Mitochondrial Dysfunction in ME/CFS and Long COVID
Why "broken mitochondria" is an oversimplification
Mitochondria are often described as the powerhouses of our cells. They help turn food and oxygen into energy the body can use. Because people with ME/CFS and long COVID often experience severe fatigue and post-exertional malaise (PEM), it's tempting to assume their mitochondria are simply broken.
The research doesn't support such a simple explanation.
Key takeaways:
Studies suggest cells can often still produce energy at rest but struggle to ramp production up when demand suddenly rises.
The problem looks less like "no energy" and more like "very little reserve."
No single mitochondrial defect has been found in every patient—the picture is one of several overlapping abnormalities, not one clean cause.
Newer research suggests immune factors (like antibodies) may directly alter how mitochondria behave, connecting immune, vascular, and energy problems.
Mitochondrial dysfunction is likely one piece of a larger picture involving immunity, blood vessels, and muscle—not the whole story.
Think of it like a phone battery that charges to 100% just fine but can't supply a sudden burst of power without the whole system lagging or overheating. The battery isn't dead—it just can't meet a spike in demand the way it used to, and pushing past that limit costs it (and you) even more later.
What Does "Mitochondrial Dysfunction" Actually Mean?
It's a broad term. It can mean that cells:
Don't use fuel normally
Don't increase energy production when needed
Use oxygen less efficiently
Respond poorly to stress
Show changes in mitochondrial shape
Are affected by immune or inflammatory signals
This matters because different studies can use the same phrase while measuring very different things. A change in mitochondrial function in an immune cell doesn't automatically mean the same thing is happening in muscle, brain, or heart cells.
What Has ME/CFS Research Found?
Several ME/CFS studies point to altered energy metabolism, but no single abnormality shows up in everyone.
One study found a broad pattern of lower blood metabolites involved in energy and nutrient metabolism. The researchers interpreted this as a coordinated metabolic slowdown similar to a survival state called "dauer"—like a phone switching into low-power mode to conserve battery (Naviaux et al., 2016).
Other studies suggest cells don't use glucose normally and instead lean more heavily on fats or amino acids for fuel (Fluge et al., 2016; Tomas et al., 2020).
Researchers have also studied immune cells from people with ME/CFS. Some of these cells produced energy normally at rest but had more difficulty increasing energy production under stress (Tomas et al., 2017; Fernandez-Guerra et al., 2021).
This is probably the most useful way to frame the findings so far: the energy-producing cells aren't switched off. They simply seem to have less ability to respond when the body suddenly needs more energy.
Why Energy Reserve May Matter More Than Energy Production
A person with ME/CFS can often sit, talk, read, or complete a small task without issue. But doing too much can trigger a delayed, sometimes severe worsening of symptoms. That pattern points away from a total inability to produce energy and toward a body operating with a very narrow margin.
Healthy cells ramp up energy production as activity increases. In ME/CFS, that response appears limited or poorly regulated in several studies.
Muscle-cell research adds a concrete example: cells from people with ME/CFS didn't respond normally when researchers tried to mimic muscle contraction. They failed to increase glucose uptake and energy-related signaling the way healthy cells did (Brown et al., 2015).
This could help explain a pattern many patients recognize: managing a low level of activity just fine, then deteriorating sharply after crossing an individual limit.
What Long COVID Research Adds
Long COVID research shows similar patterns. In one notable study, researchers took muscle samples from people with long COVID before and after an exercise test. After PEM was triggered, they found:
Lower mitochondrial energy production
Changes in muscle fuel use
More visible muscle abnormalities (Appelman et al., 2024)
This doesn't mean mitochondrial dysfunction alone caused the PEM—the same study also found signs of muscle damage and immune activity. Other long COVID studies have found changes in mitochondrial proteins and energy production in immune cells (Peppercorn et al., 2023; Macnaughtan et al., 2025).
The larger picture: Mitochondria appear to be affected by what's happening around them—inflammation, immune activity, blood flow, and muscle stress—not acting in isolation.
How Could Mitochondria Be Connected to PEM?
Post-exertional malaise is a worsening of symptoms after physical, cognitive, emotional, or sensory effort. It isn't ordinary tiredness. Symptoms can be delayed and may include flu-like feelings, weakness, pain, poor sleep, brain fog, and a major drop in function.
Mitochondrial dysfunction could contribute to PEM if cells can't increase energy production quickly enough as demand rises. Several other problems likely compound that strain:
Reduced blood flow may limit oxygen and nutrient delivery.
