How free radical formation and mitochondrial dysfunction can speed up the disease process

When you look at most of the diseases we see today, many share a few things in common.  Schizophrenia, Alzheimer's disease, Pakinson's disease, epilepsy, migraines, cardiovascular disease, diabetes, neuropathic pain, fibromyalgia, Huntington's disease, and cancer are all diseases that share three common threads.  Every one of these conditions, and even the process of aging itself, is associated with high free radical production, mitochondrial dysfunction, and inflammation(1, 2, 3).  In this blog we will discuss how these three phenomena work synergistically to take you down.

Free radical damage to cells

As discussed in my last blog, mitochondria are little organelles within your cells that are responsible for generating the bulk of your energy needs.  I also discussed how, as a natural byproduct of energy generation through the electron transport chain of the mitochondria, some free radicals are produced.  Free radicals, or reactive oxygen species(ROS) are molecules that have an unpaired electron in their outer shell.  Free radicals are very reactive, and since they are unstable until the unpaired electron finds a partner, they go around to other parts of the cell and try to steal an electron, turning that molecule in to a free radical.  It is important to note that this reaction isn't simply with free molecules that are floating around in your cells, free radicals interact with molecules that make up the machinery of your cells.  Obviously, if you want your cells to function properly, you want to keep free radicals from getting out of hand.

DNA and free radical damage

One of the problems that you run in to when free radicals get out of hand is the potential for the free radicals to alter the mitochondrial DNA.  Every one of our cells has 2 types of DNA, nuclear DNA and mitochondrial DNA.  The DNA most of us is familiar with is the nuclear DNA.  Both types of DNA contain instructions for building you, but 99.9999999% of those instructions are found in the nuclear DNA.  When your cells divide to form new cells, the nuclear DNA splits in to 2 and replicates to form a set of instructions for each cell.  If there is damage to the nuclear DNA, this can lead to copy errors which leads to unhealthy, irregular cells.

Certain types of radiation can cause damage to the nuclear DNA.  However, the nuclear DNA is surrounded by a membrane that protects it from other parts of the cell, so it probably doesn't get damaged directly by free radicals generated by the electron tranpsort chain in the mitochondria until you are producing huge amounts of them.  Since the mitochondrial DNA is within the mitochondrial membrane and is not separated from other parts of the mitochondria by a membrane, free radicals generated by the electron transport chain are free to react with the mitochondrial DNA.  While most of the important instructions are contained within the nuclear DNA, the mitochondrial DNA is mostly instructions for proteins contained within the electron transport chain.

Accumulation of free radical damage and mitochondrial dysfunction

Perhaps as free radical damage accumulates to the mitochondrial DNA, a tipping point is reached and the DNA is damaged to the point that new mitochondria made from this damaged mitochondrial DNA are dysfunctional and contain a poorly functioning electron transport chain.  This causes the generation of more free radicals leading to an environment of high free radical production and mitochondrial dysfunction.  In fact, there is scientific evidence that damaged mitochondrial DNA and a dysfunctional electron transport chain both lead to an increase in free radical production(4). As free radical production increases, so does systemic inflammation as free radicals activate genes that produce inflammatory cytokines(5).  What's more, since most of your cells contain many mitochondria(up to 2000 in liver cells), having many dysfunctional mitochondria can produce a large amount of free radicals that could eventually destroy the membrane surrounding the nuclear DNA and cause damage to it.

Keeping excessive free radical production at bay

While we cannot say for sure whether an environment of high free radical production, mitochondrial dysfunction and inflammation causes disease or that disease causes this environment, we do know for sure that this environment is not beneficial in any way to you or your cells.  If your goal is to be healthy, you should make it a point to limit excessive free radical generation by reducing the amount of energy going through your mitochondria and making sure your endogenous antioxidant defense system is generating antioxidants to help keep free radical production under control.  The easiest way to both of these things is to not over-consume calories and to get regular physical activity throughout the day, which is probably why doing both is associated with good health and a lower risk of most disease states. In fact, one could make the argument that there is a single general disease state in chronic disease, with each one of us being susceptible to different diseases based on our individual genetic code.

Why you should avoid overeating and overexercising for optimal health

Eating less is good for your health in more ways than one.  Most people can understand the detrimental effect eating more calories can have on your health from a weight gain perspective, but it actually goes much deeper than that.  The same can be said about overexercising.  To understand how this works, let's take a look at the energy generating furnaces of our cells, the mitochondria.

