Hi Taylor,

Imagine your cells trapped in a silent energy crisis as your mitochondria become overwhelmed, triggering a cascade of free radicals that fuel relentless cell damage, leading to fatigue, brain fog, and post-exertional crashes. Many living with ME/CFS, Long COVID, and other complex chronic inflammatory conditions, this isn’t just theory; it’s your daily reality.

In this edition, we unravel the vicious cycle of peroxisomal and mitochondrial dysfunction at the heart of oxidative stress, explore how free radicals ignite cellular chaos, and spotlight evidence-backed antioxidant strategies to help shield your cells. 

The science we are about to discuss can impact everyone, especially those with chronic inflammation. So, if you ever wondered exactly what oxidative stress is and how to fight against it, this issue is for you. 

Let’s dive in.

The Peroxisomal Dysfunction Mitochondrial Dysfunction Vicious Cycle in ME/CFS

For millions living with ME/CFS, the crushing fatigue, brain fog, and post-exertional crashes feel like a cellular power outage that never ends. At the heart of these symptoms could be a hidden partnership gone wrong between your mitochondria, the cell’s energy factories, and peroxisomes, their quiet recycling partners.

This failed partnership is centered on oxidative stress. Therefore, let’s start by pulling on the oxidative stress thread to learn how it damages your cells.

Oxidative Stress

Oxidative stress occurs when highly reactive molecules like superoxide, hydrogen peroxide, and hydroxyl radicals, from the mitochondria, overwhelm the cell’s antioxidant defenses, igniting cellular damage, cell death, and inflammation. These highly reactive molecules are collectively called reactive oxygen species (ROS), a category of free radicals. 

If you are living with a chronic inflammatory condition or know someone who is, chances are you have heard the buzz words ‘oxidative stress’, ‘reactive oxygen species’, or ‘free radicals’. But have you ever wondered why they are made and why they can harm your health? The answer lies in how free radicals damage your tissue.

Free Radicals Up Close

Free radicals get a bad wrap, but they aren’t always bad. Small controlled doses help your body fight infections, dilate blood vessels, and strengthen the production of your antioxidant defense mechanism. But large doses can damage lipids, proteins, DNA, and mitochondria, triggering cell dysfunction, cell death, and tissue injury. 

Here is why. Free radicals are highly reactive because they have an uneven number of electrons. They are either missing one electron or they have an extra electron.

Free Radical Defenses, Antioxidants

Let's begin by understanding what happens immediately after a free radical is produced. Free radicals missing an electron will immediately collide and strip an electron from an antioxidant defense molecule like glutathione, uric acid, alpha-lipoic acid, or vitamin E, to name a few. 

However, if the free radical happens to collide with a molecule that does not specialize in neutralizing free radicals, like a random protein, lipid, or nucleic acid (DNA or RNA), then a catastrophic chain reaction could occur. 

The Free Radical Chain Reaction

When a free radical collides with a nearby protein, it will strip an electron from the protein. Technically speaking, the ‘free radical’ is no longer a free radical. It’s happy because it is in perfect balance thanks to its new electron.

However, the unfortunate protein that was the victim of a free radical collision, let’s call it protein A, is not in a ‘happy’ state. It will collide with a nearby macromolecule, protein B, to take its electron and repeat the process. This wave of electron shuffling can damage molecules inside your cells. Here are a few examples.

1. Toxic Lipid Aldehydes

Stripping an electron from a lipid can lead to the production of toxic aldehydes like 4-HNE, MDA, and 8-iso-PGF2α, which can stiffen membranes and cause stored ions to leak from inside organelles (specialized compartments below the cell surface).

2. Protein Crosslinking

The free radical collision to the outer surface of a protein might not cause substantial damage, assuming that the protein can strip an electron from a nearby molecule to achieve a state of ‘balance’. However, if the free radical collides with a region of the protein containing a carbon atom that is double-bonded with an oxygen atom (C=O, carbonyl), that protein is in danger of crosslinking to a nearby molecule. This can deform the protein shape and potentially its function, rendering it useless.

3. Damaged DNA; Guanine Lesions

A free radical collision with guanine, one of the four ‘letters’ in your DNA code, can create an 8-OHdG lesion, a bulky side group that causes the DNA replication machinery to stall. The DNA inside mitochondria is particularly susceptible to this, as they are not wrapped around histones to buffer the free radical damage.

How are Reactive Oxygen Free Radicals Produced?

While there are many sources of free radicals, the primary source in those with ME/CFS, Long COVID, and other complex chronic conditions is from mitochondrial dysfunction. As we mentioned above, the primary types of free radicals produced by your mitochondria are superoxide, hydrogen peroxide, and hydroxyl radicals, known collectively as reactive oxygen species (ROS). Understanding how ROS are made requires a deeper understanding of how your mitochondria manufacture energy.

