Deep Dive March 7, 2026 8 min read

The Energy Crisis: How Long COVID Hijacks Your Cellular Power Plants

mitochondria WASF3 oxidative stress ME/CFS metformin oxaloacetate energy metabolism treatment
The Energy Crisis: How Long COVID Hijacks Your Cellular Power Plants

If you have Long COVID, you already know the fatigue. Not the tiredness that sleep fixes — the bone-deep exhaustion that crashes after minimal effort, that makes your body feel like it's running on empty even when you've done nothing. Science is now revealing why: SARS-CoV-2 doesn't just infect your cells and leave. It sabotages the machinery that makes energy itself.

This article traces the molecular chain from viral persistence to cellular energy failure — and surveys the treatments trying to break it.

The Engine Room: How Mitochondria Make Energy

Every cell in your body contains hundreds to thousands of mitochondria — organelles that convert food into ATP, the molecule that powers virtually every cellular process. They do this through an elegant chain of five protein complexes embedded in their inner membrane, called the electron transport chain. Electrons pass down the chain, pumping protons across the membrane, and the resulting pressure gradient drives Complex V (ATP synthase) to spin like a molecular turbine, generating ATP.

When this system works, it's extraordinarily efficient — producing about 36 ATP molecules per glucose molecule. When it breaks, everything downstream breaks with it: muscle contraction, nerve signaling, immune function, cognition. The symptoms of mitochondrial failure read like a Long COVID symptom list.

WASF3: The Protein That Breaks the Machine

In 2023, a team at the NIH led by Hwang and colleagues made a discovery that may explain the central fatigue mechanism in both ME/CFS and Long COVID. They found that a protein called WASF3 (Wiskott-Aldrich Syndrome Protein Family Member 3) was elevated in muscle biopsies from 14 ME/CFS patients compared to 10 controls. When they overexpressed WASF3 in mice, treadmill endurance dropped by 50%.

The mechanism is elegant in its destructiveness. WASF3 doesn't damage individual respiratory complexes — it prevents them from assembling into supercomplexes, the higher-order structures needed for efficient electron transfer. Without supercomplexes, mitochondrial respiration becomes leaky, inefficient, and generates excess reactive oxygen species (ROS). It's like disconnecting the gears in a transmission — the engine still turns, but power doesn't reach the wheels.

What drives WASF3 up? Endoplasmic reticulum (ER) stress. The ER is the cell's protein-folding factory. When it's overwhelmed — by viral proteins, inflammation, or metabolic disruption — it activates stress pathways that elevate WASF3 at ER-mitochondria contact sites. An experimental drug called salubrinal, which reduces ER stress, lowered WASF3 levels and restored mitochondrial function in patient-derived cells. The NIH is exploring clinical trials.

Complex V Running Backwards

In 2025, Macnaughtan and colleagues at University College London published the first live flux analysis of mitochondrial function in Long COVID immune cells. What they found was startling: in 27 Long COVID patients compared to 16 controls, ATP synthase (Complex V) was running both forward AND reverse — not just producing ATP but actively hydrolyzing it.

Think about that. The molecular turbine that's supposed to generate your energy is simultaneously destroying it. The researchers found no changes in glycolysis or mitochondrial mass — the problem wasn't fewer mitochondria or a shift to anaerobic metabolism. The machinery was present. It was just malfunctioning at the most fundamental level.

They also found sex-specific differences in mitochondrial profiles and correlations with autonomic health and quality of life — suggesting that mitochondrial dysfunction directly maps onto the symptoms patients experience.

The Oxidative Stress Signature — And the ME/CFS Convergence

In July 2025, a Stanford-led team (Shankar et al.) published a landmark paper in PNAS that may reshape how we think about both Long COVID and ME/CFS. Studying 25 controls, 27 ME/CFS patients, and 20 Long COVID patients, they found that both conditions share an identical oxidative stress signature in lymphocytes, particularly in memory T cells.