The Mitochondria

The mitochondria are interesting structures. For one, they aren't original parts of our cellular machinery.  The current theory is that they were a bacteria that was engulfed by a eukaryote, a type of cell that contains organelles as well as a nucleus that separates the cell's DNA from the rest of the cell.  Eukaryotes are the cells that make up most of the life on the planet.  In exchange for protection within their predator, the mitochondria can provide energy via aerobic pathways of energy that the eukaryotes cannot use.  Without the mitochondria, life on the planet would be quite different, if it existed at all.

Also, mitochondria have their own DNA which mostly produces structures responsible for a form of energy metabolism called the electron transport chain.  This DNA is similar in structure to a bacteria's DNA and is not protected by it's own membrane.  For these reasons, the amount of energy produced by the mitochondria can have major effects on your risk for diseases such as Alzheimer's Disease, Parkinson's Disease, Type 2 Diabetes, Cancer, and Cardiovascular Disease.

Free radicals and disease

A common thread among many of these diseases that are prevalent today is high levels of free radicals.  Free radicals are unstable molecules that contain unpaired electrons.  Since these molecules strive for stability, they steal electrons from other molecules making them free radicals in the process and causing them to become unstable.  This can cause your cells to malfunction.  Reducing free radicals is fairly important for health, but taking antioxidants doesn't typically work because antioxidants work by donating electrons, which makes the antioxidant a free radical itself.  The best way to reduce free radicals is to not make many in the first place.

How does this relate to your mitochondria?  Another common thread in all of these diseases is mitochondrial dysfunction.  Recall from above that one of the ways the mitochondria generate energy is via the electron transport chain.  The electron train is a form of producing energy where complexes in the mitochondria pass around electron to generate energy.  Do you see a common thread between free radicals and the electron transport chain?  As a natural byproduct of energy production via the electron transport chain, some electrons leak out and react with oxygen forming the free radical superoxide, which is very reactive.

While the mitochondrial DNA is contained within the mitochondrial membrane, it is not separated from the electron transport chain by a membrane.  This means that free radicals can react with and damage the mitochondrial DNA.  Since the mitochondrial DNA contains the instructions for building the electron transport chain, this can cause the electron transport chain to malfunction, potentially generating even more free radicals that can damage the cell.  A relatively recent study showed that cells with damaged mitochondrial DNA or a malfunctioning electron transport chain generate more free radicals than healthy cells(1).

So why exercise at all?  Why not just sit on your butt all day long?  At the proper dosage, exercise will activate antioxidant systems that will neutralize these free radicals.  In fact, one of the worst things you can do is just sit around as sitting will reduce the expression of genes that make your cells' internal antioxidant system, the NRF-2 pathway.

Breaking up prolonged periods of sitting has been shown to increase expression of these genes which increases the amount of glutathione your cells make, their master antioxidant(2).  Overeating while being sedentary most of the day will generate free radicals in the cell because they have to process that energy, and sitting down will reduce the amount of antioxidants that will take care of those free radicals.  Cruciferous vegetables such as broccoli, the omega 3 fatty acid DHA, blueberries, turmeric, and most sulfur containing vegetables will activate this system as well.  This is most likely the mechanism by which broccoli and other cruciferous vegetables exert their anti-cancer effect.

Conclusion

So how does all of this relate to eating fewer calories and moderate exercise being healthy?  Obviously you will generate fewer free radicals by generating less energy through your mitochondria because you will be passing fewer electrons around inside of them.  As such, you will cause less free radical damage to your mitochondrial DNA which will prevent the excess free radical production associated with mitochondrial dysfunction and a poorly functioning electron transport chain.

When you overeat, you are generating more free radicals because you are forcing more energy through the electron transport chain.  The same goes for excessive exercise.  Moderate exercise is the goal because some exercise is necessary for other parts of your body to function properly, and just sitting all day creates free radicals without generating antioxidants to take care of them.  It is also necessary to increase the number of mitochondria you have within your cells.  A higher number of mitochondria is ideal because it allows you to generate more energy while generating fewer free radicals within each one.  This causes less damage to each mitochondria and decreases the likelihood that they will malfunction.

