The Mitochondrial Signature of Long COVID: What PRDX3 Is Trying to Tell Us—And How We Might Reverse It

Introduction

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), affects an estimated 10-30% of people who contract COVID-19, regardless of how mild or severe their initial illness was. Its symptoms, including chronic fatigue, brain fog, dizziness, shortness of breath, muscle weakness, and mood disturbances, are often debilitating. Despite normal results on standard labs or imaging, many individuals find themselves unable to return to work, school, or their daily routines.

A growing body of research suggests that these symptoms may stem from hidden damage inside the body’s energy-producing structures: the mitochondria. These tiny organelles are responsible not only for generating ATP, the fuel that powers every cell, but also for regulating immune responses, inflammation, and cellular repair. In long COVID, these systems appear to be chronically impaired.

One of the most intriguing recent discoveries in long COVID research is the appearance of a protein called peroxiredoxin-3 (PRDX3) in the bloodstream. Under normal conditions, PRDX3 stays inside the mitochondria, where it plays a protective role. Its job is to help clean up reactive oxygen species- unstable molecules produced during energy production that can damage cells if they build up.

However, in people with long COVID, PRDX3 has been found outside the mitochondria, circulating in the blood. This unusual presence suggests that the mitochondria are under pressure, either damaged or overwhelmed, and may be releasing distress signals. In other words, elevated PRDX3 could be the body’s way of warning that something deeper is still wrong at the cellular level, long after the infection has cleared.

In this review, the Healthspan Research Team will break down recent research linking long COVID to mitochondrial dysfunction, exploring how the virus disrupts the body’s ability to produce energy, how chronic oxidative stress and inflammation may keep the body in a state of metabolic distress, and how biomarkers like PRDX3 are helping us see these changes more clearly. We’ll also highlight our current approach to optimizing mitochondrial health by targeting key pathways like AMPK activation, mitophagy, and redox balance, beginning with foundational lifestyle interventions, and building on them with select mitochondrial-supportive molecules.

Long COVID & Mitochondria

Mitochondria are often called the “powerhouses” of our cells, and for good reason; they are responsible for producing most of the energy our bodies need to function. Every movement we make, every thought we have, and even the basic processes keeping us alive depend on the energy generated by these tiny structures inside our cells. This energy comes in the form of a molecule called adenosine triphosphate (ATP), which acts like a rechargeable battery, fueling everything from muscle contractions to brain activity. But mitochondria do much more than just supply energy. They also help regulate the immune system, manage levels of harmful molecules in our cells, and even decide when a damaged or malfunctioning cell should be eliminated, a process known as programmed cell death or apoptosis.

One of mitochondria’s key roles is controlling oxidative stress, which happens when unstable molecules called reactive oxygen species (ROS) build up in the body. While ROS are naturally produced during normal cell processes, too many of them can damage proteins, DNA, and cell membranes, leading to inflammation and disease. [1] Mitochondria help keep this balance in check, but when they become damaged or dysfunctional, they can contribute to widespread health problems, a condition known as mitochondrial dysfunction. When mitochondria stop working properly, cells don’t get enough energy, leading to fatigue, muscle weakness, and problems in organs that require high amounts of energy, like the brain and heart.

This brings us to Long COVID, a condition that has left millions struggling with lingering symptoms long after recovering from their initial COVID-19 infection. Studies suggest that more than 70% of COVID-19 survivors continue to experience symptoms months later, even when standard tests show no obvious signs of illness. [2] The most common and debilitating complaint is chronic fatigue, which is not just ordinary tiredness but a deep, persistent exhaustion that doesn’t improve with rest. This kind of fatigue is similar to what people with chronic fatigue syndrome (CFS) experience. In this condition, even small activities can leave a person completely drained, often making it difficult to work, socialize, or carry out daily tasks.

Other symptoms of Long COVID include difficulty thinking clearly (often called brain fog), muscle weakness, shortness of breath, headaches, dizziness, sleep disturbances, and mood disorders like anxiety and depression. These cognitive difficulties, trouble focusing, remembering things, and processing information, fall under cognitive function, which refers to how well our brain performs tasks like learning, problem-solving, and decision-making. When mitochondria are not functioning properly, brain cells may not get the energy they need, leading to memory problems and mental fatigue.

Another crucial role of mitochondria is immune regulation, meaning they help control how the body responds to infections. The immune system is our body’s defense system, fighting viruses and bacteria. But if mitochondria aren’t working properly, the immune system can become overactive, leading to chronic inflammation, or underactive, making it harder for the body to recover from illness. Since COVID-19 triggers a strong immune response, some researchers believe that mitochondrial dysfunction could be one reason why some people’s immune systems stay in a heightened state, causing prolonged symptoms even after the virus is gone.

The fact that many Long COVID symptoms, like fatigue, brain fog, and muscle weakness, overlap with those seen in conditions linked to mitochondrial dysfunction raises an important question: Could SARS-CoV-2, the virus behind COVID-19, be disrupting the way mitochondria function? Emerging research suggests that this might be the case. If COVID-19 is impairing mitochondrial health, it could explain why so many people with Long COVID struggle with energy levels, cognitive function, and overall recovery.

Understanding this connection is critical, as it could open the door to new treatments aimed at restoring mitochondrial function and helping people regain their health. By exploring how SARS-CoV-2 affects mitochondria, scientists hope to unravel the mystery of Long COVID and develop strategies to manage and treat its persistent symptoms. In the coming sections, we will delve deeper into the relationship between our mitochondria and Long COVID, hoping to solve a mystery that can revolutionize treatment options. 

SARS-CoV-2 Sabotages Mitochondrial Function

Like a skilled hacker infiltrating a secure network, SARS-CoV-2 has evolved sophisticated strategies to manipulate mitochondria, bending them to its will. Instead of allowing these cellular powerhouses to fuel the body’s recovery, the virus exploits them for its purposes, impeding their ability to produce energy, undermining immune defenses, and unleashing chaos at a molecular level.

