Research Links Mitochondrial Dysfunction to Immune

Decline, Opening Paths for Cancer Treatment

Analysis by Dr. Joseph Mercola March 14, 2024

STORY AT-A-GLANCE

 New research shows mitochondrial dysfunction in T cells leads to immune system

decline, affecting the body's ability to fight infections and cancer

 The study identifies glycolysis as an inefficient way to produce energy, and the reactive
oxygen species (ROS) produced in the process damage T cells

 The findings suggest reversing mitochondrial damage could improve immune response
and cancer therapies

 Excess linoleic acid (LA) intake and estrogen dominance are major contributors to
mitochondrial dysfunction

 Strategies that will improve your mitochondrial function include lowering your LA intake,
reducing stress and taking a niacinamide supplement

Immune system weakening has long been attributed to aging and poor lifestyle choices,
but according to an October 2023 study1 in Nature Communications, the key reason for
this immune system decline is dysfunctional mitochondria, your cells' powerhouses,
particularly the mitochondria found in T cells (a type of immune cell).

When the mitochondria don't work well, the T cells don’t have the energy required to
perform their functions, which leads to a decline in immune system function. This in
turn, results in an inability to ward off both acute infections and chronic diseases. As
reported by Medical Xpress:2
 “... In the immune system, chronic infections and the defense against tumors
often lead to the phenomenon of T cell exhaustion: In this process, the T
lymphocytes gradually lose their function, which impairs their responses
against cancer and infections ...

This research has now shown that the exhaustion process is significantly
influenced by ... the mitochondria. When mitochondrial respiration fails, a
cascade of reactions is triggered, culminating in the genetic and metabolic
reprogramming of T cells, a process that drives their functional exhaustion.”

The good news, which was confirmed by the featured study, is that this decline can be
reversed with treatments that target mitochondrial function.

Poor Mitochondrial Function Can Lead to T Cell Exhaustion

In simple terms, when your body fights an infection, immune cells called CD8+ T cells
transform into cytotoxic T lymphocytes (CTLs) to destroy the infected cells. This
transformation requires changes in gene expression, cell structure and energy use.

However, in long-lasting infections or cancer, the T cells can become worn out or
"exhausted," losing their effectiveness. This exhaustion is related to energy problems
within the cells, particularly in the mitochondria. Researchers are now exploring how
fixing these energy problems can rejuvenate exhausted T cells, thereby improving
cancer treatments. Bioenergetic researcher Georgi Dinkov comments on these findings:3

“So far, the decline in immune function seen in aging had been explained with
the simplistic ‘wear and tear’ concept, and when immunodeficiency occurs in
younger people it is ascribed either to genetic vulnerability or lifestyle choices
such as alcohol/drug consumption.

In other words, to this day medicine does not seem to have a good grip on why
immune function fails in aging and disease, and what (if anything) can be done
to prevent that.
 The study ... demonstrates that the direct cause of immune decline is rather
simple — decline in mitochondrial function (OXPHOS). When T-cells (immune
cells produced by the thymus) have dysfunctional mitochondria, they have to
rely exclusively on glycolysis for energy production.

Glycolytic production of energy is insufficient to support proper T-cell

differentiation and activity, and in fact can lead to T-cell damage or even death
due to the high amount of reactive oxygen species (ROS) produced when
glycolysis is the main mode of energy production.

The study also demonstrated that such mitochondrial dysfunction is a

necessary and sufficient condition for immune decline to occur (aka T-cell
‘exhaustion’) and that the decline was reversible when mitochondrial function
was restored pharmacologically.”

Glucose Metabolism 101

So, what is “glycolytic production of energy” and why is it so detrimental? All dietary
carbohydrates are digested and broken down into glucose, a type of sugar. Glucose, in
turn, can be metabolized (burned) for fuel using two different pathways, as illustrated
below.
First, the glucose is metabolized into pyruvate. The pyruvate can then either enter the
glycolysis pathway in the cytoplasm of the cell and produce lactate, or it can be
converted into acetyl-CoA and shuttled to the mitochondrial electron transport chain.