The findings were specific: elevated glutathione (the cell's main antioxidant — cranked up in response to damage), decreased mitochondrial superoxide dismutase (SOD — the first line of defense against mitochondrial ROS), and glutathione peroxidase 4 (GPX4)-mediated lipid oxidative damage. The immune cells were under sustained oxidative assault.

Here's the insight that connects this to fatigue: immune cells consume 15-20% of your total daily energy. When those cells are damaged and burning energy inefficiently — running repair programs, producing excess ROS, hyperproliferating — they're stealing energy from the rest of your body. The fatigue isn't just mitochondria failing in your muscles. It's your immune system consuming more than its share of a diminished energy supply.

Sex Differences as a Mechanistic Clue

The Stanford data revealed a striking sex divergence. In females, the pattern was higher total ROS and mitochondrial calcium, driving T cell hyperproliferation. In males, ROS levels were normal, but there was pronounced mitochondrial lipid oxidative damage. This may help explain why Long COVID and ME/CFS disproportionately affect women — the female immune-metabolic response creates a more energy-intensive pathology.

Critically, the female hyperproliferation pattern was attenuated by metformin — an FDA-approved diabetes drug already shown to reduce Long COVID incidence by 41% in a phase III trial of over 1,300 patients.

PRDX3: A Biomarker Leaking From Damaged Mitochondria

If mitochondria are under oxidative stress, can we measure it in a blood test? A 2025 study by Szögi and colleagues in GeroScience suggests yes. They found elevated serum levels of peroxiredoxin-3 (PRDX3) in Long COVID patients. PRDX3 normally lives inside mitochondria, where it neutralizes approximately 90% of mitochondrial hydrogen peroxide. Finding it in the bloodstream means mitochondrial membranes are leaking their contents into the cell and beyond.

Intriguingly, elevated PRDX3 was an independent predictor of dizziness in patients under 50 (60.4 vs 45.9 ng/ml, p < 0.05) but was not correlated with fatigue. This suggests different Long COVID symptoms may have different mitochondrial signatures — dizziness perhaps driven by mitochondrial oxidative stress in vestibular or autonomic neurons, fatigue by the broader energy crisis. If validated, PRDX3 could become part of a panel that objectively subtype Long COVID patients.

The Self-Reinforcing Loop

These findings are not isolated. They form a self-reinforcing cycle that may be the central engine of Long COVID:

  1. Viral persistence in gut, lymph nodes, and other tissues produces ongoing viral proteins
  2. Viral proteins cause ER stress in infected and neighboring cells
  3. ER stress elevates WASF3, which disrupts mitochondrial supercomplex assembly
  4. Disrupted mitochondria produce less ATP and more reactive oxygen species
  5. ROS damage mitochondrial membranes, leaking mtDNA into the cytoplasm
  6. Cytoplasmic mtDNA activates the NLRP3 inflammasome, triggering chronic inflammation
  7. Chronic inflammation causes more ER stress — returning to step 2

Meanwhile, in a parallel track: damaged immune cells consume excess energy just trying to survive → whole-body fatigue → reduced activity → deconditioning → worse outcomes. Breaking this loop at any point could theoretically improve symptoms.

The Therapeutic Landscape

Multiple approaches are now targeting different points in this cycle. None are proven cures. Some are further along than others.

Metformin — The Pragmatic Choice

Metformin inhibits mitochondrial Complex I, which sounds counterintuitive — why inhibit an already struggling system? The answer lies in the specific dysfunction. By partially inhibiting Complex I, metformin reduces the strain on malfunctioning Complex V (which is running backwards) and decreases harmful ROS production. It also activates AMPK (the cell's energy sensor) and inhibits mTOR (a growth pathway that may be overactivated). A 2025 perspective in ACS Pharmacology & Translational Science (Fineberg et al.) laid out the mechanistic case. There's now a clinical trial specifically testing metformin for Long COVID fatigue (NCT06147050).

