably got something.

The Lipkin team noted that since Naviaux’s effort in 2016, at least five large-scale metabolomics studies have been done – and they do show a common thread: decreased levels of phospholipids and metabolic dysregulation. Phospholipids are complex compounds found in our cellular membranes which play critical roles in ATP generation, and protection of the cell membranes and the myelin sheath lining the nerves.

Results

The results of this latest study were encouragingly consistent with those of past studies but seemed more refined, and more targeted – which is what we want. We want to get past the general “metabolic dysfunction” stage and pinpoint exactly where the problem is. This study seemed like it was a step on the road to doing that, and in doing so, it showcased a part of the cell that has received almost no attention in chronic fatigue syndrome (ME/CFS).

Small Organelles Hit the Big Time

Decreased levels of the plasmalogens that protect the phospholipids in the cellular membranes from damage suggested that membranes of the ME/CFS patients’ cells were taking a beating – probably from oxidative stress.

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the human cell

Small organelles show up in a big way. The peroxisome is the little purple circle at the bottom of the cell.

The low plasmalogen levels implicated small organelles in the cell called peroxisomes. These organelles, which have not been highlighted in ME/CFS before, are the site of plasmologen synthesis. They help maintain the cellular membranes, reduce oxidative stress, and perhaps most importantly, break down very-long-chain fatty acids to metabolic intermediates that the mitochondria can use to produce ATP. Without the peroxisomes breaking down those fatty acids, the mitochondria won’t have the fuel they need to produce ATP.

All three of these functions appear to have been damaged in ME/CFS. Oxidative stress is high, there is evidence of cellular membrane damage, and ATP production appears to be limited.

The authors concluded that a disrupted peroxisome/mitochondrial connection likely contributes to the fatigue and cognitive problems found in ME/CFS. In doing so, they referenced the work of an Australia researcher, Paul Fisher, who recently came to a similar conclusion. Fisher’s findings suggested that reduced levels of the same substrates (metabolized long-chain fatty acids) that Lipkin highlighted in his study were causing reductions in energy production as well.

Novel Approach Brings New Insights Into ME/CFS Mitochondria

Carnitines Low – Again

oxidative stress

Many studies, including this one, have found evidence of increased oxidative stress in ME/CFS.

The Lipkin group also found that people with ME/CFS had reduced levels of carnitine – another key figure in energy production and membrane health. Carnitines play at least 3 major roles in energy production, and low carnitine levels are associated with increased oxidative stress, as well as the reduced health of the cellular and mitochondrial membranes.

The reduced carnitine levels appear to have contributed to an accumulation of long-chain triglycerides in ME/CFS patients. Because those long-chain fatty acids are ripe for free radical attack, and when attacked can emit substances that then impair mitochondrial functioning, the long-chain triglyceride finding feeds into the oxidative stress/mitochondria inhibition chain. Because the peroxisomes are supposed to step in to compensate for low carnitine levels – and apparently failed to do so in ME/CFS – they’re potentially implicated in the low carnitine levels.

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The depleted plasmalogen levels, the high levels of unsaturated triglycerides, and the reduced carnitines all pointed at one logical target – damage to the little peroxisome organelles littering the cell.

Cell membrane

The cell membranes may be taking a pounding in ME/CFS.

The Gist

  • Ian Lipkin’s NIH-funded research center produced the biggest and most comprehensive metabolomics study yet in ME/CFS. The study contained more people (197) and examined more metabolites (888) than any study done to date.
  • The study ended up showcasing a small organelle in our cells that we’ve heard almost nothing about until now – the peroxisome. While tiny, peroxisomes perform several crucial functions: they help maintain the cellular membranes,  they reduce oxidative stress, and perhaps most importantly, they break down very-long-chain fatty acids to metabolic intermediates that the mitochondria can use to produce ATP. Without the peroxisomes breaking down those fatty acids, the mitochondria won’t have the fuel they need to produce ATP.
  • The authors believe the last issue – that the peroxisomes are failing to deliver the mitochondria the resources they need to produce ATP (energy) – may be a key in ME/CFS.
  • Three things implicated the peroxisomes: depleted plasmalogen levels, high levels of unsaturated triglycerides, and reduced carnitines.
  • The reduced carnitine levels appear to contribute to the accumulation of long-chain triglycerides in ME/CFS patients which, in the oxidative stress-rich environment found in ME/CFS, are likely emitting substances that impair mitochondrial functioning. This is one of several studies which have found low carnitine levels in ME/CFS.
  • Low levels of unsaturated phosphatidylcholines (PCs) are probably also impairing the structural integrity of the cellular membranes, and interrupting the flow of proteins across the mitochondrial membrane – thereby impairing mitochondrial functioning.
  • Low choline levels may indirectly impair mitochondrial functioning and affect autonomic nervous system functioning.
  • Notice that the authors found reductions in four metabolites all of which impair mitochondrial functioning (and most of which impair membrane integrity and increase oxidative stress.). Plus the study also found increased levels of 3 metabolites all of which impair mitochondrial functioning as well.
  • Plus the increased levels of two intermediates in the Krebs or aerobic energy production cycle suggest something has gone awry in the complex process of producing ATP.
  • The study with its interlocking findings presented perhaps the most coherent story yet of mitochondrial dysfunction in ME/CFS.
The plot thickened further when reduced levels of unsaturated phosphatidylcholines (PCs) were found. The most abundant fats in the mitochondrial membranes, the PCs play a critical role in maintaining the structural integrity of the cellular membranes. Low levels of PCs can interrupt the flow of proteins across the mitochondrial membrane – once again, blocking the mitochondria off from nutrients and potentially shutting them down. Since PCs are metabolized into a number of different mitochondrial products, low levels of PCs can affect mitochondrial functioning in numerous ways.

