How Oxidative Stress Harms Nervous System Health
Posted on May 03, 2021

Hi, Dr. Warner here -

Today, I want to talk about the effects of oxidative stress on the nervous system.


Neurodegeneration is characterized by the progressive loss of selective neural subtypes in the CNS (central nervous system).

Accumulating evidence shows this is mediated by mitochondrial damage.

The common mechanism for lifestyle and non-communicable chronic diseases (NCDs) is mitochondrial dysfunction.


Mitochondria are responsible for energy production in cells. They produce the fuel used by all other cellular processes.  

Think of mitochondria as a central processing unit. It takes external nutrient input and then produces energy output.

Energy is in the form of ATP (adenosine triphosphate), and they also produce important lipid species and provide metabolic substrates for post-translational modifications for cell signaling by DNA.

Part of the process of the electron transport chain (ETC) which is how mitochondria make energy is a byproduct called ROS (reactive oxygen species).

These unpaired electrons or free radicals can damage the mitochondria, mitochondrial DNA, and other cellular processes.

The mitochondria have a system to check the ROS from damaging cells, but it is often overwhelmed due to chronic inflammation and excessive oxidative stress.

The mitochondria create energy from nutrients in the inner mitochondrial membrane. Here in the oxidative phosphorylation chain, superoxide is made.

This is a common ROS in the cell formed at complexes I and III during the ECT. This is formed when an oxygen molecule gaines an electron.

The superoxide anion is then converted to hydrogen peroxide by superoxide dismutase (SOD); this is an important ROS producing enzyme.

The H2O2 molecule can then become a massively damaging hydroxyl radical.

This is highly reactive and causes oxidative damage to everything it touches.

ATP is made from ADP in the mitochondria by ATP synthase. This charges the battery of the cell.

ATP is the main form of energy and is able to discharge the energy whenever needed by other cells and cell processes.

2ADT molecules can also be converted to an AMP and and ATP molecule by adenylate kinase. These levels of AMP are monitored by AMPK.

If AMPK senses too much AMP, then the cell is under-energized.

Likewise, too little AMP means the cell is making too much energy. Low energy states prompt AMPK to initiate protective functions and longevity functions of the cell.


The brain and nervous system require a massive amount of energy to function, and this energy is provided by mitochondria.

Dysfunctional mitochondria basically can’t adapt to a changing environment.

Normally, these organelles inside our cells are able to change according to demand. The demand changes according to the stress applied and environment.

Mitochondrial failure causes too little energy to be produced and not enough repair and detoxification ability for the brain.

When the brain struggles to neutralize free radicals, this results in oxidative stress - which causes neuroinflammation and neurodegeneration.

Neurons are generally very long-lived cells; they do not turn over very fast. This means that neurons accumulate damage over time.

Mitochondrial failure causes too little energy to be produced and not enough repair and detoxification ability for the brain.

This ultimately results in neuroinflammation and neurodegeneration.

The mitochondria play a critical role in nerve and neuron function. Cells in the PNS (peripheral nervous system) and CNS rely on mitochondrial integrity.

Aberrant mitochondrial quality control plays a large role in degeneration of the nervous system.

Human cells have developed systems for mitochondrial quality control to protect cells from the overproduction or under-neutralization of reactive oxygen species.  

Mitochondrial quality control includes:

  • Proteostasis
  • Biogenesis
  • Dynamics
  • Mitophagy
  • Autophagy


A key cause of inflammatory pathways is failure of mitochondrial biogenesis, or biogenetic failure.

In these situations there is an increase in calcium levels in the cytoplasm, there is oxidative stress (from ROS) and there is a decrease in normal mitochondrial DNA.

Mitochondria undergo fusion and fission on a continual basis.

Fusion allows for more energy production. Fission allows for the repair or removal of damaged mitochondrial DNA and organelles.

A failure of either will lead to an accumulation of inflammation and ROS within the brain which then damages neurons.

