What Does Mitochondrial Dysfunction Mean in Chronic Fatigue?
In several studies, cells from people with ME/CFS made energy less well. What that finding leaves open, and why pushing through can backfire.
Photo: Andy Feliciotti / Unsplash
When researchers say ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) involves mitochondrial dysfunction, they mean something narrower than it sounds. In several studies, cells taken from people with ME/CFS produced energy less well than cells from healthy people. That finding means neither that there is a test for it nor that there is a fix. It also isn't proof that mitochondria started the illness.
Keeping a measured abnormality separate from a proven cause changes what you'd reasonably do with this research. It also explains why the advice to exercise your way to more mitochondria can backfire when you have post-exertional malaise (PEM), the delayed worsening of symptoms after exertion.
What do mitochondria do?
Mitochondria are small structures inside almost every cell. Their main job is turning fuel from food into ATP (adenosine triphosphate), the molecule your cells spend as energy. They do it with oxygen, through a chain of steps called oxidative phosphorylation. Cells also have a faster route that doesn't need oxygen, called glycolysis. It makes far less ATP from the same fuel and leaves byproducts like lactate behind.
A healthy cell keeps spare capacity, too. At rest it works well below its maximum, so it can make more when demand goes up.
What researchers have measured in ME/CFS
In 2017, Tomas and colleagues drew blood from 52 people with chronic fatigue syndrome and 35 healthy controls. They isolated immune cells and measured how much oxygen those cells used. Cells from the CFS group had lower readings on several measures of mitochondrial function. The most consistent was maximal respiration, which is how hard a cell can work when it's pushed. When the researchers stimulated the cells to work as hard as they could, the CFS cells raised their respiration by 47 percent over baseline, a little under half again. The control cells nearly doubled theirs, at 98 percent. Glycolysis, the backup route, looked about the same in both groups.
The authors were careful about what this shows. In the paper's discussion section they write that the results don't establish whether these differences are a cause or a consequence of CFS. They call the work preliminary and name sample size as its main limitation. These were also blood cells, not muscle or brain.
A 2020 systematic review from Griffith University in Australia gathered 19 case-control studies of mitochondria in ME/CFS. The studies used different cell types, lab methods, and diagnostic criteria. Three found lower ATP levels in patients, and three others found no change. The reviewers concluded that the role of mitochondria in ME/CFS is difficult to establish from the studies so far. The genetic studies they included found no disease-causing variants. That led them to suggest ME/CFS isn't a primary mitochondrial disorder, and that mitochondrial decline might be a secondary effect of other disrupted pathways.
Muscle before and after a crash
One study that sampled muscle before and after a crash was done in long COVID, a post-viral illness in which PEM is common. In 2024, Appelman and colleagues in Amsterdam took thigh-muscle biopsies from 25 people with long COVID. Their comparison group was 21 people who had fully recovered from a mild COVID infection. Everyone was sampled before a maximal exercise test and again the day after, and every patient developed PEM.
Before the test, the patients' muscle had a lower capacity for oxidative phosphorylation. After it, a marker of mitochondrial content called succinate dehydrogenase activity dropped in the patients but not in the controls. The patients' muscle also showed signs of tissue damage. In their limitations paragraph, the authors describe the study as observational and write that it can't establish causality. They also note that the sample was relatively small, so the results need replication in other groups of patients.
Why "exercise to build mitochondria" can backfire
In a video interview, Dr. Jordan Knieff explained that the way to build more mitochondria in a healthy body is steady aerobic strain on the muscles. Training a pathway tells the body to make more of what that pathway needs. That is sound exercise physiology, and it assumes your body recovers normally from the effort.
A 2-day cardiopulmonary exercise test (CPET) checks that assumption. You ride a stationary bike to exhaustion while your oxygen use and heart rate are measured, rest 24 hours, and do it again. Keller and colleagues ran it in 84 people with ME/CFS and 71 sedentary controls, which the authors describe as the largest 2-day CPET study of ME/CFS to date. The controls reproduced their first-day results. The ME/CFS group couldn't. On day two their work output, oxygen use, and heart rate at peak effort all fell, and the same decline showed up in 55 pairs matched for fitness, age, and sex.
