Metabolic Theory of Cancer: Cellular Energy Generation 2 - Mighty Mitochondria

We meet again!

If you’re new here, we are in the midst of exploring a fascinating theory regarding the etiology of cancer. We’ve already covered some ways in which cancer cells differ from normal, healthy cells, but we’re holding off on looking at three or four of the most striking hallmarks that make cancer cells different from healthy cells until we have a good understanding of how our cells generate energy.

If you’re just tuning in, you’ll want to check out the previous posts in this series:

1. Introduction
2. Cells Behaving Badly
3. Energy Generation 1 - Glycolysis

Last time, we looked at the biochemical pathways known as glycolysis and fermentation, both of which are old and somewhat “primitive,” and are relatively inefficient ways of harvesting ATP from carbohydrates (glucose, specifically). We briefly introduced the more complex pathway called oxidative phosphorylation (OxPhos), also called cellular respiration. Recall that “respiration” is a good way to think of this, since this pathway requires oxygen. OxPhos takes place within specialized structures inside cells, called mitochondria.

If it seems like we’re veering off course to explore all this energy and mitochondrial “stuff,” I promise, these brief forays into cell biology are building a very necessary foundation, without which we won’t be able to make sense of the metabolic theory of cancer. After all, how can we understand cancer as a metabolic disease if we don’t have at least a cursory familiarity with cellular metabolism?

BASIC MITOCHONDRIAL STRUCTURE

So let’s get back to the mitochondria. I explained last time that mitochondria generate large amounts of ATP (cellular energy) by using oxygen. And unlike glycolysis, which is a metabolic pathway that exclusively uses glucose as its fuel source, the cellular respiration that takes place inside mitochondria uses acetyl CoA—and acetyl CoA can come from glucose, fatty acids, and ketones. In terms of foods, this means carbohydrates and fats. (Note: We can also use protein as a fuel source, but as I explained in this post, that is mostly in times of serious energy/caloric scarcity, as protein is far too valuable for other uses [such as building muscles and making enzymes] to be siphoned off to make ATP. Generally speaking, protein is not a primary energy/ATP source—not even accounting for gluconeogenesis on a very low-carb diet. Protein is used to make glucose in that case, but it’s not the primary fuel source powering the body.)

Fatty acids and ketones need oxygen in order to be converted into ATP, and that means they need mitochondria. Recall from our discussion last time that glycolysis does not require oxygen, and that it occurs in the cytoplasm. Unlike glucose, fatty acids and ketones cannot be converted into ATP in the cytoplasm. This needs to happen inside the mitochondria. I said it last time, and I'll say it over and over again: If a cell has no mitochondria, not enough mitochondria, or mitochondria that aren’t working properly, that cell will not harvest any appreciable amount of energy from anything but glucose. As I mentioned last time, this is a gigantic point. GI-GAN-TIC. We will come back to it. Just let it keep getting bigger as it sits in the back of your mind.

Okay, so, in terms of cellular energy generation, mitochondria are a big deal. And the lesson on day one of any good biochem class is: STRUCTURE DETERMINES FUNCTION. The way something works inside the body is the direct result of how it’s built. When things are built properly, they work properly. When they’re not built properly, they don’t work properly. (Again, GI-GAN-TIC, and we will revisit this.) To get an appreciation for the importance of structure & function on a macro level, take a look at that thing at the end of your arm. Yeah, your hand. See the opposable thumb? That is a structure that allows human beings to perform functions unavailable to other animals, such as buttoning dress shirts. (I don’t know why a giraffe or a walrus would want to button a dress shirt; I’m just pointing out that if one did, it’d be out of luck.)

Operating under the guiding principle that structure and function are critically linked, now it’s time to start learning about mitochondrial structure. Here is a very simplified illustration of what a mitochondrion looks like:

Image source: By Kelvinsong, via Wikipedia Creative Commons

Mitochondria have two layers. There’s an outer membrane, and an inner membrane. (Both circled in red so you can see what they’re pointing to.) Embedded within the inner membrane is ATP synthase—an enzyme, or, rather, the enzyme, that creates ATP. (Yep, it’s called “ATP synthase” because it synthesizes ATP. And in biochemistry, almost all enzymes end in “-ase,” like lipase, and amylase, enzymes that digest fats and starches, respectively.)

Something to note is that the inner membrane contains lots of folds. (Notice in the illustration how squiggly it looks.) The formal term for these folds is cristae, and you can see them labeled above. What all this folding does is increase the surface area of mitochondria. And since we need tons of ATP to run our bodies, and this is where most of it is produced, we need all the surface area we can get. All these folds allow for much more ATP synthase to be crammed in. (The same principle applies to the small intestine with regard to digestion--tons of folds to allow for a much greater surface area to absorb nutrients.)

So we’ve got the outer membrane, an inner membrane, and the matrix. The matrix is the space contained by the inner membrane. Say you had a small beach ball inside a larger beach ball. The matrix is the space inside the smaller ball. And inside the matrix is where the first step toward making lots more ATP happens. (Please, no Keanu Reeves jokes...)