One of the ways SARS-CoV-2 interferes with mitochondria is through its viral proteins, particularly ORF9b, Nsp12, and Nsp13. These proteins act like saboteurs, directly targeting mitochondrial components and disrupting their function. ORF9b, for instance, infiltrates mitochondria and shuts down the mitochondrial antiviral signaling protein (MAVS), a crucial part of the immune system’s early-warning system. By disabling MAVS, the virus weakens the body’s ability to detect and fight the infection, allowing SARS-CoV-2 to persist and spread. 

Meanwhile, Nsp12 and Nsp13 interfere with mitochondrial RNA polymerase, the machinery responsible for producing key mitochondrial proteins. This disruption cripples mitochondria at their core, preventing them from generating the energy cells need to function properly. [3]

But the viral assault doesn’t end there. SARS-CoV-2 also unleashes a storm of oxidative stress, an overproduction of harmful molecules like ROS. Under normal circumstances, mitochondria produce small amounts of ROS as a natural byproduct of energy production. However, when the balance is thrown off, excessive ROS can wreak havoc by damaging proteins, fats, and even mitochondrial DNA (mtDNA). This damage triggers a downward spiral: defective mitochondria struggle to generate ATP, leading to fatigue, muscle weakness, and cognitive impairments.

Biomarkers of Mitochondrial Dysfunction in Long COVID

Further proof that mitochondrial dysfunction plays a central role in Long COVID comes from biomarker studies. These scientific investigations look for biological clues in the blood to assess how well cells are functioning. Researchers have discovered elevated levels of certain biomarkers that point to oxidative stress and mitochondrial damage in Long COVID patients.

One key finding is the presence of F2-isoprostanes and malondialdehyde (MDA), chemicals produced when free radicals attack the body’s tissues. [4] This process, called oxidative stress, is similar to rust forming on metal: it gradually wears down and weakens mitochondria, making them less efficient at producing energy.

At the same time, researchers have found that coenzyme Q10 levels are significantly lower in Long COVID patients. Coenzyme Q10 is a vital antioxidant, meaning it helps neutralize free radicals and protect mitochondria from damage. [5] When coenzyme Q10 levels drop, mitochondria become even more vulnerable, struggling to generate enough energy for the body to function properly. The combination of increased oxidative stress and reduced mitochondrial protection suggests that mitochondria in Long COVID patients are under continuous attack, unable to recover from the damage.

In addition to these blood markers, genomic studies, which examine changes in gene activity, have revealed alterations in the expression of genes linked to mitochondrial function and immune system regulation in COVID-19 patients. [6, 7] Some of these changes seem to be direct effects of the virus, as SARS-CoV-2 can hijack the cell’s genetic machinery. Others may be secondary consequences of the immune system’s response to the infection, potentially leading to long-term dysfunction.

Either way, these findings reinforce the idea that mitochondrial dysfunction is not just a side effect of Long COVID; it is a major driver of its wide-ranging symptoms.

The Consequences of Mitochondrial Dysfunction in Long COVID

When mitochondria are damaged, the entire body suffers. Since mitochondria generate the energy that powers our cells, their dysfunction leads to one of the most common and life-altering symptoms of Long COVID: chronic fatigue. Patients often feel exhausted even after simple activities, like walking up a flight of stairs. This happens because mitochondria can no longer produce enough ATP, which fuels every process in the body, leaving cells, tissues, and organs struggling to function.

Muscles are especially dependent on mitochondria, which explains why muscle weakness and exercise intolerance are common in Long COVID. Even mild physical activity can leave patients feeling drained, as if they had just run a marathon. Similarly, the brain is an energy-hungry organ, and when mitochondrial function declines, so does cognitive function. This results in brain fog, a frustrating condition where people experience difficulty concentrating, memory lapses, and mental exhaustion.

Mitochondria also help regulate the immune system, and when they are impaired, the immune response can spiral out of control. In Long COVID, this often leads to chronic inflammation, where the body remains stuck in a prolonged state of immune activation. This ongoing immune imbalance is believed to contribute to a range of symptoms, from persistent fevers to neurological issues and cardiovascular problems. [8]

Mitochondrial Dysfunction in Other Post-Infectious Syndromes

Long after an infection clears, some people continue to experience exhaustion, body aches, and brain fog, symptoms that don’t seem to have a clear cause but significantly affect their daily lives. Long COVID is just one example of this phenomenon, but it’s far from the only one. Many infections leave behind lingering health issues, and researchers have identified mitochondrial dysfunction as a possible culprit in several of these conditions. Since mitochondria are responsible for generating the energy our cells need, any disruption in their function can have widespread effects. Examining other post-infectious syndromes where mitochondria have been implicated can offer insight into what might be happening in Long COVID and possible treatment approaches.

One of the best-studied conditions in this category is myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). It often develops after a viral infection, and its symptoms, persistent fatigue, muscle pain, unrefreshing sleep, and trouble concentrating, bear a striking resemblance to those seen in long COVID. Research suggests that people with ME/CFS have trouble producing energy at the cellular level. Their mitochondria appear to function less efficiently, struggling to generate the ATP needed to fuel the body. Studies have also found abnormalities in mitochondrial structure and evidence that these energy-producing organelles may be under constant stress. Since long COVID and ME/CFS share so many symptoms, they may share underlying mitochondrial dysfunction as well. [9]

Another example comes from post-treatment Lyme disease syndrome (PTLDS). Lyme disease, caused by the bacterium Borrelia burgdorferi, is usually treated successfully with antibiotics. Still, some patients continue to experience fatigue, joint pain, and cognitive difficulties even after the infection is gone. Research suggests that mitochondria may not fully recover from the infection in these cases. Some studies indicate that Borrelia bacteria can interfere with mitochondrial function, and remnants of bacterial proteins or an ongoing immune response may continue to disrupt normal energy production. This could explain why some people never quite regain their full health, despite no longer having an active infection. 

Borrelia affects mitochondria by triggering long-term inflammation, the body’s defense response to infection. This happens because Borrelia produces special molecules called lipoproteins, such as OspA, OspB, and OspC. Lipoproteins are fat-coated proteins that help bacteria survive, but in Borrelia, they also act as a warning signal that activates the immune system. These lipoproteins attach to special receptors on immune cells, specifically Toll-like receptor 2 (TLR2). Toll-like receptors (TLRs) are security sensors on immune cells that detect harmful invaders. When Borrelia’s lipoproteins bind to TLR2, the immune system reacts aggressively by releasing chemical messengers called cytokines.

Cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), help fight infections by alerting more immune cells and increasing inflammation. However, if too many cytokines are produced for too long, they start harming the body. 

One of the ways they do this is by damaging mitochondria. For example, cytokines trigger the release of nitric oxide (NO), a molecule that disrupts the mitochondria’s ability to generate energy by blocking a key part of the energy production system called complex IV of the electron transport chain (ETC). The ETC is like a power plant inside mitochondria that converts nutrients into usable energy (ATP). When complex IV is blocked, mitochondria struggle to make ATP, leading to low energy levels and symptoms like extreme fatigue and muscle weakness.

Inflammation also causes another problem, oxidative stress. Normally, the body has a process called mitophagy, where damaged mitochondria are broken down and removed, making room for new, healthy ones. But Borrelia seems to interfere with this process, leading to an accumulation of defective mitochondria that not only produce less energy but also release more ROS, worsening the damage over time.

A similar pattern can be observed in chronic Q fever fatigue syndrome (QFS), which occurs in some people after infection with Coxiella burnetii, the bacterium responsible for Q fever. Patients with QFS report severe fatigue, muscle pain, and difficulty concentrating, symptoms that overlap significantly with ME/CFS, PTLDS, and long COVID. While fewer studies have investigated mitochondrial dysfunction in QFS, its symptom profile suggests a potential link. Given what is known about mitochondria’s role in other post-infectious conditions, it is plausible that lingering immune activation or bacterial remnants continue interfering with mitochondrial function in these patients. [13]

When viewed together, these conditions reveal a common thread: after an infection, mitochondrial dysfunction may persist, leading to chronic fatigue, cognitive difficulties, and other debilitating symptoms. Whether triggered by viral proteins, bacterial fragments, or an overactive immune response, the result appears to be the same: mitochondria struggle to generate sufficient energy, and patients are left feeling drained and unwell for months or even years. Understanding how infections lead to mitochondrial dysfunction in these conditions may help researchers develop better treatments, not just for long COVID, but for a range of post-infectious syndromes that continue to affect millions worldwide.

Serum Peroxiredoxin-3: A New Clue in Long COVID’s Mitochondrial Puzzle

Scientists investigating mitochondrial damage in long COVID have identified a promising lead: peroxiredoxin-3 (PRDX3). This protein may offer important insights into why many individuals with long COVID continue to experience persistent fatigue, brain fog, and muscle weakness.

PRDX3 is an antioxidant enzyme located inside mitochondria. Its primary role is to neutralize hydrogen peroxide (H₂O₂), a reactive byproduct of energy production that can cause significant damage if not properly managed. Research indicates that PRDX3 is responsible for eliminating up to 90 percent of the hydrogen peroxide generated within mitochondria. [18]

Because of this central role in managing mitochondrial oxidative stress, PRDX3 is often considered a useful biomarker for mitochondrial redox balance. When mitochondria are under stress, PRDX3 levels may increase as part of the cell’s antioxidant response, or the protein may undergo oxidation itself. 

Experimental models have shown that higher PRDX3 expression or oxidation correlates with elevated mitochondrial reactive oxygen species (ROS). In clinical settings, the presence of PRDX3 in the bloodstream has become a key focus. Under normal conditions, PRDX3 is confined to mitochondria and is not typically found in high levels in the blood. However, during cellular stress or injury, such as from cell turnover, apoptosis, or secretion via extracellular vesicles, PRDX3 can be released into circulation. Elevated serum PRDX3 levels are therefore interpreted as a signal of mitochondrial oxidative stress, a sort of "leak" indicating that the mitochondria are under duress. [18]

This concept is not unique to long COVID. In fact, PRDX3 has already been studied as a serum marker in other conditions involving oxidative stress. For example, elevated serum PRDX3 levels have been observed in patients with hepatocellular carcinoma, where it reflects increased oxidative stress in tumor mitochondria. [18]

Researchers propose that measuring serum PRDX3 may offer a window into mitochondrial health in long COVID. If patients with lingering post-COVID symptoms show elevated levels of PRDX3, it suggests that their mitochondria are experiencing oxidative strain or damage. Based on this hypothesis, several peer-reviewed studies have investigated PRDX3 levels in long COVID cohorts to determine whether the protein could serve as an objective biomarker of mitochondrial dysfunction in this condition.

Evidence of Elevated PRDX3 in Long COVID Patients

One study by Doykov et al. examined patients 40 to 60 days after SARS-CoV-2 infection, including individuals with only mild or asymptomatic cases. Despite clinical recovery, these patients continued to show signs of a prolonged inflammatory response. Among the most notable findings was an increase in serum PRDX3 levels and a decrease in CPS1, another mitochondrial enzyme. This pattern, elevated PRDX3 alongside reduced CPS1, was interpreted as a marker of disrupted mitochondrial function and impaired stress-response mechanisms. The researchers described this lingering biochemical signature as part of the "long tail of COVID-19," highlighting how the virus can leave behind persistent cellular abnormalities even after acute symptoms resolve. [19]

Additional studies have corroborated the idea that mitochondrial damage lingers in long COVID. Some patients exhibit suppressed activity of enzymes like citrate synthase and electron transport chain components, both essential for mitochondrial energy production. These deficits align with clinical symptoms such as chronic fatigue and exercise intolerance. [19]

Building on Doykov’s findings, a larger longitudinal study by Captur et al. in 2022 followed healthcare workers from the point of infection through their recovery period. The researchers identified a distinct plasma protein signature marked by sustained inflammation and metabolic disruption in individuals who later developed long COVID. PRDX3, in particular, remained elevated four to six weeks after the acute phase of infection. While antioxidant levels in most individuals typically normalize as they recover, those with long COVID showed persistently high mitochondrial PRDX3 levels. The study authors interpreted this continued PRDX3 elevation as a sign of ongoing oxidative stress and a lingering disturbance in mitochondrial redox regulation. This supports the theory that for some individuals, COVID-19 leaves behind a chronic mitochondrial imbalance that contributes to long-term symptoms. [19]

PRDX3 and Symptom-Specific Signatures in Long COVID

Another focused study in 94 post-COVID patients in Hungary has provided some more direct clinical data on PRDX3 as a long COVID marker. All these patients had lingering symptoms beyond 4 weeks of infection, and the researchers measured serum PRDX3 levels alongside symptom assessments. 