The sections below will require some extra brain power to process, especially if you are unfamiliar with how your mitochondria function. We don’t want your brain fog to turn into a brain storm, so we also took the time to break it down in a video format that you can watch at your leisure (also referenced below).

How Your Mitochondria Make Energy

Your mitochondria make cellular energy called adenosine triphosphate (ATP), similar to how a hydroelectric dam makes electricity. A hydroelectric plant can generate electricity because there is more water on one side of the dam wall, creating a water pressure gradient. When a gate opens at the bottom of the dam, the water flows through a channel with enough force to spin a turbine that generates electricity. Just as the function of the dam is dependent on the (water) gradient, the energy production capacity of your mitochondria is similarly dependent on a gradient, a hydrogen ion gradient.

The Hydrogen Ion Gradient

Your mitochondria have several unique features, the most important for this discussion being their two plasma membranes, which help maintain the hydrogen ion gradient. The cartoon image of a mitochondrion depicts these two membranes, the outer and inner membranes, as dark red lines. The inner membrane has a larger surface area than the outer membrane, giving the mitochondria their characteristic maze-like appearance (image below). 

Here is why this is important. The inner mitochondrial membrane is densely packed with proteins that act as hydrogen ion pumps (see #1 in the image below). These pumps push hydrogen ions into the light-red space between the inner and outer mitochondrial membranes, known as the intermembrane space. Similar to how (many) water molecules flow from high pressure to low pressure, generating hydroelectric power, the hydrogen ions flow through a protein channel called ATP synthase (#3 in the image below), generating ATP.

Electron Transport In The Mitochondria

The three different colored hydrogen ion pumps embedded in the inner mitochondrial membrane are powered by electrons that literally flow through the proteins. This electron flow, called the electron transport chain, provides the pumping power.

The Electron Flow Is Different Than That Triggered By Free Radicals

However, this electron flow is different from what we described earlier. The electrons aren’t stripped from one protein to another in a free radical-induced chain reaction; instead, they flow through the protein pumps because they are rich in iron-sulfur clusters. Similar to how electrons flow through copper wires, to power your household electrical items, electrons also flow through these densely packed iron-rich bundles in the H⁺ pumps to power them.

Now that you know the basics, let’s learn how ROS is made inside your mitochondria.

Why Mitochondrial Dysfunction Can Cause Excessive ROS Production

Mitochondria need oxygen to manufacture ATP. That’s because oxygen soaks up the electrons at the end of the electron transport chain when a protein called cytochrome c oxidase (pictured in purple) combines electrons, oxygen, and hydrogen ions to make water (H2O) (pictured above in brackets). 

Electron Leakage

The curved black line, with the yellow electron circles, represents the correct path that electrons take to power the H⁺ pumps. This flow has a clear starting line (NADH oxidation) and a clear finish line (where they are combined with oxygen and hydrogen to form water, shown above). But in mitochondrial dysfunction, the electrons can prematurely exit the normal electron transport chain, a phenomenon called electron leakage. 

Consequences of Electron Leakage

Think of electrons as carts on a rollercoaster. There is a clear start and finish, and a premature exit of the cart from the tracks could cause collateral damage as the cart flies off the tracks. 

If electrons leak, they can spontaneously bind a nearby oxygen molecule, giving it an extra electron and forming a superoxide radical (O₂^-), a reactive oxygen species. These superoxide radicals can collide and damage important lipids in the inner mitochondrial membrane, including cardiolipin, mitochondrial DNA, proteins in the electron transport chain, and more.

This damage can cause even more mitochondrial dysfunction, creating more superoxide radicals, trapping the mitochondria in an oxidative stress doom loop. 

Peroxisomes Collaborate With Mitochondria

What Are Peroxisomes?

Peroxisomes are small, membrane-bound organelles that function as the cell's specialized recycling and detoxification hubs. They break down very-long-chain fatty acids through beta-oxidation to spare mitochondrial workload. The resulting, simplified lipids can then be transferred into the mitochondria via the carnitine shuttle, where they can be converted into a source of electrons in the mitochondria. 

Research suggests that peroxisomes also act to neutralize ROS produced by the mitochondria. Specifically, a new research study found that peroxisomes physically anchor to mitochondria. These anchor points increase when the mitochondria are in a state of oxidative stress, allowing the free radicals to funnel into the peroxisome, where they can be neutralized, protecting the cell.

Peroxisomal Dysfunction In ME/CFS

Data from Dr. Ian Lipkin’s lab at Columbia University suggests that patients with ME/CFS have dysfunctional peroxisomes. It is theorized that these dysfunctional peroxisomes don’t provide enough lipids to the mitochondria.