So what should you do if you are just looking to be healthy?  Basically what I've recommended in nearly every blog I've written.  Eat a Paleo Diet relatively low in carbohdyrate(150g per day or so), get 10,000 steps per day, stay off your butt, and strength train a couple of days per week to maintain muscle mass.  Avoid things like bootcamps, high volume/high intensity exercise, extremely long duration cardio, and worst of all sitting.

Healthy mitochondria: The key to optimal health and wellbeing

While most people tend to look at human beings as an individual unit composed of organs and tissues with regard to health, it is important to realize that the health of individual cells will dictate how healthy your organs and tissues, and thus you, are.  Of course all parts of the cell serve a vital purpose to our survival, but one organelle appears to be particularly important for your health: The mitochondria.  Your mitochondria serve many roles in your cells that are critical to proper function including generating the bulk of ATP(Energy), cell specialization, apoptosis, control of the cell cycle, and cell growth.  The role of the mitochondria is so important to health that mitochondrial dysfunction is found in many of the chronic diseases people experience today including Cancer, Diabetes, Alzheimer's, Parkinson's and a host of others.  Let's take a look at the mitochondria and their impact on health.

A look at a single mitochondrion through a microscope

An interesting tidbit on the mitochondria

The mitochondria are interesting little organelles found within our cells.  Organelles are little structures within our cells that carry out tasks.  Each cell within in an organ has organelles that perform the function of that organ.  For example, one of the functions of your liver is detoxification and many of the cells within the liver contain organelles that do just that.  The mitochondria, which along with energy generation have many functions critical to survival, can be found in just about any cell within a multicellular organism.  The predominant theory on how mitochondria came to be in our cells is referred to as endosymbiosis.

Endosymbiosis is the theory that many of the organelles within our cells came to be there due to a mutually beneficial relationship with the host cell.  In the case of the mitochondria, the theory goes that the mitochondria were bacteria that were engulfed by a separate single celled organism.  There is plenty of evidence for this, and the fact that mitochondria contain their own DNA in the shape of a circle, something primarily found in viruses and bacteria, lends support to this theory.  Over time, the mitochondria became organelles within the cell and lost some of their DNA to the nucleus.  However, to this day, the mitochondria still contain some DNA that cannot be found in the nucleus of the cell.  This DNA primarily codes for proteins found in the electron transport chain, something we will discuss a little later.

What do the mitochondria do?

While the mitochondria within your cells do quite a few things, the role they are most famous for is generating most of the ATP.  ATP, or adenosine triphosphate, is the form of energy your cells use to accomplish the many tasks they perform.  Some cells create hormones, some cells create movement, some cells transmit nerve impulses, and some cells relay information within the body.  Any cell that requires energy to power it's processes uses ATP to do so.  Most cells have many mitochondria, and the number of mitochondria within the cell is in proportion to the energy needs of the cell.  In addition to generating energy for cells, mitochondria also have a prominent role in apoptosis, or cell suicide.

While the concept of cell suicide may sound bleak, apoptosis is a critical process that begins when you are developing as a fetus.  The formation of fingers and toes is accomplished by apoptosis of the cells between the fingers and the toes.  In people with webbed feet or hands, this process did not operate efficiently when they were in the womb.  Apoptosis helps remove unwanted or unhealthy cells before they become a problem.  When apoptosis doesn't occur, bad things happen.  Cancerous cells somehow override apoptosis which is how they proliferate and become tumors.  As long as apoptosis is working properly, irregular cells are terminated.  In fact, thousands of cancer cells develop and go through apoptosis ever day.  It's when apoptosis doesn't work smoothly that cancerous cells proliferate and become tumorous.

As you can see, healthy mitochondria are important for health.  By eating the proper foods and getting regular physical activity, you can keep your mitochondria working smoothly.  Let's take a look at the foods you should be eating and things you should be doing to maintain healthy mitochondria.

Foods for healthy mitochondria

Many foods are beneficial to healthy mitochondria, chief among them are vegetables high in sulforaphane.  Sulforaphane is a molecule found in cruciferous vegetables that helps to increase intracellular glutathione levels.  Glutathione is your body's master antioxidant.  One of the ways your mitochondria makes ATP is the electron transport chain(ETC).  The ETC generates energy by passing electrons between molecules in the mitochondria which creates an electrochemical gradient.  It's not important to understand the specifics of this energy generating process, but it is important to understand that this process generates free radicals as a natural byproduct of making ATP.