They found baseline PRDX3 levels averaged around 50 ng/mL in these long COVID patients. When stratifying by fatigue severity (one of the most common long COVID symptoms), PRDX3 did not differ significantly between those with severe fatigue and those with milder fatigue. On the surface, this suggests that a higher PRDX3 is not simply proportional to how tired a patient feels, indicating it’s not a universal marker of symptom severity. However, a very interesting pattern emerged with a specific symptom: dizziness. [18]

Patients who reported ongoing dizziness, often related to autonomic dysfunction or neurovascular complications, had significantly higher serum PRDX3 levels than those without dizziness. The median PRDX3 concentration in the dizziness group was 58.4 ng/mL, compared to 47.9 ng/mL in the non-dizzy group. This difference was statistically significant (p = 0.026). [18]

When the researchers focused specifically on patients under 50 years of age (reducing the influence of age-related mitochondrial decline), they found that PRDX3 was an independent predictor of post-COVID dizziness. Within this younger subgroup, individuals with elevated PRDX3 had a higher likelihood of experiencing dizziness, and those affected also tended to report more severe fatigue and a broader range of symptoms. These findings point to a possible subset of long COVID in which mitochondrial oxidative stress plays a central role in neurocognitive and autonomic symptoms. [18]

Restoring Mitochondrial Health: What Elevated PRDX3 Reveals in Long COVID

Emerging evidence suggests that elevated levels of PRDX3 in long COVID may be a key signal of lingering mitochondrial stress. When levels of PRDX3 are elevated in the blood, it suggests that the body is still responding to an internal imbalance, one likely driven by sustained oxidative stress inside mitochondria. This could be due to ongoing inflammation (cytokines can stimulate ROS production in mitochondria) or residual viral proteins causing metabolic imbalance. [20]

PRDX3 upregulation is essentially the cell’s adaptive response to counteract this ROS. In long COVID patients, one can imagine their cells are still “in fight mode,” boosting antioxidant enzymes to cope with a lingering oxidative burden. This concept is supported by the observation of concurrent inflammatory cytokines in long COVID; for instance, patients with long COVID often have elevated IL-6 and other cytokines that can drive mitochondrial ROS generation. PRDX3 induction is a downstream effect of such chronic immune activation and metabolic stress. [19]

If PRDX3 is elevated, it might also indicate that mitochondrial function is impaired. High ROS within mitochondria can damage components of the electron transport chain and TCA cycle, leading to energy production issues. 

In the muscle tissue of long COVID patients with fatigue, researchers have found lower activity of mitochondrial enzymes and shifts in dynamics (more fission, less fusion) consistent with mitochondrial distress. 

PRDX3 could be viewed as a compensatory mechanism trying to preserve mitochondrial function; its elevation might be an attempt to prevent further damage to mitochondria. However, if ROS production outstrips even the increased PRDX3 capacity, oxidative damage can still accumulate (e.g., oxidizing lipids in mitochondrial membranes or causing mtDNA mutations). Thus, elevated PRDX3 could be a double-edged sword: it’s a protective response and a sign that the mitochondria are under enough attack to warrant that response. [20]

Seeing PRDX3 in serum might also mean that some cells are dying or being turned over, releasing their contents. Mitochondrial ROS can trigger cell death pathways (apoptosis via cytochrome c release, etc.). If long COVID involves tissue damage (say, in the brain or endothelium), PRDX3 might leak out as those cells break apart. 

Another possibility is active secretion: cells under stress sometimes secrete antioxidant enzymes in exosomes or microvesicles as a way to signal distress or to help other cells. Regardless of the mechanism, serum PRDX3 acts like a “smoke signal” from stressed mitochondria, alerting us to underlying oxidative injury. This is analogous to how cardiac troponin in the blood signals heart muscle damage; here, PRDX3 signals “mitochondrial damage.” [20]

Recognizing the central role of mitochondrial dysfunction in Long COVID has opened up a promising avenue for therapeutic interventions. By targeting the restoration of mitochondrial health, researchers and clinicians are exploring a range of strategies to alleviate the burden of this perplexing condition.

Mitochondrial DNA Damage: A Hidden Driver of Long COVID?

While much of the focus in long COVID research has centered on mitochondrial bioenergetics—how well mitochondria generate energy—another, less visible mechanism may be fueling chronic symptoms: mitochondrial DNA (mtDNA) damage and its role as an inflammatory trigger.

Mitochondria contain their own DNA, distinct from the DNA in the nucleus. This mtDNA encodes essential proteins involved in oxidative phosphorylation, and because of its proximity to the electron transport chain, it is particularly vulnerable to oxidative stress. When mitochondria are damaged—as appears to occur in long COVID due to viral interference, ROS overload, and impaired quality control pathways—fragments of mtDNA can leak into the cytosol or even the bloodstream.

Outside the mitochondrial matrix, mtDNA is recognized by the immune system as a damage-associated molecular pattern (DAMP). Structurally, mtDNA resembles bacterial DNA—unmethylated and circular—making it an alarm signal for the innate immune system. Cytosolic mtDNA activates pattern recognition receptors like Toll-like receptor 9 (TLR9) and cGAS-STING, triggering type I interferon responses and the release of pro-inflammatory cytokines such as IL-6, TNF-α, and IFN-β. [22]

This immune activation may persist even after viral clearance, keeping the body in a state of chronic low-grade inflammation, a hallmark of long COVID. Several studies have now detected elevated circulating mtDNA in patients with COVID-19, correlating with disease severity, endothelial dysfunction, and cytokine elevation—even weeks after infection resolution. [23] This lingering mtDNA leakage may reflect an ongoing failure in mitochondrial maintenance pathways such as mitophagy, allowing damaged mitochondria to accumulate and continually release inflammatory signals.