Mitochondrial fission regulates the release of pro-inflammatory mediators.

It does so through nuclear factor kappa light chain enhancer of activated B cells (NF-kB) and MAPK (mitogen activated protein kinase) signaling.

Chronic activation of microglial (CNS support cells) can contribute to neuronal defection.

One theory is that the accumulation of mitochondrial ROS activates the NLRP3 inflammasome-dependent pathway that elicits chronic inflammation.

The NLRP3 inflammasome complex triggers the production of pro-inflammatory cytokines and induces mitochondrial fragmentation. This impairs energy production and disrupts the CNS cell balance.

While the NLRP3 inflammasome complex is crucial for defence against pathogens, it is also the source of many NCDs (AD, gout, autoinflammatory disease, DM, atherosclerosis).

Precise control of the NLRP3 inflammasome pathway is mandatory for the health of the cell.    


There are ways to improve the function and quality of mitochondria. Two well-known and studied methods are calorie restriction and exercise.

Both methods employ a negative balance in terms of nutrient input and energy output needs. By producing a negative balance, the mitochondria are challenged.

A challenged mitochondria will improve its function and abilities.

The challenged mitochondria is better at biogenesis, energy production, and other tasks.

The unchallenged mitochondria fragments and fails; this is the heart of the NCD problem.  

There is a profound effect on mitochondria by exercise.

Sustained strenuous physical exercise can double the mitochondrial contents and activity. It will also increase the coupling of mitochondria and improve efficiency and function.

One of the ways that enhanced function of mitochondria during calorie restriction or exercise is the AMPK (AMP-activated protein kinase) path.

AMPK is an energy sensor.

This molecule is deacetylated during fasting or exercise by SIRT-1. Deacetylation of AMPK increases its activity.

AMPK functions to sense energy imbalances in the cell and then to initiate cell protection.

When the energy supply is low, the cell and organism will respond by slowing down aging and increasing protection from many age-related problems.  

Providing antioxidants also improves mitochondrial function by allowing for excessive levels of ROS to be removed from the organelles and cells.

Additionally, anti-inflammatory molecules also improve function by protecting the cell membranes and changing the environment of chronic inflammation to a more healthy one.

Less inflammation means less reactive oxygen species and less oxidative stress.  

There must be harmony in the generation of mitochondrial components from the nuclear and mitochondrial genomes.

This is achieved by the PPAR-gamma, SIRT1 and AMPK signaling pathway.

There must be a balance between mitochondrial fusion and fission.

Fusion is the interconnection and enlargement of mitochondria to produce more energy. Fission is the repair/replace cycle for damaged mitochondria.

For example, an abnormal accumulation of autophagy vacuoles from fission is a prominent feature of neurons in AD.  

Defective oxidative phosphorylation in the mitochondria leads to excessive amounts of ROS and therefore elevation of oxidative stress. This causes more mitochondrial damage and a negative feedback loop happens.

The role of antioxidants and anti-inflammatories is to stop this loop and to remove the unneeded ROS.  


Dr. Meredith Warner, the inventor of The Healing Sole and Well Theory, purposefully designed her Nervous System Multi to help ward off the damaging effects of oxidative stress, like neurodegeneration.

This formula is highly antioxidant and anti-inflammatory.

With resveratrol, luteolin, chlorella, and more, you can bolster your system against free radicals, heavy metals, and inflammation.

Reach for this supplement today - or any of Dr. Warner's pain-fighting and wellness-enhancing products from The Healing Sole or Well Theory!


Dr. Meredith Warner is the creator of The Healing Sole and Well Theory. She is a board-certified and fellowship-trained Orthopedic Surgeon and Air Force Veteran.

Dr. Warner has treated countless patients for heel pain and plantar fasciitis pain in her private practice, Warner Orthopedics and Wellness.

She developed The Healing Sole so that wearers can harness the body's natural healing power and have an option for everyday relief, without the need for surgery or expensive medical intervention.