Oxaloacetate — Feeding the Krebs Cycle

Oxaloacetate is a metabolite at the heart of the Krebs cycle — the metabolic pathway that feeds electrons into the mitochondrial chain. The RESTORE-ME trial (82 ME/CFS patients, randomized, double-blind) showed a 32-35% reduction in fatigue with 2,000 mg/day oxaloacetate versus ~10% with placebo. About 40% of the treatment group were "enhanced responders" with >25% improvement. A companion REGAIN trial in 69 Long COVID patients showed significant symptom reduction on the DePaul Symptom Questionnaire. Both were published in Frontiers in Neurology in late 2024. Oxaloacetate is available as a supplement, though not FDA-approved for these conditions.

Nicotinamide Riboside — Boosting NAD+

NAD+ is a coenzyme essential for mitochondrial function that declines with age and illness. Nicotinamide riboside (NR), a precursor to NAD+, was tested in 58 Long COVID patients at Massachusetts General Hospital (2,000 mg/day). Published in eClinicalMedicine (a Lancet journal) in late 2025, the trial successfully boosted NAD+ levels and showed individual improvements in executive function, fatigue, sleep quality, and mood — but did not meet its primary endpoints at the group level, likely due to small sample size and high dropout. The signal is there; the statistical power isn't. Larger trials are needed.

Urolithin A — Clearing Damaged Mitochondria

Sometimes the best fix for broken mitochondria is to clear them out and build new ones. Urolithin A induces mitophagy — the selective destruction of damaged mitochondria — via the PINK1-Parkin pathway, while simultaneously upregulating mitochondrial biogenesis genes. The MitoImmune trial, published in Nature Aging in 2025, showed that 1,000 mg/day of urolithin A in healthy older adults expanded naive CD8+ T cells, reduced T cell exhaustion markers, and shifted immune cell metabolism toward cleaner energy production. No direct Long COVID trials yet, but a 650-participant brain health study is expected in 2026. The theoretical rationale — enhanced mitophagy + mitochondrial renewal + immune rejuvenation — is strong.

Salubrinal — Targeting the Root

If WASF3 elevation is driven by ER stress, then reducing ER stress should lower WASF3 and restore mitochondrial function. Salubrinal does exactly this in cell models, and the NIH team that discovered the WASF3 pathway is exploring clinical applications. A 2025 assessment in Trends in Molecular Medicine confirmed salubrinal restores mitochondrial function in ME/CFS patient fibroblasts. This is the most mechanistically targeted approach — but it remains preclinical.

Other Candidates

Elamipretide (Forzinity), which stabilizes cardiolipin in the inner mitochondrial membrane, received FDA accelerated approval for Barth syndrome in September 2025 — the first approved therapy targeting mitochondrial disease. However, it failed primary endpoints in a larger mitochondrial myopathy trial. MitoQ, a mitochondria-targeted antioxidant, is being tested with exercise rehabilitation in Long COVID veterans (NCT05373043), results pending. CoQ10, alpha-lipoic acid, and resveratrol are in various stages of investigation.

What This Means

The energy crisis in Long COVID is not a mystery anymore. It is a cascade with named molecules at every step: viral persistence driving ER stress, WASF3 breaking respiratory supercomplexes, Complex V running backwards, oxidative damage leaking into the bloodstream, immune cells burning through the body's energy budget. The mechanism is shared with ME/CFS at the molecular level — which means treatments for one may work for the other.

We don't yet have a proven solution. But for the first time, we have targets — specific proteins, specific enzyme dysfunctions, specific metabolic bottlenecks that drugs can be designed or repurposed to address. The RESTORE-ME and REGAIN trials show that even a simple metabolite like oxaloacetate can move the needle on fatigue. Metformin, already prescribed to millions, may help through a different mechanism entirely. And the WASF3-salubrinal pathway offers the prospect of treating the root cause rather than the downstream consequences.

The research is converging. The loop can be broken.

Key References