The fascinating miniature world of the mitochondria—its precious role in our healthy cells and how mitochondria gone bad can lead to cancer. Part 2 of a 4-article series about Dr. Thomas Seyfried's vitally important book, Cancer as a Metabolic Disease. [To read article #1, click here.]
O, mighty mitochondria!
Mitochondria turn the food we eat into energy. Mitochondria are beautifully complex structures living within almost all of our cells. Inside mitochondria are intricately folded membranes studded with special enzymes, fats, and proteins that are used to run elegant chemical reactions. These chemical reactions are what turn hamburgers into horsepower. You can see from the diagram that mitochondria (those little orange guys) float around in the outer region of the cell (called the cytoplasm). The cell’s chromosomes (DNA) live inside the nucleus. (Mitochondria have their own DNA, but that’s another story).
Mitochondria are sophisticated power generators that break open the chemical bonds within food molecules to get at the energy inside. Chemical bonds consist of positive charges called protons and negative charges called electrons, which hold onto each other tightly. Mitochondria wrench the electrons away from the protons, and then funnel the electrons through an “electron transport chain,” creating current. This electrical energy is used to create ATP molecules, each of which includes a very high-energy phosphate bond. ATP (adenosine triphosphate) is like a miniature chemical battery; our cells can break ATP phosphate bonds apart whenever they need energy to do anything. Oxygen waits at the end of the ATP assembly line to catch the cascading electrons, and then binds to them, forming water as a harmless by-product. Because this process requires oxygen and results in a high energy phosphate bond, it is called “oxidative phosphorylation,” aka “respiration.”
In the first article in this series there is a list of differences between normal cells and cancer cells. But I left out one key difference because it would have been confusing to mention it too early.
The most important fundamental difference between normal cells and cancer cells is how they make energy.
Normal cells use the sophisticated process of respiration to efficiently turn any kind of nutrient (fat, carbohydrate, or protein) into high amounts of energy. This process requires oxygen and breaks food down completely into harmless carbon dioxide and water. Cancer cells use a primitive process called “fermentation” to inefficiently turn either glucose (primarily from carbohydrates) or the amino acid glutamine (from protein) into small quantities of energy. [Note that fats cannot be fermented. This will be important later on.] This process does not require oxygen, and only partially breaks down food molecules into lactic acid and ammonia, which are toxic waste products.
Now, normal cells sometimes have to resort to fermentation if they are temporarily experiencing an oxygen shortage (a cool example is deep-diving animals). But no cell in its right mind would ever choose to use fermentation when there’s enough oxygen around. Why would it? It doesn't produce nearly as much energy and creates toxic byproducts. In short, fermentation is primitive, wasteful, and dirty. You get much more bang for your buck with respiration. Respiration is modern, smart, and clean.
Cancer cells are bizarre in that they use fermentation even when there’s plenty of oxygen around. This is called the Warburg Effect, which is considered the “metabolic signature” of cancer cells. If you see a cell turning glucose into lactic acid when there's oxygen available, you've found yourself a cancer cell. Why would cancer cells do this, when there’s oxygen available? Are they stupid?
No, they are not stupid. They are desperate. They can’t rely on their fancy respiration system for energy production because their mitochondria are damaged. Respiration cannot run smoothly unless the all of the delicate interior structures inside mitochondria are nicely intact. Fermentation also takes place inside mitochondria, but the key difference is that fermentation is very simple and doesn't require the complex inner machinery of the mitochondria.
What kinds of things can damage our mitochondria?
- Cancer-causing chemicals
- Chronic inflammation
One way these things can cause problems for mitochondria is by generating reactive oxygen species (ROS), which damage respiration. You can think of ROS as unstable molecular pinballs, wreaking havoc with molecules around them, causing random damage wherever they strike.
It just so happens that some of the genes most strongly linked to cancer (“oncogenes”) are those that code for mitochondrial proteins. Mutations in these genes are sometimes found in cancer cells:
- BRCA-1 (breast cancer gene)
- APC (colon cancer gene)
- RB (retinoblastoma gene)
- XP (xeroderma pigmentosum gene)
It also is interesting to note that some of the viruses most strongly linked to cancer are known to damage respiration:
- Kaposi’s sarcoma virus
- Human papilloma virus (cervical cancer)
Mitochondria and cancer
In what ways are cancer cell mitochondria damaged? Compared to healthy cells, cancer cells have:
- Fewer mitochondria per cell
- Misshapen mitochondria with unnaturally smooth inner surfaces
- Reduced activity of critical respiration enzymes such as cytochrome oxidase and ATPase.
- Smaller amounts of (deformed) cardiolipin (a crucial mitochondrial fat)
- Less DNA within their mitochondria
- Leaky, uncoordinated electron transport chains that cause some precious energy to be wasted as heat instead of turned into ATP. [This abnormal situation is called “uncoupling.” It has been shown that faster-growing tumors are actually warmer because of this effect.]
Malignant cancer cells have been shown to have substantially lower respiration rates compared to normal cells. In one study of human metastatic rectal cancer, the cancerous cells had respiration rates 70% lower than the surrounding normal cells.
How do damaged mitochondria switch from respiration to fermentation?