The implications of this are significant. Persistent mtDNA release could help explain the immune dysregulation seen in long COVID, including elevated interferon signatures, autoimmune-like symptoms, and the inability of the immune system to fully return to homeostasis. It also offers a molecular rationale for symptoms that span multiple organ systems—since mtDNA can enter circulation, it may act systemically to provoke inflammation in tissues far removed from the initial site of injury.

Additionally, chronic exposure to mitochondrial DAMPs may impair energy metabolism even further. Inflammatory cytokines induced by mtDNA-TLR9 or cGAS-STING activation can inhibit mitochondrial respiration, exacerbate ROS production, and disrupt the balance of mitochondrial fission and fusion. This creates a vicious cycle: mitochondrial damage leads to mtDNA release, which in turn amplifies inflammation and further impairs mitochondrial function.

From a therapeutic standpoint, targeting mtDNA release or DAMP signaling pathways may hold promise for breaking this cycle. Strategies that improve mitochondrial integrity—such as mitophagy activators like Urolithin A or rapamycin—or antioxidants that prevent oxidative mtDNA damage (e.g., methylene blue, CoQ10, or SS-31) may not only restore bioenergetic function but also reduce immune activation at its source.

Mitochondrial-Targeted Interventions: Protecting Cellular Energy

Exercise-Induced Mitochondrial Adaptation

Among individuals suffering from persistent fatigue, exercise intolerance, and muscle weakness following SARS-CoV-2 infection, growing evidence points to impaired mitochondrial bioenergetics as a contributing factor. Structured physical activity, when appropriately tailored, can help reverse many of these dysfunctions by targeting the underlying deficits in energy metabolism, oxidative stress regulation, and mitochondrial capacity.

At the cellular level, exercise triggers a biological program that tells the body to produce more and better-functioning mitochondria. This response is coordinated by a protein called PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), often described as the master regulator of mitochondrial biogenesis. 

When you engage in physical activity, especially activities that repeatedly contract muscle fibers, signals like increased calcium inside the cell and changes in the ratio of ATP to AMP activate PGC-1α. This protein then switches on genes that control how mitochondria grow, divide, and function. Over time, this leads to greater mitochondrial density and improved energy production capacity, helping reverse the energy deficits that underlie symptoms in long COVID.

Exercise also enhances how mitochondria use fuel. With consistent aerobic activity, cells become better at switching between burning glucose and fats for energy. This improved metabolic flexibility is crucial in long COVID, where studies suggest that mitochondrial enzyme activity may be suppressed, leading to early fatigue during even mild exertion. Training the mitochondria to use fuel more efficiently helps prevent lactate buildup and other byproducts contributing to fatigue and post-exertional symptoms.

Another important benefit of exercise is how it affects the body’s redox balance. During movement, cells temporarily generate more ROS, which at high levels can damage mitochondria. But in the right dose, this brief increase in ROS acts as a signal to strengthen the body’s own antioxidant defenses—a process known as hormesis. Repeated, moderate exercise increases the production of antioxidant enzymes like superoxide dismutase, catalase, and glutathione peroxidase, which protect mitochondria from oxidative damage over the long term. This adaptation reduces inflammation, improves mitochondrial integrity, and supports more resilient energy production.

However, these benefits depend on the right intensity and pacing. Many people with long COVID are sensitive to exertion and may experience post-exertional malaise (PEM)—a worsening of symptoms following even mild activity. This sensitivity may reflect a mismatch between energy demand and the impaired ability of mitochondria to meet that demand. To avoid symptom flare-ups, exercise must be introduced gradually and individualized for each patient’s baseline tolerance. Programs often begin with low-intensity activities such as stretching, slow walking, or breathing-based movement, progressing only as tolerated. Monitoring tools like heart rate variability (HRV), perceived exertion tracking, or pacing techniques can help guide safe activity levels. These strategies ensure that exercise supports recovery rather than exacerbating symptoms.

Nutrition and Mitochondrial Support

Nutrition plays a central role in mitochondrial health and is particularly important in the context of long COVID, where energy metabolism is often disrupted and systemic inflammation remains elevated. Mitochondria rely on a steady supply of micronutrients, cofactors, and structural components to carry out oxidative phosphorylation, manage ROS, and repair internal damage. In patients with lingering post-viral symptoms, strategic nutritional support can help reestablish metabolic homeostasis and support the regeneration of healthy mitochondrial function.

A number of specific nutrients are known to directly influence mitochondrial performance. One group of particular relevance is the B-complex vitamins, which serve as essential cofactors in nearly every stage of mitochondrial energy metabolism. Deficiencies in any of these vitamins can impair ATP production and increase the generation of ROS. In long COVID, where chronic inflammation or gut dysfunction may reduce nutrient absorption, restoring optimal B-vitamin status may help stabilize energy output and support mitochondrial recovery.

Another key player is magnesium, a mineral required for over 300 enzymatic reactions in the body, many of which are centered in the mitochondria. Magnesium stabilizes the structure of ATP (which exists as Mg-ATP in cells), facilitates the activity of ATP synthase (Complex V), and regulates mitochondrial calcium channels. It also plays a protective role against mitochondrial swelling and permeability transition, processes that can trigger apoptosis when dysregulated. In the setting of mitochondrial stress, low magnesium may worsen oxidative damage and energy deficits, while repletion can support mitochondrial resilience and metabolic control.

Omega-3 fatty acids, particularly EPA and DHA, found in marine sources, contribute to mitochondrial health through both structural and signaling roles. These long-chain polyunsaturated fats integrate into mitochondrial membranes, enhancing fluidity and reducing susceptibility to lipid peroxidation. More importantly, omega-3s help resolve chronic inflammation, a central feature of long COVID, by serving as precursors to specialized pro-resolving mediators (SPMs) like resolvins and protectins. They also suppress inflammatory pathways such as NF-κB, which are known to drive ROS production and mitochondrial dysfunction. By reducing inflammatory pressure and improving membrane integrity, omega-3s help create an environment more conducive to mitochondrial repair.

In addition to isolated nutrients, the overall dietary pattern has a significant impact on mitochondrial function. Diets rich in phytonutrients, antioxidants, and unprocessed whole foods provide the substrates needed for mitochondrial biogenesis and defense. Conversely, diets high in refined carbohydrates, processed seed oils, and synthetic additives can increase mitochondrial ROS production and disrupt membrane architecture, exacerbating the energy instability seen in long COVID.