Cancer cells are notorious for using the glycolysis pathway — the same pathway glucose
goes through when your glucose metabolism is impaired in mitochondria. Basically, this
is the pathway your body uses whenever it reaches its limit to how much ATP can be
produced in the mitochondria (which is the most efficient and least damaging way to
produce energy).

The Downstream Hazards of Glycolysis

While the glycolysis pathway is wonderful when you need quick fuel, if this is the
primary way you burn glucose, then you are in a constant state of activating stress
hormones and promoting insulin resistance and diabetes, which in turn creates loads of
lactate as a waste product instead of healthy carbon dioxide (CO2) and metabolic water.

Lactate increases reductive stress, which causes reverse electron flow in the
mitochondria and increases the ROS to 3% to 4%, which is 30 to 40 times more than
when glucose is burned in the mitochondria. This elevated ROS production is what
causes T cell damage and death.

What’s more, glycolysis generates only two ATP for every molecule of glucose, which is
95% less energy than would be generated if the glucose was metabolized in your
mitochondria.

The Devil’s in the Details

Now, you’ve probably heard that sugar promotes cancer, because cancer cells
preferentially use glycolysis. However, it’s a mistake to think that all glucose uses the
glycolysis pathway. As illustrated above, glucose can also be burned in the electron
transport chain of the mitochondria, which is the most efficient way to produce energy.
So, when it comes to the “sugar fuels cancer” issue, it’s important to make a distinction
between the sources of the carbs. While it is technically accurate to call all carbs sugar,
there is a radical difference in the source of the carbs — ripe whole fruits versus
starches, for example, and whole fruits versus refined processed sugar (ex: table sugar
and high fructose corn syrup).

Refined sugars, as well as many starches, are a common cause of endotoxin production
in your gut, which destroys mitochondrial function and results in cancer metabolism,
whereas the fructose present in whole foods does not typically result in the production
of endotoxin.

This is one of the primary differences between refined sugar and fructose from ripe fruit
and helps explain why refined sugars fuel cancer while natural fructose does not. So, to
be clear, it’s not sugar that is driving the cancer process per se. It’s really rooted in
mitochondrial dysfunction, and fatty acid oxidation (the metabolism of fats instead of
glucose) is part of what causes that dysfunction.

You Want to Burn Glucose in Your Mitochondria

For a long time, I believed fats burned “cleaner” than carbs — that’s one of the “selling
points” for keto — but I’ve since realized we had it backward. Glucose, when burned in
the mitochondria, actually burns far cleaner than fat.

So, it’s important to get your macronutrient ratios right, because if the glucose you eat is
constantly shuttled into glycolysis, you’re fueling cancer. At the same time, the fat you
consume ends up in fat storage rather than being used up for fuel.

Ultimately, you want to burn glucose in your mitochondria, and the way you ensure that
is by keeping your dietary fat intake below 35% of your total calories. The reason for this
is because when fat intake is too high, glucose gets shuttled into glycolysis. For a more
in-depth explanation of this metabolic switch, see “Understanding the Randle Cycle.”

If you’re insulin resistant, which means you’re metabolically inflexible, that threshold
may be closer to 20% or even 10%. So, if you’re insulin resistant, you’ll want to
significantly lower your fat intake until your insulin resistance is resolved. Then you can
increase it to 30%.

Dysfunctional T Cells and Cancer Cells Use Glycolysis

The reason cancer cells use the glycolysis pathway is because they have severely
dysfunctional mitochondria. The mitochondria are so damaged, they cannot burn
glucose. As a result, the cancer cells must rely on the backup system, glycolysis, to
survive. This is what the Warburg Effect is all about.