Mitochondria evolved a process called the retrograde response, which helps them deal with temporary stress or damage. It is called a retrograde (backwards) response because under normal circumstances, the DNA inside the nucleus calls the shots and sends orders out to the mitochondria in the cytoplasm. However, if a mitochondrion is damaged, and respiration is endangered, the mitochondrion sends an SOS message to the nucleus saying "we don't have enough energy . . . we need to begin fermentation!" It essentially tells the nucleus to activate fermentation genes instead of respiration genes. You can think of fermentation as a clunky backup generator. The retrograde response triggers the following events:
A variety of genes spring into action—genes that code for proteins required to run fermentation instead of respiration. [For you gene groupies out there, examples include Myc, Ras, HIF-1alpha, Akt, and m-Tor.] These same genes also happen to be known in the cancer research world as “oncogenes” (genes that are associated with increased cancer risk). It is likely that the reason why genes needed to run fermentation are also the same genes associated with cancer is that fermentation (and/or lack of respiration) increases cancer risk.
While these fermentation/oncogenes are revving up, their respiration counterparts are gearing down. And who might they be?
Genes like p53, APE-1 and SMC4. These genes code for DNA repair proteins and are associated with respiration. These same genes also happen to be known in the cancer world as “tumor suppressor genes” (genes that prevent cancer). Turning down the activity of DNA repair proteins is not something you want long-term.
The retrograde response was designed for temporary emergency use, not long-term use. Cancer cells stay in this mode forever because they have no other choice.
Being in full throttle fermentation mode with respiration only limping along has the following effects:
- Reactive oxygen species (ROS) are generated, causing random damage.
- Iron-sulfur complexes are injured. These are needed in the electron transport chain.
- P-glycoprotein is activated, which pumps toxic drugs out of cells. This can make tumor cells resistant to most chemotherapy.
- The ability of mitochondria to initiate programmed cell suicide (apoptosis) fails. When something serious goes wrong within a cell, it is the mitochondrion's job to make sure the cell bows out gracefully, for the sake of the organism. This is how cancer cells with all kinds of strange mutations survive; fermentation allows weird cells to live on.
- Calcium leaks out of mitochondria and into the cytoplasm. Proper calcium flow is critical to normal cell division because the mitotic spindle, which is the structure that helps chromosomes separate properly, is calcium-dependent. Faulty spindles increase the risk of lopsided cell divisions—with one daughter cell getting too many chromosomes and the other daughter cell not getting enough.
The scientific evidence linking mitochondrial damage to cancer
Remember from the first article how transplanting (mutant) DNA from cancer cells into healthy cells only caused cancer in 2 out of 24 cases at best? Let’s look at some mitochondria transplant results for comparison:
- Fusing tumor cytoplasm (mitochondria) with normal cells (with healthy DNA in their nuclei) and then injecting these hybrid cells into animals produces tumors in 97% of animals.
- Transplanting normal cytoplasm (mitochondria) into tumor cells (with mutant DNA in their nuclei) reduces cancerous behavior.
- Fusing normal cytoplasm (mitochondria) with tumor nuclei (with mutant DNA inside) reduces the rate and extent of tumor formation.
- If you pre-treat normal cytoplasm (mitochondria) with radiation, it loses its ability to rescue tumor cells from cancerous behavior (because radiation damages mitochondria).
- Transferring healthy mitochondria into cells with damaged mitochondria reduces cancerous behavior.
What these results boil down to is this: the status of the DNA is not what’s important. Damaged mitochondria can turn healthy cells into cancerous cells and healthy mitochondria can reverse cancerous behavior in tumor cells. This tells us that cancer is not a genetic disease. Cancer is a mitochondrial disease.
How do damaged mitochondria cause cancer?
Billions of years ago, before plants took hold on our planet, earth’s atmosphere had very little oxygen, and so living creatures used fermentation to generate energy. Organisms were very simple, without sophisticated controls to help them decide when to reproduce; they just reproduced as fast as they possibly could. Mitochondria appeared about 1.5 billion years ago, about a billion years after oxygen became available, and probably already had the ability to switch back and forth between fermentation and respiration, depending on how much oxygen was around.
Many cells will simply die if their mitochondria are damaged, but if the damage is not too sudden or too severe, some cells will be able to adapt and survive by switching back to fermentation to make energy. Mitochondrial damage unlocks an ancient toolkit of pre-existing adaptations that allow cells to survive in low-oxygen environments.
Mitochondria are so good at producing energy that their arrival on the evolutionary scene is thought to be largely responsible for the increase in complexity of living things. Building and supporting elaborate new creatures with specialized organs and capabilities takes a lot of energy. If you’re not constantly pouring energy into a living thing to maintain its form and function, it will gradually succumb to entropy, or chaos. For cells, this means regressing . . . DNA becomes unstable; cells lose their unique shapes, become disorganized, and start reproducing uncontrollably. Sound familiar? Sound . . . cancerous?
The bottom line about mitochondria and cancer
Any number of environmental hazards can damage mitochondria—these are the same kinds of things we typically think of as damaging our DNA and causing cancer. But hopefully the first article in this series convinced you that damaged DNA is not the primary cause of cancer after all. It’s our mitochondria we have to worry about. Mitochondria take care of our cells and our DNA. Studies show that mitochondrial damage happens first, and then genetic instability follows.
Even though there’s plenty of oxygen around, damaged mitochondria have no choice but to resort to fermentation, which, if you’ll remember, is primitive, wasteful, and dirty. This is no way to run a fancy modern animal. Cells cannot stay in shape and under control under these circumstances. They may be able to live, but it won’t be pretty. Cells with damaged mitochondria, if they survive, are at high risk for becoming cancerous.
So, what does this mean?
What can we do to protect our mitochondria and prevent cancer? What if we already have cancer—what then? Can mitochondrial damage be reversed, or at least reduced? I answer these questions and more in my next article in the series: "Cancer Part III: Dietary Treatments."