Ultimately, a nutrient-dense, anti-inflammatory diet, centered on vegetables, quality proteins, healthy fats, and minimally processed foods, serves as a foundation for restoring mitochondrial function. This dietary approach supplies the building blocks needed for mitochondrial enzyme activity, redox balance, membrane repair, and energy generation. In the context of long COVID, it may also help reduce symptom severity by addressing the cellular-level damage that underpins fatigue, brain fog, and systemic dysfunction.

AMPK Activation and Nutrient Signaling

In long COVID, where mitochondrial dysfunction contributes to fatigue, cognitive slowing, and metabolic instability, a key therapeutic goal is to restore mitochondrial quality and quantity. One promising avenue is through activation of AMP-activated protein kinase (AMPK), a central metabolic regulator that detects low energy states and initiates mitochondrial repair programs.

Similar to exercise, when activated, AMPK promotes a shift from energy-consuming to energy-generating processes. It increases fatty acid oxidation, enhances glucose uptake, and stimulates mitochondrial biogenesis through the upregulation of PGC-1α. This creates a cellular environment that is more capable of meeting energy demands while also activating autophagy and mitophagy, the quality-control processes that eliminate damaged cellular components and dysfunctional mitochondria.

Several interventions are known to activate AMPK and promote mitochondrial adaptation:

• Caloric restriction or intermittent fasting, which naturally lowers energy availability and triggers AMPK activation.

• Exercise increases the AMP/ATP ratio and calcium flux.

• Polyphenols such as resveratrol and quercetin can activate AMPK indirectly through sirtuin pathways.

Berberine, metformin, SGLT2 inhibitors, Urolithin A, alpha-lipoic acid, plant-derived compounds, have been shown to activate AMPK and improve insulin sensitivity and mitochondrial function.

Urolithin A: A Mitophagy Activator

Urolithin A is a postbiotic compound produced by gut bacteria from dietary polyphenols—particularly ellagitannins found in foods like pomegranates, walnuts, and certain berries. What sets Urolithin A apart from traditional antioxidants is not its ability to directly neutralize reactive oxygen species, but its role in enhancing the cell’s internal housekeeping system. Specifically, it activates mitophagy, the selective recycling of damaged or dysfunctional mitochondria, and supports mitochondrial biogenesis, the creation of new, functional mitochondria.

By promoting the removal of faulty mitochondria and stimulating the generation of healthier ones, Urolithin A helps reduce oxidative stress at its source—rather than merely cleaning up after the damage. This unique mechanism has been shown in preclinical studies to improve endurance, muscle function, and mitochondrial gene expression. In early-phase human trials, Urolithin A supplementation led to increases in mitochondrial biomarkers and enhanced cellular energy efficiency, making it a promising candidate for mitochondrial support in the context of long COVID, where impaired energy metabolism, redox imbalance, and mitophagy dysfunction are increasingly recognized as central to symptom persistence.

One of the most debilitating aspects of long COVID is post-exertional malaise—a paradoxical worsening of symptoms following even minor physical or cognitive activity. This may be driven, in part, by an accumulation of dysfunctional mitochondria that are unable to meet the body’s energy demands, leading to lactate buildup, excessive ROS production, and an exaggerated inflammatory response. By restoring mitophagy, Urolithin A may help prevent this cascade by clearing damaged mitochondria before they can disrupt redox signaling or trigger metabolic crashes. This could be especially beneficial for individuals experiencing muscle fatigue, exercise intolerance, or neurovascular symptoms tied to mitochondrial stress.

The compound has been extensively studied by Professor Johan Auwerx’s laboratory at EPFL (École Polytechnique Fédérale de Lausanne), a world leader in mitochondrial biology. Their translational research—spanning C. elegans, rodent models, and human trials—has consistently demonstrated Urolithin A’s ability to enhance mitophagy and improve mitochondrial function. Several landmark studies from this group have been published in high-impact journals, including Nature Metabolism, Nature Medicine, and JAMA.

One intriguing aspect of Urolithin A is the variability in its natural production. Only an estimated 30–40% of individuals can generate it from ellagitannin-rich foods, depending on the presence of specific gut bacteria such as Gordonibacter urolithinfaciens and Ellagibacter isourolithinifaciens [24]. As a result, most people do not produce sufficient amounts of Urolithin A endogenously, highlighting the utility of direct supplementation to ensure therapeutic levels are reached—particularly in individuals with microbiome disruption following viral illness or antibiotic use.

Initial findings from 2016 demonstrated that Urolithin A increased lifespan in C. elegans by 45%, an effect attributed largely to enhanced mitochondrial function and mitophagy [25]. Subsequent studies have used sensitive fluorescent reporter systems—such as MitoKeima—to quantify mitophagy in muscle cells. After just 24 hours of Urolithin A exposure, mitophagy levels were shown to increase by over 100% compared to controls [25].

These benefits extend beyond cell culture. In rodent models, middle-aged adults, and older humans, Urolithin A supplementation has been observed to upregulate the expression of key genes and proteins involved in mitochondrial quality control, including PINK1, Parkin, and regulators of mitochondrial dynamics. By activating these pathways, Urolithin A may offer a therapeutic route to restore mitochondrial function in long COVID—particularly in individuals suffering from fatigue, muscle deconditioning, cognitive dysfunction, and persistent oxidative stress.

Rapamycin Induced Mitophagy

Rapamycin is widely recognized for its ability to induce autophagy through inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). Given that mitophagy is a specialized form of autophagy, it stands to reason that rapamycin might enhance mitochondrial quality control to improve Long COVID pathology. Yet surprisingly, direct evidence linking rapamycin to mitophagy has remained limited until recently.