Immune activation may increase energy needs.
Inflamed or damaged tissue may require more energy to recover.
Muscle cells may not use glucose normally.
Oxidative stress may increase after exertion.
The mitochondria are unlikely to be acting alone. PEM likely results from several systems failing to adjust and recover properly after exertion, not one broken component.
Are Antibodies Attacking the Mitochondria?
Recent work suggests immune factors may directly change mitochondrial behavior. Researchers studied IgG complexes—a major type of antibody—taken from people with post-infectious ME/CFS, including post-COVID ME/CFS.
When these IgG complexes were added to blood-vessel cells in the lab, the mitochondria changed shape, and the cells changed how they handled energy and inflammation (Liu et al., 2026). The mitochondrial network became more fragmented, meaning it broke into smaller sections.
It's tempting to describe this as antibodies "attacking" mitochondria. That wording is too simple. The study didn't show antibodies directly destroying mitochondria throughout the body. Mitochondria naturally change shape in response to stress, and fragmentation can sometimes be protective, though persistent changes may interfere with normal function.
The more important finding is that immune abnormalities appear able to change how mitochondria behave. This helps connect immune dysfunction, blood-vessel problems, and altered energy production in ME/CFS. The study was done in cultured cells, so it still needs confirmation in larger studies and human tissue.
Is ME/CFS a Mitochondrial Disease?
Not in the classic sense. Primary mitochondrial diseases are usually caused by genetic changes that directly affect how mitochondria work.
ME/CFS instead appears to involve secondary mitochondrial dysfunction—mitochondrial behavior altered by other disease processes, such as:
Infection
Immune activation
Inflammation
Autoantibodies or immune complexes
Oxidative stress
Blood-vessel dysfunction
Abnormal metabolic signaling
A review of the ME/CFS research found several kinds of mitochondrial abnormalities, but no single defect appearing consistently across every study or every patient (Holden et al., 2020).
Is Mitochondrial Dysfunction Found in Fibromyalgia?
Yep. Studies have found changes in energy production, oxidative stress, and mitochondrial structure in blood cells and small tissue samples from people with fibromyalgia (Cordero et al., 2010; Macchi et al., 2024).
These findings may contribute to fatigue, pain, and reduced exercise tolerance, but the evidence is still limited—there's no single mitochondrial abnormality established across all fibromyalgia patients.
Fibromyalgia and ME/CFS can overlap, but they aren't the same condition. Widespread pain is central to fibromyalgia; post-exertional malaise is central to ME/CFS.
Can Nutrition and Supplements Support Mitochondrial Function?
Mitochondria need nutrients to function. Protein, fats, carbohydrates, vitamins, minerals, and other compounds provide fuel or support energy-producing reactions. Poor food intake or nutrient deficiencies can add extra strain to an already energy-limited system.
But mitochondrial dysfunction in ME/CFS and long COVID can't be explained by a simple lack of nutrients. If immune activity, blood-vessel dysfunction, inflammation, or abnormal cell signaling are driving mitochondrial behavior, supplements may support certain pathways without correcting the underlying problem.
I've written separately about several compounds involved in cellular energy production—CoQ10, NAD+, carnitine, and creatine. Each has a different role and a different level of evidence. They shouldn't be treated as interchangeable "mitochondrial support."
What the Research Does Not Prove
Current research does not show that:
Everyone with ME/CFS or long COVID has the same mitochondrial problem
Mitochondria are permanently damaged
Mitochondrial dysfunction is the only cause of fatigue or PEM
Blood-cell findings apply to every tissue in the body
Supplements can repair the underlying disease mechanism
More exercise will improve mitochondrial function in someone with PEM
Some mitochondrial changes may contribute to illness. Others may be protective responses or downstream effects of immune and vascular dysfunction. Researchers are still working out which changes are causes and which are consequences.
The Bottom Line
The mitochondria in ME/CFS and long COVID don't appear to be simply broken. A more accurate picture: cells struggle to use fuel, respond to stress, and increase energy production when demand rises.
This can leave patients with very little reserve during physical activity, cognitive work, infection, prolonged standing, or immune activation. Newer research also suggests antibodies and other immune factors may directly alter mitochondrial behavior.
Mitochondrial dysfunction is likely one part of a much larger problem involving immunity, blood vessels, muscles, metabolism, and recovery after exertion. The key question isn't whether cells can make energy at all; it's whether they can make enough energy, at the right time, and recover afterward.