Data also suggests that the carnitine shuttle, the mechanism allowing lipids to enter the mitochondria, is impaired. This would suggest that the peroxisomes are not helping provide mitochondria with a source of lipids used in energy production, which could ironically contribute to mitochondrial dysfunction.

The Vicious Cycle

The dysfunctional mitochondria can also cause peroxisomal dysfunction when the ROS overwhelms the peroxisome's ability to neutralize the ROS. This has recently been described as the vicious cycle, or the bidirectional connection between peroxisomal dysfunction and mitochondrial dysfunction.

This  ‘vicious cycle’ has recently been hypothesized as a contributing force behind chronic fatigue and PEM in ME/CFS. However, more research is needed to understand if peroxisomal dysfunction is contributing to mitochondrial dysfunction and vice versa. 

To our knowledge, peroxisomal dysfunction has not yet been described in Long COVID.

Oxidative Stress Shielding: Antioxidant Supplements to Combat Oxidative Stress

While oxidative stress drives much of the cellular chaos in chronic inflammatory conditions, a targeted lineup of antioxidant supplements might help reinforce your defenses—acting as electron donors, chain-breakers, and gene activators to tame ROS before they spiral out of control.

The table below outlines evidence-backed options, their primary mechanisms, and practical notes for daily use.

Medical Disclaimer: The information provided about supplements is for educational purposes only and is not intended as medical advice, diagnosis, or treatment. ME/CFS, Long COVID, and related conditions are complex and vary widely between individuals. Supplements may interact with medications, affect lab results, or be contraindicated in certain health states. Always consult a qualified healthcare provider before starting any supplement, especially if you are pregnant, nursing, on prescription drugs, or managing a chronic illness. The authors and publishers assume no liability for any adverse effects resulting from the use of this information.

Conclusion

Boosting your cells' antioxidant defenses won’t be the panacea to your health struggles. However, learning about your medical condition might help you take actionable steps that, in aggregate, could result in a noticeable difference in your health. Boosting your antioxidant defenses might be one of those ‘little things’ in addition to complementing it with red light therapy.

Speaking of red light therapy, did you know it might act to restore electron flow during oxidative stress? We explain what this means in the video below.

The Science Behind Red Light Therapy And Improved Mitochondrial Function

As of November 2025, over 64,000 peer-reviewed articles in the NIH’s PubMed database mention the keywords ‘red light therapy.’ Countless red and near-infrared light devices are on the market, promising boosted energy, youthful skin, and even thicker hair. But can red light therapy help the millions suffering from chronic neuroinflammatory conditions?

While there is little evidence that these wavelengths can penetrate the skull directly, there are innovative nasal delivery methods that might reach select brain tissues. Therefore, in this video, we teach you how inflammation sparks oxidative stress, and—most importantly—how red light therapy may heal your mitochondria at the cellular level. This video is worth 20 minutes of your time, regardless of your health status.

Disclaimer: This video is for educational purposes only and does not constitute medical advice. We have no affiliation, sponsorship, or financial relationship with any red light therapy company or product mentioned. Always consult a qualified healthcare professional before starting any new health intervention.

Brain Storm Briefs

The following are concise highlights from recently published scientific studies that could reshape medical perspectives on conditions, drive innovations in diagnostics or treatments, or deliver broad technological breakthroughs to deepen our understanding of 30+ diseases that are of interest to the Brain Inflammation Collaborative.

1. Landmark Genetic Study Uncovers Brain-Based Roots of Fibromyalgia

A major genetic study of over 2.5 million people identified 26 DNA regions linked to fibromyalgia, revealing its biological roots in the brain rather than muscles or joints. These gene variants, especially one in the Huntingtin gene, heighten pain sensitivity by altering neural circuits, explaining widespread pain, fatigue, brain fog, and poor sleep. The condition shares genetic ties with chronic fatigue, IBS, and mood disorders, but is not primarily autoimmune, with no major differences between men and women. This exciting discovery was recently published as a preprint and is still awaiting peer review. However, this study might offer hope for early detection via risk scores and targeted brain-focused treatments to restore normal nerve signaling.

2. Disease Sequence, Not Just Presence, Drives Long COVID Risk

A new study of over 10,000 people shows that the order and interaction of past illnesses, such as anxiety before depression or asthma followed by obesity, predict Long COVID risk better than having any single condition alone. Researchers identified 38 disease sequences, mostly involving mental health, neurological, respiratory, or metabolic issues, that significantly raise the chance of long COVID, especially in women, even after mild infections. Genetics plays a minor role, with weak links to neurological and musculoskeletal traits but no strong overall inheritance. Tracking health trajectories over time could enable early warnings and personalized prevention for long COVID and other chronic illnesses.