A 2022 study published in Cell Metabolism by Dr. Tom McWilliams offers new insight into this connection. Using advanced mitophagy reporter systems he helped develop during his doctoral work, McWilliams investigated the effects of rapamycin in a mitochondrial disease model characterized by respiratory chain defects, “ragged-red fibers,” and the accumulation of dysfunctional mitochondria—features that mirror mitochondrial decline seen in aging, particularly in octogenarians. [26,27]

In this model, rapamycin treatment (8 mg/kg/day for 70 days) resulted in a 125% increase in mitophagy. Intriguingly, the muscle tissue of mitochondrial disease patients exhibited an 80-fold increase in the autophagy adapter protein p62, a sign of impaired or stalled autophagy. Rapamycin treatment reduced p62 levels by ~90%, effectively restoring autophagy flux and reducing the pathological accumulation of damaged mitochondria. [26]

Further support for rapamycin’s role in enhancing mitochondrial remodeling comes from research on mitochondrial biogenesis. In aged mice, rapamycin treatment increased mitochondrial protein synthesis by nearly 40%, as demonstrated using state-of-the-art stable isotope tracer techniques. Notably, this effect was not observed in younger mice, highlighting an age-specific mitochondrial response [27].

Complementary findings from Alzheimer’s disease models offer valuable insight into how rapamycin might address the neurological symptoms of long COVID. In an 8-week study, daily administration of rapamycin (1 mg/kg/day) improved learning, memory, and synaptic plasticity—cognitive domains often impaired in long COVID patients experiencing “brain fog.” These functional gains were accompanied by enhanced mitochondrial quality control, suggesting a potential mechanistic link between mitophagy and cognitive resilience. Although the study did not utilize a Mito-QC reporter, the authors employed co-localization of TOM20 (a mitochondrial outer membrane marker) and LC3B (an autophagosome marker) as a proxy for mitophagy activity. Rapamycin treatment increased TOM20–LC3B co-localization by over 400%, indicating a robust induction of mitochondrial-specific autophagy. [32]

Crucially, these changes were observed only in the mitochondrial fraction of the brain, not in whole-brain homogenates—highlighting the importance of analyzing mitochondrial-specific compartments, particularly in conditions like long COVID where symptoms may stem from localized dysfunction rather than overt tissue loss. Within this mitochondrial-enriched fraction, rapamycin also upregulated key mitophagy-related proteins including Parkin, LC3B, and p62, supporting its role in enhancing mitochondrial turnover. Given the parallels between neurodegenerative disease and the cognitive impairments seen in long COVID, these findings suggest that rapamycin may help restore neuronal energy balance and protect against ROS-induced damage by rejuvenating mitochondrial networks in the brain. [32]

Taken together, these studies reinforce rapamycin’s potential as a mitochondrial rejuvenation therapy. While most data come from preclinical models, the convergence of mitophagy activation, restored autophagic flux, and enhanced mitochondrial protein synthesis paints a compelling picture—especially in aging tissues, where mitochondrial dysfunction plays a central role in fatigue, neurodegeneration, and immune dysregulation.

Given the accumulating evidence of mitochondrial dysfunction, impaired mitophagy, and persistent oxidative stress in long COVID, rapamycin’s ability to restore mitochondrial quality control may have important therapeutic implications. In long COVID, elevated markers such as PRDX3 suggest that damaged mitochondria remain uncleared, contributing to a chronic redox imbalance and metabolic bottleneck. By promoting mitophagy and resolving stalled autophagic flux, rapamycin may help remove dysfunctional mitochondria that continue to generate excess ROS and amplify inflammatory signaling. This mechanism could be particularly relevant in patients exhibiting post-exertional malaise, cognitive impairment, or muscle fatigue—hallmark symptoms tied to energetic deficits and mitochondrial distress. While clinical studies in long COVID are still needed, preclinical data from aging and neurodegenerative models suggest that rapamycin has the potential to recalibrate mitochondrial turnover and break the cycle of cellular stress that sustains long COVID symptoms.

Methylene Blue: Reviving the Electron Transport Chain

One of the most fundamental disruptions observed in long COVID is a breakdown in efficient mitochondrial respiration. As described earlier, excessive oxidative stress and viral interference with mitochondrial proteins (such as ETC complexes) compromise ATP production and increase the leakage of electrons, generating excess reactive oxygen species (ROS). In this redox-imbalanced state, cells struggle to meet energy demands—especially in high-demand tissues like the brain, muscles, and heart.

Methylene blue, a compound with a long history of medical use, has recently garnered attention for its unique role in supporting mitochondrial respiration and restoring redox balance. Unlike conventional antioxidants, which scavenge ROS after they form, methylene blue acts upstream by intercepting the source: it shuttles electrons directly within the electron transport chain. Specifically, methylene blue can accept electrons from NADH and donate them to cytochrome c, effectively bypassing damaged complexes (like Complex I or III) and preserving ATP synthesis. [29]

This makes methylene blue a redox mediator, capable of restoring controlled electron flow and minimizing ROS production at the source. In stressed mitochondria—like those seen in long COVID—this property may be particularly valuable. By improving electron flux, methylene blue helps reduce the electron “traffic jams” that lead to oxidative leakage and energy deficits. Preclinical studies have shown that methylene blue can enhance mitochondrial membrane potential, increase ATP production, and protect against mitochondrial toxins. [29]

In neural tissue, methylene blue is especially promising. The brain is one of the most mitochondrially dense organs and is highly vulnerable to energy disruption and oxidative damage. Cognitive symptoms in long COVID, including brain fog, slowed processing, and memory impairment, may stem from impaired mitochondrial energy metabolism. In animal models, methylene blue has demonstrated nootropic effects, improving memory and enhancing cerebral blood flow—likely due to its dual role in supporting mitochondrial function and reducing neuroinflammation. [30, 31]

Furthermore, methylene blue has been shown to upregulate antioxidant enzymes, offering a multi-layered defense against long COVID's molecular hallmarks: mitochondrial dysfunction, ROS accumulation, and metabolic inflexibility [30,31]. Unlike direct stimulants, methylene blue works by enhancing cellular energy efficiency rather than increasing energy demand—making it particularly suitable for patients with post-exertional malaise or limited metabolic reserve.

While more clinical research is needed, the existing mechanistic and preclinical data suggest that methylene blue may serve as a bridge between mitochondrial support and cognitive recovery in long COVID. Its ability to restore electron flow, reduce ROS at the source, and support energy production makes it an attractive adjunct to other mitochondrial interventions like Urolithin A, rapamycin, and targeted exercise.

