December 11, 2014

Metabolic Theory of Cancer: Mitochondrial Dysfunction 1




Welcome to the next installment in my ongoing series exploring the metabolic theory of cancer.

If this is your first visit, you might want to check out the posts leading up to this:
  1. Introduction
  2. Cells Behaving Badly
  3. Cellular Energy Generation 1 - Glycolysis
  4. Cellular Energy Generation 2 - Mitochondria

Last time, we started exploring the structure and function of mitochondria, our cells’ main energy generators. I have been saying all along that mitochondrial dysfunction—the inability of mitochondria to generate sufficient energy (ATP)—is at the heart of the metabolic origins theory of cancer. Another leg of this table is mitochondrial insufficiency—too few mitochondria, even if they are functioning perfectly well. For today, though, we’ll focus on dysfunction.

The previous post left off saying we would take a look at a few things that can cause structural damage to mitochondria. And let’s remember: since structure determines function, if mitochondrial structure is compromised, then function will be compromised as well.



MEMBRANE OXIDATION & FREE RADICALS


Recall from last time that the electron transport system—which is the ultimate mechanism by which large amounts of ATP are generated—is embedded within the inner mitochondrial membrane. So, clearly, we need that inner membrane to be built correctly and maintained well.

And recall from this post about fats that fatty acids are subject to damage via oxidation. What is oxidation? As it relates to food, when fats oxidize, they turn rancid. (If you’ve ever had a container of nuts or a jar of oil sit around too long and go bad, the horrible smell it takes on is the result of the fats being oxidized.)

As it relates to fatty acids as structural components of membranes, oxidation requires a little more explanation. As we proceed through, keep in mind that oxidation is a normal physiological process. It is inevitable and unavoidable, and happens as a result of normal, healthy metabolism. It becomes a problem only when it gets out of control and overwhelms the body’s capacity to contain and repair the damage.

Normal amounts of antioxidants 
from foods? Good to go. 
Megadosing from supplements? 
Not so fast…
If you read health publications or follow health stories in the news, you have probably heard the term “free radicals.” For our purposes here, we can think of free radicals as being pinballs inside our cells (and inside the mitochondria): they bang around and crash into things here and there, only instead of racking up points like you do in a video game, each time the pinball hits into something (such as the fatty acids that make up the mitochondrial membranes), it causes damage. This damage is called oxidation. And in looking to repair this damage, whatever was hit tries to steal resources from some other place, resulting in a chain reaction of oxidation. (The nutrients you know of as antioxidants are helpful for limiting this damage and sometimes preventing it from occurring in the first place. HOWEVER, keep in mind that oxidation is not always a bad thing. Like so much in biology and biochemistry, CONTEXT MATTERS. For example, one of the ways the human immune system attacks and neutralizes pathogens is by oxidizing them, so we don’t want to load up willy-nilly on anti-oxidants. We do need some oxidation to occur. We will come back to this in regard to cancer. In the meantime, check out this article for a little preview on why loading up on antioxidants might not be a wise strategy when it comes to the big C.)

Electrons, like people, 
don’t like to be alone.
So what are these “pinballs” inside us, anyway? Technically speaking, these free radicals are “reactive oxygen species” (ROS). Biochemically, they are molecules with an unpaired electron. Molecules don’t like having unpaired electrons. They will “steal” electrons from somewhere else in order to remedy this unpaired situation, now leaving that molecule with an unpaired electron, and on and on, in the aforementioned chain reaction. (When something loses an electron, it is said to be "oxidized.") Reactive oxygen species are everywhere: in nasty heated vegetable oils, and all kinds of other dietary and environmental “toxins.”

HOWEVER, the single largest source of ROS/free radicals in the human body is our own cellular metabolism. That’s right: the biggest source of free radicals in the human body is the human body, itself! The running of the electron transport system is the number one source of ROS in the body.

Remember that nifty graphic from last time, showing a very basic representation of the electron transport system? Here it is again, in case you’ve forgotten. (With different things circled this time.)