Free radicals are unstable substances with an unpaired electron in their outer shell that react with healthy components of your cells.  It is important to limit free radicals because they can interfere with proper functioning of the cell.  Antioxidants donate electrons to free radicals but become weaker free radicals in the process.  Glutathione, being the master antioxidant, donates electrons to free radicals as well as antioxidants that have become free radicals.  Having high glutathione levels, then, can allow you to limit free radical production and limit the amount of damage free radicals can do to your mitochondria.  This is important because most of the antioxidants you eat cannot enter the mitochondria and since the mitochondria has DNA that codes for the proteins in the ETC, damage to that DNA can accelerate free radical production.

Eating cruciferous vegetables such as broccoli, cauliflower, cabbage, asparagus, and kale is important to help keep your glutathione levels high.  Studies have shown the sulforaphane found in these vegetables helps induce cell apoptosis in cancer cells(1).  However, since these vegetables are also goitrogenic meaning they can interfere with thyroid function, you want to limit consumption of these foods to five or six servings a week.  Cruciferous vegetables are not the only foods found to increase glutathione levels, whey protein(2) and blueberries(3) both contain compounds that increase glutathione levels as well.

Supplements for healthy mitochondria

While keeping glutathione levels high should be one of your goals, supplemental glutathione won't work because it is destroyed by stomach acid.  N-Acetylcysteine does appear to work very well at keeping glutathione levels high(4).  However, when looking at maintaining good mitochondrial health and a healthy number of mitochondria in your cells, there is more to it than just increasing glutathione levels.

Magnesium deficiency has been shown to lead to fewer mitochondria in cells(5), so getting sufficient levels of magnesium is important to generating many mitochondria.  Iodine is another important nutrient to make sure you are getting enough of to support healthy mitochondria.  In addition to it's role as a component of thyroid hormone which regulates metabolism throughout the body, iodine also has an important role to play in cell apoptosis(6) which it apparently mediates through mitochondrial mechanisms(7, 8).  In one study, iodine was shown to induce apoptosis in human breast cancer cells but not in healthy cells that surround the cancerous cells(7).  In another, iodine helped induce apoptosis in 4 out of 5 breast cancer cell lines.  For the most part, people tend to be deficient in iodine unless they consume large amounts of fish or low to moderate amounts of seaweed.  Table salt is iodized but few people use iodized salt and the iodine tends to evaporate out of the salt over time.

Lifestyle factors for healthy mitochondria

Given what we've discussed thus far about mitochondria, you may be able to figure out the things you should be doing to have many, healthy mitochondria.  Calorie restriction has been shown to boost the health of mitochondria which makes sense.  Fewer calories going through the mitochondria means fewer free radicals that can potentially react with healthy parts of the cell.  Ketogneic diets tend to lead to healthy mitochondria, potentially via an increase in glutathione levels(9).  It is important to note that one should not randomly undertake a long term ketogenic diet as these types of diets require modulating the intake of other nutrients for safe implementation.

Another thing people can do to maintain healthy mitochondria is exercise.  Daily physical activity is important to signal cells to keep many mitochondria on hand.  There is probably a sweet spot you should shoot for as excessive exercise should, in theory, lead to greater free radicals via increased mitochondrial free radical production.  If I were to ballpark it I would say running for 3-5 miles per day is probably ok but anything above that would provide no added benefit with potential negative consequences, but there are no studies to back up this assertion.  As far as strength training, a normal strength training program is probably fine but bootcamp or circuit style training could potentially cause problems in excess.  Regardless, any situation where you are calling on your body to produce lots of energy will create lots of free radicals that you should attempt to keep in check by keeping glutathione levels high and eating foods high in antioxidants(fruits and veggies).

Conclusion

Keeping healthy cells is important to maintaining your health.  While all components of your cells are important, the mitochondria are crucial for energy generation and proper cell functioning.  There are many things you can do to keep many, healthy mitochondria.  Eating foods that boost glutathione levels as well as making sure you are getting enough magnesium and iodine are nutritional strategies everyone should utilize.  In addition, regular physical activity that is not excessive can signal your cells to increase production of mitochondria without the netative side effect of creating too many free radicals.