Elamipretide: Stabilizing Mitochondrial Architecture and Function

In long COVID, mounting evidence points to structural and functional damage within mitochondria—including compromised electron transport, excessive reactive oxygen species (ROS) production, and leakage of mitochondrial components like PRDX3 and mtDNA. A major contributor to this dysfunction is injury to the inner mitochondrial membrane, where the electron transport chain resides and where ATP synthesis is coordinated. Elamipretide (SS-31) is a novel therapeutic peptide designed to directly target and repair this critical interface.

Elamipretide is a mitochondria-penetrating tetrapeptide that selectively binds to cardiolipin, a unique phospholipid found almost exclusively in the inner mitochondrial membrane. Cardiolipin plays a crucial role in maintaining the structural organization and efficiency of the electron transport chain. In pathological states—such as oxidative stress, viral injury, or aging—cardiolipin becomes oxidized, leading to membrane destabilization, ETC uncoupling, and increased ROS leakage. [32]

By interacting with cardiolipin, elamipretide stabilizes the mitochondrial membrane, reduces cardiolipin peroxidation, and restores optimal conditions for electron flow and ATP generation. In preclinical models, elamipretide has been shown to improve mitochondrial respiration, reduce ROS production, and enhance mitochondrial membrane potential across a variety of tissues—including skeletal muscle, brain, and heart. [33,34] These effects are especially relevant in long COVID, where systemic fatigue, cognitive dysfunction, and cardiovascular symptoms may all stem from impaired mitochondrial energetics and structural degradation.

What distinguishes elamipretide from traditional antioxidants is its membrane-localized mechanism of action. Rather than scavenging ROS indiscriminately, it prevents their formation at the source by improving electron transport chain coupling and reducing electron leakage. This upstream redox modulation is particularly valuable in long COVID, where chronic oxidative stress perpetuates cellular injury and impairs recovery.

In early-phase human trials, elamipretide has demonstrated promise in improving exercise tolerance and mitochondrial function in patients with mitochondrial myopathy and heart failure—conditions that share key features with long COVID, such as reduced ATP production, elevated fatigue, and tissue-level hypoxia. [35] While it has not yet been studied specifically in long COVID cohorts, its mechanism of action aligns well with the emerging pathophysiology: a blend of membrane destabilization, redox imbalance, and impaired mitochondrial turnover.

As we deepen our understanding of the mitochondrial signatures in long COVID—such as elevated serum PRDX3, suppressed ETC enzyme activity, and persistent mtDNA release—elamipretide offers a targeted approach to address mitochondrial dysfunction at its structural core. Its potential to restore mitochondrial membrane integrity and improve energetic resilience makes it a compelling candidate for future clinical investigation in post-viral fatigue syndromes.

What's Next in This Line of Research?

The interventions listed above converge on the same cellular axis: AMPK → PGC-1α → mitochondrial biogenesis, with complementary support from NAD⁺-dependent sirtuins and mitophagy regulators like Urolithin A. When used in combination, nutritional strategies, targeted supplements, and appropriately dosed physical activity, these tools may help restore metabolic flexibility and mitochondrial health in long COVID.

Yet translating these mechanistic insights into real-world clinical outcomes will require a deliberate and evidence-based path forward. While the promise of mitochondrial-targeted therapies is clear, the clinical application remains limited by several major challenges, including the need for standardized diagnostics, well-powered clinical trials, and biomarker-driven personalization. [18]

One of the most pressing gaps is the lack of consensus around how to define and diagnose mitochondrial dysfunction in the context of long COVID. Unlike primary mitochondrial diseases, where diagnostic criteria and genetic markers are more established, post-viral mitochondrial impairment is subtler and more heterogeneous. Currently, there are no universally accepted clinical guidelines or validated biomarkers that reliably quantify mitochondrial dysfunction in this population. This lack of standardization makes it difficult to assess disease severity, monitor response to therapy, or stratify patients for targeted interventions.

To address this, researchers are actively exploring novel tools for assessing mitochondrial health in vivo. Advanced imaging modalities such as phosphorus magnetic resonance spectroscopy (³¹P-MRS) may allow for real-time measurement of ATP turnover and mitochondrial oxidative capacity in skeletal muscle and brain tissue. At the molecular level, the identification of serum biomarkers, such as peroxiredoxin-3 (PRDX3), lactate-to-pyruvate ratios, or even circulating mitochondrial DNA fragments, could offer noninvasive ways to track mitochondrial stress, biogenesis, or mitophagy activity. The integration of multi-omics platforms, including metabolomics, proteomics, and transcriptomics, may also help create a more nuanced understanding of mitochondrial signatures in long COVID subtypes.

Equally important is the need for robust clinical trials to evaluate the safety and efficacy of mitochondrial-directed therapies. While early-phase studies and observational reports have generated encouraging signals—from improvements in fatigue scores to enhanced mitochondrial biomarkers—these findings must be confirmed in larger, placebo-controlled trials. Key questions remain around dosing, treatment duration, and therapeutic combinations. Importantly, trials must also account for the heterogeneity of long COVID and be designed to detect differential responses among distinct clinical phenotypes, such as those with dysautonomia, post-exertional malaise, or cognitive impairment.

Moving forward, identifying patient subgroups most likely to benefit from these therapies will be key. Not every individual with long COVID will have the same degree or pattern of mitochondrial dysfunction. Some may experience dominant oxidative stress, others impaired mitophagy, and still others NAD⁺ depletion or chronic inflammatory signaling. Personalized approaches, guided by biomarker profiles, symptom clusters, and metabolic signatures. will likely be necessary to optimize outcomes.

Despite these differences, a unifying mechanism may be emerging. Across these varied clinical presentations, many of the most debilitating symptoms, fatigue, cognitive dysfunction, muscle weakness, and chronic inflammation, appear to trace back to a shared breakdown in core cellular processes. Specifically, disruptions in mitochondrial energy production, redox regulation, and cellular repair may form the biological backbone of long COVID.

By decoding the molecular disruptions caused by SARS-CoV-2 and identifying biomarkers like PRDX3 that reflect this damage, researchers are beginning to piece together a new model for understanding and treating long COVID. This shift in perspective opens the door to interventions that focus not just on symptom relief but also on repairing the underlying cellular machinery driving long COVID.