WHERE/WHY FREE RADICALS LEAK OUT

Sometimes, electrons “leak out” of the pipes & tubes they need to pass through inside the mitochondrial membrane in order to create ATP. And when they do, they become those free radical pinballs, likely to inflict damage. WHY do they leak out? There are a few reasons:
  1. The membrane is not constructed properly due to fatty acid imbalances. (Perhaps there are too many polyunsaturated oils in the diet?) If the membrane, itself, is not built properly, then all the stuff that needs to happen within the membrane probably isn't going to go so well.
  2. Deficiency of nutrients required to shuttle the electrons along safely. (See the “Q” in the illustration of the ETS? [Circled in red.] I am simplifying here, but that stands for quinone/ubiquinone, and you can think of that as CoQ10, a nutrient found in all kinds of foods, but most highly concentrated in hardworking tissue, such as animal heart, liver, and muscle meats. As CoQ10 is absolutely required for proper functioning of the ETS, lack of CoQ10 causes more electrons to leak out. Because it shuttles electrons safely along and prevents them from oxidizing other stuff in the membrane, CoQ10 is a potent antioxidant(For any of you out there who happen to be taking a statin drug to lower your cholesterol, please know that one of the effects of statins is depletion of CoQ10. I say “effect,” rather than side-effect, because CoQ10 depletion is not a “side” effect. It is a direct effect of the biochemical mechanism by which statins disrupt production of cholesterol. If you are on a statin, you should absolutely also be on a CoQ10 supplement. I am not a doctor, and I am not giving you medical advice here, but if your doctor failed to give you that bit of advice, please fire him/her as soon as possible and find someone who knows what they’re doing.)
  3. Iron is another critical nutrient for proper function of the ETS. Iron excess in the body can be a pretty big problem, and it gets a lot of attention in the ancestral health world because of our embrace of red meat and liver. But iron deficiency is a big deal, too. The cytochrome proteins that help carry electrons through the ETS require iron. (You can see an example in the illustration above--labeled “cyt C,” circled in yellow. This is a very simplified illustration. There are actually multiple cytochrome proteins in the ETS.) Cytochromes are heme proteins. If that reminds you of “hemoglobin,” pat yourself on the back. Anytime you hear heme, think iron. These cytochrome proteins, which are essential parts of the ETS, require iron to work properly. This is why fatigue is one of the hallmarks of iron-deficiency anemia: when you are iron-deficient, you literally cannot produce adequate energy (ATP). Of course, CoQ10 and iron are not the only nutrients required for proper functioning of the ETS and limiting free radical damage. They’re just two examples. You can check out other illustrations of the ETS and see the use of CoQ here and here.
  4. Overconsumption of carbohydrates. I must shamefully admit my ignorance here, as I am not well-versed in the exact mechanism, but the production of free radicals happens to a larger and more overwhelming degree when the body is trying to create energy from glucose than from fatty acids and ketones. The generation of
    ATP from these different substrates is slightly different on a molecular level, and this slight difference is enough to account for a greater amount of ROS from glucose than from fats or ketones. It has to do with where
    along the ETS certain things enter. I keep referring to parts of the ETS as “tubes and pipes,” but they are actually called “complexes” among science professionals: complex I, II, III, and IV. Different substrates enter the ETS at different complexes, resulting in generation of more or fewer ROS. It also has to do with scary-sounding things like “uncoupling proteins,” which I also don’t understand well enough to explain to anyone. (I am 100% sure Bill Lagakos [Calories Proper blog] or Petro "Peter" Dobromylskyj [Hyperlipid blog] can explain this beautifully. They probably already have, if you have the time to go digging through their sites.)

ANTIOXIDANTS


How do we limit mitochondrial damage from ROS? One way is via the “in house” antioxidants our own bodies produce—most notably glutathione, superoxide dismutase (S.O.D.), and catalase. Another way is by consuming foods that contain antioxidants, or the building blocks for antioxidants. (To name just a few: vitamins A, C, and E, cholesterol, CoQ10, selenium, and some of the phytochemicals in things like rosemary, red wine, and oregano.) And a third way would be, of course, to limit consumption of foods that contain pre-existing ROS and/or lead to production of excessive ROS inside us, such as processed vegetable oils, and copious amounts of refined carbohydrates.

Even for the antioxidants we generate endogenously (a fancy word that means “inside us”), we can only generate them and have them perform their intended functions if we have the nutritional building blocks required for the reactions. For example, catalase requires iron; mitochondrial S.O.D. requires manganese; the S.O.D. in blood plasma requires copper & zinc; recycling of glutathione requires selenium and vitamin C.