Keller's team didn't put this on mitochondria alone. They wrote that their results implicate a dysregulated autonomic nervous system in how blood flow and oxygen get delivered for energy production. The autonomic nervous system is the branch that controls blood flow without you having to think about it. In their discussion, they add that people with ME/CFS switch toward anaerobic energy at a much lower workload than even sedentary people do. For many of them, walking at a normal pace is enough to bring on fatigue.
Is this just deconditioning? Keller's team concluded that fitness level doesn't account for it, because the decline held in the fitness-matched pairs. Appelman's group also noted that inactivity is linked to muscle wasting and lower mitochondrial content, which they didn't see in patients before the test.
This is the problem with the advice to push through. Exercise is how a healthy body builds mitochondria, and exertion is what sets off PEM. The CPET researchers describe pacing, meaning activity planned to stay under your own threshold, as an approach that has gained acceptance in ME/CFS, and they describe a heart rate monitor as one way to track it. The CBT and ME/CFS post covers why graded exercise therapy was dropped from UK guidance in 2021. The practitioner you work with can help you work out where your threshold is.
Where mitochondria fit in a fatigue workup
In clinic, before I think about mitochondria at all, I work through the common explanations for fatigue: sleep, including sleep apnea, then mood, medications and supplements, iron and B12, thyroid, blood sugar, and kidney and liver function. ME/CFS is a diagnosis made after those are ruled out. Iron has a second connection here, for mitochondria need iron to make energy, and ferritin can look normal while iron is still low.
There isn't a mitochondrial test that diagnoses ME/CFS, and researchers are still looking for a reliable biomarker. For the larger mechanistic picture, there is a separate post on a unified model of ME/CFS, based on a 2026 review that proposes one model for ME/CFS and post-viral illness.
If chronic fatigue is part of your picture, ME/CFS, Reconsidered is an upcoming course on ME/CFS, post-viral fatigue, and pacing. You can join The Weekly Well, our free newsletter, to hear when the course opens.
FAQ
Is ME/CFS a mitochondrial disease?
Not in the genetic sense. The DNA studies gathered in a 2020 systematic review found no disease-causing variants in people with ME/CFS, and the authors suggested it isn't a primary mitochondrial disorder. They added that the mitochondrial changes researchers have measured may be a secondary effect of other disrupted pathways.
Can a blood test show mitochondrial dysfunction in chronic fatigue?
Not as a diagnostic test. The oxygen-use measurements in these studies are research assays run on isolated blood cells, and the results have varied between labs and cell types. Researchers are still looking for a reliable biomarker for ME/CFS.
Does exercise help mitochondria if I have ME/CFS?
In a healthy body, steady aerobic training is how you build more mitochondria. When post-exertional malaise is present, exertion is what sets off the crash, and on a 2-day exercise test people with ME/CFS couldn't reproduce their first day's results. That is why the researchers behind that test discuss pacing, and any plan to increase activity is one to work out with a clinician who has examined you.
Is post-exertional malaise just deconditioning?
Two of these studies looked at that question, and both found reasons to doubt it. In the 2-day exercise test study, people with ME/CFS still declined on day two when they were compared with controls matched for fitness, age, and sex. A long COVID muscle study also didn't find the lower mitochondrial content that inactivity is linked with in patients' muscle before exercise.
Is long COVID fatigue the same as ME/CFS at the mitochondrial level?
That hasn't been shown yet. A 2024 study found lower mitochondrial capacity in the thigh muscle of people with long COVID, and a drop in mitochondrial content after exercise. The authors thought it unlikely that post-exertional malaise works completely differently in ME/CFS, but wrote that whether it works the same way still needs to be studied.
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