Likewise, when the mitochondria inside T cells become dysfunctional, the T cells are
forced to rely on glycolysis for energy production, which is what causes immune system
weakening and failure.

As mentioned in the featured study, T cell exhaustion is a feature of cancer, which

makes sense when you consider that it’s all tied to mitochondrial dysfunction. The
cancer starts because the mitochondria in cells are severely damaged, and as the
disease progresses, the mitochondria in the T cells begin to fail as well.

“ Once you fix the mitochondria so that they can

generate sufficient energy again, then the cancer will
typically regress and immune function will be
restored, as they no longer need to rely on
glycolysis.
”
Since mitochondrial dysfunction is at the heart of it all, the most effective strategy is to
use metabolic therapies that address why the cells are unable to oxidize (burn) sugar in
the mitochondria. Once you fix the mitochondria so that they can generate sufficient
energy again, then the cancer will typically regress and immune function will be
restored, as they no longer need to rely on glycolysis.
What Causes Mitochondrial Dysfunction?

There are four primary contributors to mitochondrial dysfunction:

Excess linoleic acid (LA) intake

Estrogen dominance

Electromagnetic field (EMF) exposure

Endotoxin — Refined sugars and many starches are more likely to cause gut
dysbiosis that leads to the production of endotoxin. This endotoxin is one of the
factors that destroys mitochondrial function, resulting in the Warburg Effect (cancer
metabolism), where glucose is burned through glycolysis

These all play major roles, but excess LA and estrogen dominance, I believe, are the
leading contributors to mitochondrial dysfunction. This is largely because LA and
estrogen negatively impact your body in similar ways. They both:

Increase free radicals that cause oxidative stress and damage your mitochondria’s
ability to produce energy.

Increase calcium intake inside the cell that causes an increase in nitric oxide and
superoxide that increases peroxynitrite that also increases oxidative stress.

Cause an increase in intracellular water causing your body to retain water.

Slow down your metabolic rate and suppress your thyroid gland.

Nearly everyone in the developing world has 10 times the amount of LA in their tissues
than their ancestors of 100 years ago had. This polyunsaturated fat (PUFA) is very
susceptible to oxidative damage, and produces free radicals like reactive aldehydes in
your body that destroy your mitochondria.

These toxic metabolites of LA create enormous amounts of reductive stress as a result

of electrons building up in the ETC and blocking the forward movement of electrons to
complex IV and V to create ATP. And, because LA is embedded in the inner
mitochondrial membrane, it gets damaged and leaks protons that normally build up in
the inner mitochondrial space.

This proton gradient is responsible for driving the nano motor in complex V to create
ATP. Both processes combine to shut down and ultimately prematurely destroy the
mitochondria. Also, when you eat starches, they can end up feeding endotoxin-
producing bacteria in your intestine, and endotoxin is a potent mitochondrial poison.

Solutions

In closing then, some of the key solutions, if you want to improve or restore your
mitochondrial function, would be to:

Lower your LA intake as low as possible by avoiding processed foods, seed oils,
chicken, pork, seeds and nuts.

Make sure you’re eating healthy carbs such as ripe fruit, raw honey and maple
syrup.

Decrease lactate production and increase carbon dioxide, as they have opposing
effects.4 You can learn more about this in “The Biology of Carbon Dioxide.”

Reduce your stress, as chronic stress promotes cortisol release, which is a potent
suppressor of mitochondrial function and biogenesis. Progesterone can be quite
helpful here, as it’s a potent cortisol blocker. You can learn more about this in “What
You Need to Know About Estrogen and Serotonin.”

Take supplemental niacinamide, as your mitochondria cannot make energy without

it. I recommend taking 50 mg of niacinamide three times a day.

Sources and References

1 Nature Communications 2023; 14, article number 6858

2 Medical Xpress November 2, 2023
3 Haidut.me February 26, 2024 (Archived)
4 RayPeat.com Mitochondria and Mortality