Frequently Asked Questions: Mitochondrial Dysfunction in Postviral Conditions
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Research has found changes in fuel use, cellular energy production, immune-cell metabolism, and stress responses in ME/CFS. However, there's no single mitochondrial abnormality found in every patient.
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Some studies have found lower mitochondrial energy production in muscle and immune cells in long COVID. That doesn't mean every patient has permanently damaged mitochondria.
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It may contribute by limiting how well cells respond when energy demand rises. PEM likely also involves the immune system, blood flow, the autonomic nervous system, and muscle tissue.
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Lab research suggests IgG complexes from people with post-infectious ME/CFS can change mitochondrial shape and energy behavior in blood-vessel cells. The findings don't show antibodies directly destroying mitochondria throughout the body.
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ME/CFS is not considered a primary genetic mitochondrial disease. It may involve secondary mitochondrial dysfunction caused or influenced by immune, vascular, inflammatory, or metabolic problems.
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Supplements may support specific energy pathways, but they haven't been shown to correct all mitochondrial abnormalities or treat the underlying cause of ME/CFS or long COVID.
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No—and pushing through fatigue can make things worse. Because PEM involves a delayed crash after exceeding an individual's energy limit, standard exercise programs that gradually increase exertion can trigger relapses in ME/CFS. This is different from deconditioning in other illnesses, where graded exercise usually helps. Most current guidance favors pacing—staying within one's energy envelope—over exercise therapy for ME/CFS.
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It isn't fully understood, but current research points to several contributing factors rather than one single cause: persistent immune activation, inflammation, blood-vessel dysfunction, and possibly lingering viral effects. These may combine to alter how cells produce and use energy, especially under physical or cognitive demand.
References
1. Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016;113(37):E5472-E5480. doi:10.1073/pnas.1607571113
2. Fluge Ø, Mella O, Bruland O, et al. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. 2016;1(21):e89376. doi:10.1172/jci.insight.89376
3. Tomas C, Elson JL, Newton JL, Walker M. Substrate utilization of cultured skeletal muscle cells in patients with CFS. Sci Rep. 2020;10(1):18232. doi:10.1038/s41598-020-75406-w
4. Tomas C, Brown A, Strassheim V, Elson JL, Newton J, Manning P. Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS One. 2017;12(10):e0186802. doi:10.1371/journal.pone.0186802
5. Fernandez-Guerra P, Gonzalez-Ebsen AC, Boonen SE, et al. Bioenergetic and proteomic profiling of immune cells in myalgic encephalomyelitis/chronic fatigue syndrome patients: an exploratory study. Biomolecules. 2021;11(7):961. doi:10.3390/biom11070961
6. Brown AE, Jones DEJ, Walker M, Newton JL. Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome. PLoS One. 2015;10(4):e0122982. doi:10.1371/journal.pone.0122982
7. Appelman B, Charlton BT, Goulding RP, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun. 2024;15(1):17. doi:10.1038/s41467-023-44432-3
8. Peppercorn K, Edgar CD, Kleffmann T, Tate WP. A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndrome. Sci Rep. 2023;13(1):22068. doi:10.1038/s41598-023-49402-9
9. Macnaughtan J, Chau KY, Brennan E, et al. Mitochondrial function is impaired in long COVID patients. Ann Med. 2025;57(1):2528167. doi:10.1080/07853890.2025.2528167
10. Liu Z, Hollmann C, et al. Immunoglobulin G complexes from post-infectious ME/CFS, including post-COVID ME/CFS, disrupt cellular energetics and alter inflammatory marker secretion. Brain Behav Immun Health. 2026;52:101187. doi:10.1016/j.bbih.2026.101187
11. Holden S, Maksoud R, Eaton-Fitch N, Cabanas H, Staines D, Marshall-Gradisnuk S. A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease. J Transl Med. 2020;18(1):290. doi:10.1186/s12967-020-02452-3
12. Cordero MD, De Miguel M, Moreno Fernández AM, et al. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease. Arthritis Res Ther. 2010;12(1):R17. doi:10.1186/ar2918
13. Macchi C, Giachi A, Fichtner I, et al. Mitochondrial function in patients affected with fibromyalgia syndrome is impaired and correlates with disease severity. Sci Rep. 2024;14(1):30247. doi:10.1038/s41598-024-81298-x
