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.
For 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 post, 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 have ever wondered precisely what oxidative stress is and how to fight against it, then this article is for you.
Let’s dive in.
The Peroxisomal Dysfunction Mitochondrial Dysfunction Vicious Cycle
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 can damage 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, which can be produced inside your mitochondria, 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 rap, but they aren’t always bad. Small controlled doses help your body fight infections, dilate blood vessels, and strengthen your antioxidant defense mechanisms. 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 have an extra electron.
Free Radical Defenses, Antioxidants
Free radicals that are missing one 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 protein, lipid, or nucleic acid (DNA or RNA) that does not specialize in neutralizing free radicals, 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, this molecule can no longer be described as a ‘free radical.’ It’s happy because it is in perfect balance thanks to its new electron. However, the protein it collided with, let’s call it protein A, is not in a ‘happy’ state. It will collide with a nearby macromolecule, say 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, such as 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 it is 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 free radicals produced by your mitochondria are superoxide, hydrogen peroxide, and hydroxyl radicals, collectively known 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 (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, creating a water-pressure gradient. When a gate at the bottom of the dam opens, 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 reliant 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. The cartoon image of a mitochondrion in the upper right quadrant below 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 (#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
But what powers the hydrogen ion pumps? Electrons flow through these hydrogen ion pumps, providing the power for pumping.
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. Just as electrons flow through copper wires to power your household electrical items, electrons also flow through these densely packed iron-rich bundles of proteins (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 (pictured in purple) called cytochrome c oxidase combines electrons, oxygen, and hydrogen ions, to make water (H2O) (pictured above).
Electron Leakage
The curved black line with the yellow electron circles represents the correct path electrons take to power the H+ pumps. This flow has a clear starting point (NADH) and a clear endpoint (where they are combined with oxygen and hydrogen to form water, shown above). But in mitochondrial dysfunction, electrons can prematurely exit the standard electron transport chain, a phenomenon known as 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 to a nearby oxygen molecule, giving it an extra electron and creating a superoxide radical (O2-), an active oxygen species.
Superoxide radicals can collide with and damage essential lipids in the inner mitochondrial membrane, including cardiolipin, mitochondrial DNA, and proteins of the electron transport chain. This damage can cause even more mitochondrial dysfunction, generating additional superoxide radicals and trapping 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 to the mitochondria via the carnitine shuttle, where they can serve as a source of electrons.
Research suggests that peroxisomes also neutralize ROS produced by mitochondria. Specifically, a new research study found that peroxisomes physically nestle next to mitochondria by anchoring to them. 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 peroxisomes from someone with ME/CFS don’t provide enough lipids to the mitochondria. Data also suggest that the carnitine shuttle, which allows lipids to enter the mitochondria, is impaired. This would indicate that peroxisomes provide mitochondria with a source of lipids for energy production, which, ironically, can cause mitochondrial dysfunction.
The Vicious Cycle
Dysfunctional mitochondria can also cause peroxisomal dysfunction when ROS overwhelm the peroxisome’s ability to neutralize free radicals. This has recently been described as a vicious cycle, or a bidirectional connection between peroxisomal and mitochondrial dysfunction. This ‘vicious cycle’ has recently been hypothesized as a contributing force behind chronic fatigue and PEM in ME/CFS. To our knowledge, peroxisomal dysfunction has not yet been described in Long COVID.
Top Antioxidant Supplements to Combat Oxidative Stress
While oxidative stress drives much of the cellular chaos in ME/CFS and Long COVID, 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. The table below outlines evidence-backed options, their primary mechanisms, typical dosing from clinical studies, and practical notes for daily use.
| Supplement | Key Mechanism | Notes |
|---|---|---|
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Plugs electron transport chain leaks at Complex I/III; regenerates vitamin E |
Split doses with fat; monitor blood pressure |
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Recycles glutathione, vitamins C & E; enters mito/peroxisome |
Take on an empty stomach; may lower glucose |
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Direct electron donor; restores redox ratio |
Refrigerated; best morning + evening |
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Stops lipid peroxidation chains in membranes |
Natural d-alpha; with meal |
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Grows new mitochondria; repairs cardiolipin |
Pair with CoQ10 for synergy
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GSH precursor; breaks disulfide bonds |
Sustained-release to avoid GI upset |
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Activates Nrf2 → ↑ Superoxide Dismutase, Catalase and Glutathione Peroxidase |
Take with food, check for cruciferous sensitivity |
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Direct scavenger of free radicals |
Your body makes endogenous melatonin. Will cause drowsiness. |
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 laboratory results, or be contraindicated in certain health conditions. 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.
Reduce Oxidative Stress to Protect Your Mitochondria
Boosting your cells’ antioxidant defenses won’t be the panacea to your health struggles. However, learning about your unique cellular biology and 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.
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?
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.
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. Learn more by following us on social media and learn about
Written By
Matthew Menendez, Ph.D.
Director of Science Communication, Brain Inflammation Collaborative
Dr. Menendez has a passion for empowering patients navigating complex chronic diseases. Through innovative educational strategies, he bridges the gap between cutting-edge research and real-world understanding, helping individuals advocate for better care, access timely treatments, and reclaim their quality of life.