Low Choline Levels – Again

The (almost significantly) low choline levels were potentially illuminating as choline is almost completely devoted to the synthesis of PCs, which as was noted above, is needed for mitochondrial functioning.

The authors pointed out that because choline plays a role in the production of epinephrine, choline deficiency could play a role in the autonomic nervous system problems found in ME/CFS, which may produce reduced blood flows and oxygen supply and ultimately hypoxia (low oxygen levels), and ischemia (blood vessel blockage).

This is the third time low choline levels have been found in ME/CFS.

Hypometabolic State?

A number of factors that are critical to mitochondrial production appear to be low in ME/CFS – suggesting that a hypometabolic state is indeed present:

  • Low plasmalogen levels inhibit the breakdown of long-chain fatty acids to compounds the mitochondria needs to produce ATP. (The low plasmalogen levels implicate the peroxisome organelles in the cell).
  • Low levels of carnitine may be interfering with ATP production.
  • Reduced levels of unsaturated phosphatidylcholines (PCs) may interfere with mitochondrial functioning by impairing the flow of proteins into the cell.
  • Low choline levels may indirectly impact mitochondrial functioning by impairing the production of PCs.

Increased Levels of Mitochondrial Antagonists

While people with ME/CFS appear to have low levels of helpful mitochondrial compounds, they appear to have high levels of compounds that can damage the mitochondria.

  • High levels of triglycerides plus high levels of oxidative stress suggest the triglycerides may be emitting substances that are impairing ATP production.
  • Finding high levels of two intermediate metabolites (α-ketoglutarate (α-KG), succinate) in the electron transport chain where ATP is produced suggested that a blockage or inefficiency had occurred. Increased levels of these substances have been associated with severe metabolic impairments, inflammation, and, once again, increased oxidative stress.

Moderate Predictive Capacity

For all the interesting findings, the authors were unable to use machine-learning techniques to differentiate the ME/CFS patients from the controls. (They could, however, differentiate the female ME/CFS patients from the female healthy controls). Adding another dataset into the mix helped, but the predictive values were not as high as seen in some other studies. (The models correctly predicted 51-74% of entire ME/CFS group and 62-78% of female ME/CFS patients.)

Conclusion

pathway for ME/CFS

The clearer pathway highlighted in this study was encouraging.

There’s just no substitute for size. Compare the 84 participants and 612 metabolites assessed in Naviaux’s 2016 study, and the 52 participants and 832 metabolites assessed in Hanson’s 2018 study, with the 197 participants and 888 metabolites assessed in the NIH-funded Lipkin study, and you can see why NIH-funded studies are the cat’s meow.

This present study’s size suggests it’s providing us the most up-to-date assessment of metabolomics to date in ME/CFS. This study’s general findings (decreased phospholipids, problems with ATP generation) did jive with those of past studies, but the specific findings were quite different.

Peroxisomal dysregulation – something that’s hardly been mentioned in ME/CFS before – took center stage in the largest and most comprehensive metabolomic study to date. The nice thing about the peroxisomal dysregulation and other findings in this study was how nicely they fit together.

The reduced plasmalogen levels pointed a finger at the peroxisomal dysregulation, which helped explain the accumulation of the long-chain fatty acids. Besides potentially causing mitochondrial problems, the low carnitine levels may, in part, be due to peroxisomal dysregulation as well. Every one of these problems also potentially increases oxidative stress and impairs membrane integrity.

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Reduced levels of unsaturated phosphatidylcholines (PCs) and choline may also impair mitochondrial functioning, plus reduced choline levels could help explain the autonomic nervous system problems in ME/CFS. The fact that both low carnitine and choline levels have been found a number of times in ME/CFS suggests these findings may stick.

Finally, the increased levels of two intermediates in the Krebs or aerobic energy production cycle suggest something has gone awry in the complex process of producing ATP.

Given the size and the increased statistical strength of this study, it was surprising to see that it had a much lower predictive value than Lipkin’s past, smaller study. The fact that merging both metabolomic and metagenomic data points produced a much higher predictive value (.836) than found in this study – with its focus on metabolomic data alone – suggested that a future biomarker for ME/CFS may very well involve multiple systems.

All in all, the study with its interlocking findings presented perhaps the most coherent story yet of mitochondrial dysfunction in ME/CFS.

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