Nikhil Prasad Fact checked by:Thailand Medical News Team Aug 18, 2026 48 minutes ago
Scientists investigating why some Long COVID patients suffer debilitating crashes after even modest activity may have a new biological explanation. A newly proposed theory suggests that the problem could involve mitophagy, the cellular process responsible for removing damaged mitochondria, and an inability of cells to complete this essential cleanup efficiently.
Researchers propose that failed mitophagy and mitochondrial cleanup could help explain the delayed and debilitating
PEM crashes experienced by some Long COVID patients
The hypothesis was proposed by Robert Groysman, an independent researcher from the Covid Institute, Plano, Texas, United States, who describes the possible condition as “fragile mitophagy.” Rather than claiming this mechanism explains all Long COVID cases, the researcher proposes it as a possible biological subtype affecting patients whose illness is dominated by post-exertional malaise.
Why PEM Is More Than Ordinary Tiredness
Post-exertional malaise, better known as PEM, is a major problem for many people with Long COVID. It refers to an abnormal worsening of symptoms following physical, mental or other forms of physiological stress.
Unlike normal tiredness after exercise, PEM can appear 24 to 72 hours after activity and may take days to resolve. Patients can experience severe fatigue, cognitive problems or “brain fog,” pain, disturbed sleep, dizziness, rapid heartbeat, headaches, flu-like symptoms and increased sensitivity.
The mystery has been why exertion can produce such a delayed deterioration instead of simply causing immediate exhaustion.
Damaged Mitochondria May Not Be Properly Cleared
Mitochondria are microscopic structures inside cells that generate much of the energy needed for cellular functions. When mitochondria become damaged, cells normally identify and dispose of them through mitophagy.
Groysman proposes that Long COVID patients with severe PEM may initiate mitophagy but fail during its later stages. Damaged mitochondrial material is normally transported to structures called lysosomes, which function like cellular recycling and waste-disposal centers.
If lysosomes cannot complete this job efficiently, mitochondrial fragments, mitochondrial DNA, damaged proteins and oxidized fats could remain behind.
As this Thailand
Medical News report explains, these cellular leftovers could potentially behave as danger signals, activating inflammatory, immune, vascular and neurological responses. This gradual biological amplification could help explain why a patient initially tolerates an activity but experiences a major crash one or two days later.
Repeated Exertion Could Create a Dangerous Backlog
The theory also offers an explanation for why repeated exertion can progressively lower a patient's baseline.
If another period of activity occurs before mitochondrial debris from an earlier stress has been cleared
, cellular damage and cleanup demands could accumulate. Each new episode could therefore place additional pressure on an already overloaded disposal system.
This could mean that PEM is not simply the result of insufficient energy production. Instead, some patients may have enough energy to perform an activity but lack the cellular “recovery reserve” needed to clean up afterward and return to their previous baseline.
Researchers Want the Theory Put to The Test
Importantly, fragile mitophagy has not been proven in Long COVID, and no routine clinical blood test currently diagnoses it. Existing patient studies have identified mitochondrial abnormalities, but they have not demonstrated the specific mitophagy-and-lysosome failure proposed in this paper.
The researcher recommends studies comparing Long COVID patients with severe PEM, patients without PEM, recovered individuals and healthy controls. Testing before exertion and at 24, 48 and 72 hours afterward could reveal whether worsening PEM corresponds with impaired lysosomal function and incomplete mitochondrial clearance.
Conclusions
The hypothesis provides a compelling and testable explanation for delayed PEM by shifting attention from how much energy mitochondria produce to how effectively damaged mitochondria are removed after exertion. However, direct patient evidence remains essential before fragile mitophagy can be considered an established Long COVID mechanism or used to guide clinical treatment.
The study findings were published in the peer reviewed journal: Frontiers in Medicine.
https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2026.1905758/full
Read Also:
https://www.thailandmedical.news/articles/long-covid 
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