OTHER THINGS THAT (might) MESS WITH MITOCHONDRIA


Of course, oxidative damage via diet is not the only way mitochondria can become so compromised that they no longer function properly. There are plenty of other things that can cause mitochondrial dysfunction, as well as a decrease in the total number of mitochondria. I’m not going to go into great detail here (we'll revisit these things down the line, when we speculate about possible cancer prevention strategies), but some of the other things that can potentially cause mitochondrial mayhem are:
  1. Substances that inhibit oxidative phosphorylation & the ETS: There’s a wide array of OxPhos inhibitors. They include things like certain kinds of pesticides, environmental toxins, and straight-up poisons: carbon monoxide, cyanide, and hydrogen sulfide. (And, of course, there are all the wacky preservatives and additives used in foods and beauty/cosmetic products. [Ex: pthalates, parabens, BHT, BHA.] I’m not saying they cause cancer [via mitochondrial dysfunction]. But I don’t think we can say they’re totally safe, either, when used day-in, day-out, for decades. Most of these compounds are studied in isolation, by themselves, when they're tested for safety. We know almost nothing about the synergies that might occur when they're combined and ingested and/or slathered onto the skin every day for years. I am absolutely not a Chicken Little "sky is falling" type person, nor am I a conspiracy theorist. I'm just raising questions.)
  2. Insufficient physical movement: Simple concept—move ‘em or lose ‘em. Give your mitochondria a reason to proliferate and stay healthy. Walk, run, lift, stretch, MOVE. There is a fancy term for “making more mitochondria.” It is mitochondrial biogenesis. Our bodies are fairly good at taking care of themselves; when they need more mitochondria, they will make some. Physical movement (particularly at high-ish intensities) gives the body a stimulus to make more mitochondria. It’s just like muscles getting stronger, or a callous forming: give the body the message that it needs to be stronger/faster/harder, and it will respond. If you are regularly engaging in activity that challenges the mitochondria, they will rise to the task.   
  3. Over-exercising: This is a more pertinent concern in the ancestral health/Paleo community than it is in the world at large, where the problem is more likely not moving enough. Rest days are not a joke, and they’re not a convenience. They are absolutely necessary. The harder you hit your workouts, the harder you need to rest! Remember: at a cellular level, exercise is extremely stressful. [Oxidative
    stress, that is!] That’s the whole point, in fact: intense activity damages the body. It is in repairing from the damage and gearing up for the next time you hit it hard that the body actually gets stronger. A nice, calm walk isn’t going to hurt anyone, but if you are frequently engaging in all-out efforts (whether of strength or speed), you need to frequently engage in all-out resting and relaxing as well. (And make sure you’re taking in some good antioxidants.) Give your mitochondria too much of a beating too often, and why would they stick around? You punish them, they’ll punish you right back. So there’s a happy medium, somewhere, in between too little movement and too much.
  4. Overeating: A once-in-a-while big feast at your favorite guilty pleasure food place probably isn’t going to be that big a deal. But if you are stepping away from the table stuffed to the gills after three meals a day, every day, think of it this way: you might be “overloading” the mitochondria. (Not to mention your liver, which really takes the brunt.) All that “stuff” coming in has to go somewhere. Some of it will be stored as glycogen and adipose, yes. But some of it will get processed and sort of “overwhelm” the system. Think of it like a sewer drain that gets clogged up during a severe storm. When so much rain comes so fast, it overwhelms the drain’s capacity to accommodate it, and the water just keeps rushing past, instead of going down like it should. There might be (might be, this is just my personal speculation) something similar going on with mitochondria. (And my guess would be that this applies to all macronutrients: protein, fat, and carbs. Probably more so with carbs, but I don't care how ketogenic you are; no one needs to be eating seven sticks of butter a day, know what I mean?)

Okay, WHEW!


That’s enough on mitochondrial structure, function, ROS, and other potentially damaging agents. We’ve covered a couple of things that can cause structural damage to mitochondria. Next time, we’ll start exploring the consequences. Now that we know what mitochondria look like and how they work, it’s time to angle our discussion back toward cancer and begin exploring what happens when mitochondria don’t look and work the way they’re supposed to.


(I know what you’re thinking: IT’S ABOUT TIME!!)


Continue to the next post: Mitochondrial Dysfunction 2: They ARE broken.




Remember: Amy Berger, M.S., NTP, is not a physician and Tuit Nutrition, LLC, is not a medical practice. The information contained on this site is not intended to diagnose, treat, cure, or prevent any medical condition.

5 comments:

  1. Thanks Amy. Pieces are falling into place for lots of things - not just cancer. Keep these post coming. Love them!

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  2. Me again Amy. A query that is not relevant....I am always curious as to how much a "stick" of butter is. It is a term that seems to be used widely in the US, but not here in Australia. Hope you can put me straight on this one.

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    1. A stick of butter is 8 Tbsp, or 4oz by weight here in the U.S. (They're usually sold in packages of 4 sticks, for 1 pound of butter.)

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    2. Sorry...being American again! It's about 113 grams. ;D

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  3. Amy, you are right on. You have gems in every installment, but the gem in this one that EVERYONE should learn by heart is quoted here:

    "CoQ10 is a potent antioxidant. (For any of you out there who happen to be taking a statin drug to lower your cholesterol, please know that one of the effects of statins is depletion of CoQ10. I say “effect,” rather than side-effect, because CoQ10 depletion is not a “side” effect. It is a direct effect of the biochemical mechanism by which statins disrupt production of cholesterol. If you are on a statin, you should absolutely also be on a CoQ10 supplement. I am not a doctor, and I am not giving you medical advice here, but if your doctor failed to give you that bit of advice, please fire him/her as soon as possible and find someone who knows what they’re doing.)"

    Keep up the great work. A & F

    ReplyDelete