3. Childhood Trauma Triggers Depression via Brain Protein SGK1

A new study reveals that high levels of the stress protein SGK1 in the brain drive depression and suicidal ideation, specifically in people who have suffered childhood trauma or adversity. About 60% of depressed U.S. adults and two-thirds of suicide attempters experienced early hardship, and standard antidepressants often fail this group due to SGK1’s role. Brain samples from suicide victims and genetic studies in teens confirm SGK1 is doubled in trauma survivors, while mouse tests show SGK1 blockers prevent stress-induced depression. This paves the way for targeted SGK1-inhibiting drugs and genetic screening to treat or prevent depression in those with early-life trauma.

4. Gazyva Significantly Reduces SLE Activity in Phase III Trial

In a Phase III trial, Gazyva (obinutuzumab) added to standard lupus therapy significantly reduced disease activity in adults with active Lupus (SLE), with more patients achieving a key improvement score after 1 year than with placebo. The drug, already FDA-approved for the treatment of lupus nephritis, targets B cells and may help prevent organ damage. If approved for broader SLE use, it would be the first anti-CD20 therapy specifically for this condition.

5. Breathing Disorders Found in 71% of Chronic Fatigue Patients

A new study of 57 chronic fatigue syndrome (CFS) patients found that 71% had breathing problems, nearly half with dysfunctional breathing patterns and a third hyperventilating, compared to just 16% of healthy controls. These issues, often unnoticed by patients, include irregular or chest-only breathing and may worsen fatigue, brain fog, dizziness, and post-exertional malaise, possibly due to dysautonomia affecting blood vessels and muscles. Researchers suggest the problems could be treated with breathing exercises, yoga, swimming, or biofeedback to restore normal patterns and ease symptoms. Targeting these breathing abnormalities opens a promising new path to potentially alleviate CFS suffering.

6. Doxycycline Linked to 30–35% Lower Schizophrenia Risk in At-Risk Teens

A large study of over 56,000 adolescents in mental health care found that those prescribed doxycycline had a 30–35% lower risk of developing schizophrenia in adulthood compared to those given other antibiotics. The protective effect may come from doxycycline’s ability to reduce brain inflammation and regulate synaptic pruning, a process linked to schizophrenia when excessive. While observational and needing clinical trial confirmation, the findings suggest repurposing this common antibiotic as an early intervention for high-risk youth. This could open a new preventive path for severe mental illness.

7. Nine Early Signs Predict Persistent Symptoms After Mild Brain Injury

A study of 803 adults seen in the ER about 90 minutes after a mild traumatic brain injury found 9 early factors linked to symptoms lasting 30 days or more: female sex, higher BMI, injury from falls/crashes/abuse, prior headaches/migraines/depression/anxiety, and initial headache, focal neurological signs, or multiple CT scans. Patients with any of these traits were over twice as likely to have ongoing post-concussion issues like fatigue or dizziness. Identifying them quickly allows early follow-up and interventions to prevent prolonged recovery.

Why We Do What We Do

Complex chronic conditions, including infection-associated chronic illnesses (e.g., Long COVID, ME/CFS, post-treatment Lyme disease syndrome), autoimmune disorders (e.g., lupus, autoimmune encephalitis), and neurodegenerative diseases (e.g., multiple sclerosis), share common hallmarks such as neuroinflammation, overlapping immunopathologies, overlapping symptoms and comorbidities, and treatment responses. For instance, many with Long COVID also have POTS or MCAS, while children and adolescents with PANDAS/PANS can also present with POTS, OCD, and eating disorders involving restrictive eating. The parallels between these conditions are staggering.  

That is why we are among the first non-profits to take a collaborative approach to research. Our mission is to complement the work of single-condition advocacy groups by fostering a collective research framework that spans 30+ related conditions. 

These conditions affect millions in the United States, yet no cures exist. You can help us change that. We are actively using our clinical health platform, unhide®, to not only help patients (children, adolescents, and adults) like you uncover hidden patterns in your health, but also to build a collaborative network of researchers with different clinical and scientific backgrounds needed to study these medical conditions with the all-encompassing approach it deserves. You can help by:

1. Download the MyDataHelps App and choose the unhide®/Solve Together Project, or directly set up an account. 

     >IPhone App Store Download

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2. Recruiting a healthy control to participate, preferably someone similar in age

3. Donating just $10 per month to help us build out this research network 

We humbly thank you in advance for your continued support! Together we can make a difference. 

Sincerely,
The Brain Inflammation Collaborative Team

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