We need to talk just a little bit of biochem here. (Don't get scared! You know I’m all about keeping this simple.) 

OXPHOS & KREBS CYCLE

Our end goal is generating ATP, right? And as we established last time, we’ve got some pyruvate kicking around the cell, because pyruvate and 2 ATP are the end products of glycolysis. The 2 ATP are going to be used to power some sort of reaction in the body, so now we’re left with the pyruvate. And we said last time that in the presence of oxygen, and assuming we have healthy mitochondria, the pyruvate generally won’t ferment into lactate. Instead, this pyruvate will eventually yield us 36 additional ATP, for a total of 38 (when added to the 2 ATP we got from glycolysis). Different sources will tell you it's anywhere from 32-38. The point is, it's a lot more than we get from glycolysis alone.

But this doesn’t happen magically. Those additional ATP don’t just show up out of nowhere. In order to get all that ATP, we first have to take the pyruvate and convert it into something called acetyl CoA. We take the acetyl CoA, do a whole bunch of stuff to it, and end up with byproducts that can be used to create ATP.

The process of “doing stuff” to acetyl CoA is called oxidative phosphorylation (OxPhos, for short, or cellular respiration). That’s the biochem term for it, and it happens in a kind of loop, or cycle. It’s best thought of as a cycle because there’s really no start and no end; it’s a loop. And acetyl CoA isn’t the only thing that can enter this loop. Our bodies produce other substances that can enter the loop at other places besides the point at which acetyl CoA does. (For example, the amino acid glutamate can be transformed into α-ketoglutarate, and the amino acid aspartate can be transformed into oxaloacetic acid [OAA]. Both α-ketoglutarate and OAA are “intermediaries” of this cycle, and they can enter it at other starting points, so we’ve got lots of different things entering this cycle at different points, not just acetyl CoA. You can see these intermediaries in the illustration below.)

You can see pyruvate being converted into acetyl CoA and entering the cycle toward the upper left (green box), and α-ketoglutarate and OAA circled in orange. DO NOT BE OVERWHELMED BY ANY OF THIS. You absolutely do not have to understand the details here. I'm just giving you a look at the astounding amount of “stuff” that goes on inside our mitochondria, so we can build a foundation for appreciating the physiological devastation that might ensue if our mitochondria were to malfunction.

Check it out: This is the Krebs cycle / Oxidative Phosphorylation:

Image credit: By Narayanese, courtesy of Creative Commons.

The biochemical reactions that occur in the cycle are OxPhos, and they involve complex stuff I’m not going to bore you with, because it goes beyond our needs for understanding the metabolic basis of cancer. But the name given to the cycle itself is the Krebs cycle. It also goes by “citric acid cycle” and “tricarboxylic acid cycle.” Don’t ask me why it has so many names. Probably somebody didn’t like Dr. Krebs and didn’t want to use his name for it. (Maybe they were jealous that he won the Nobel Prize in 1953 for his work in identifying how this all works.) I will call it the Krebs cycle because that’s what I’ve been calling it since high school biology three zillion years ago.

Okay, OxPhos. Krebs cycle. So what? 
Patience, grasshoppers.

ELECTRON TRANSPORT CHAIN

The Krebs cycle happens inside the mitochondrial matrix. As the cycle…well, cycles, it churns out the byproducts I mentioned above—the ones that ultimately help generate ATP. The way these byproducts do this is by passing through something called the electron transport chain. (You might also see this called the electron transport system, or ETS. Same thing.)

We can think of the ETS as a series of pipes, or tubes, through which electrons (and protons!) must pass in order for us to make ATP. The crucial thing to note here is that these pipes/tubes are embedded within the inner mitochondrial membrane. These byproducts go up and down these tubes, and the final stop is ATP synthase. It all happens within the inner membrane.

Here is a snazzy illustration of the ETS, with the pertinent parts we've discussed so far circled in red or yellow:

Image credit: By Fvasconcellos, via release in public domain.

As you can see, the Krebs cycle (called citric acid cycle here) occurs inside the matrix. And you can also see that the tubes (the light blue things labeled with roman numerals) making up the ETS are embedded within the inner mitochondrial membrane. 

Since the ETS, with its final stop of ATP synthase, is what actually makes ATP, and since the ETS is housed within the membrane, our next order of business is to talk about membranes.

MITOCHONDRIAL MEMBRANES

The mitochondrial membranes—like most membranes in our cells—are made up primarily of phospholipids (phosphate groups attached to lipids). Recall that lipids are fats. (Here’s a handy primer I did on membranes way back when no one but me was reading this blog.)

Since understanding mitochondrial structure and function is so critical for our appreciation of the metabolic theory of cancer (not to mention multiple sclerosis and Alzheimer’s), let’s go into a little bit of detail regarding membrane structure. (Remember what I said at the beginning of this post: structure and function are inextricably linked.)

Like just about every membrane in animal cells, the mitochondrial membrane is a phospholipid bi-layer. That is geek-speak for “a double layer of fatty acids & phosphate groups.” Say what? An illustration will help us here. This is an extremely simplistic illustration. Membranes typically have tons of stuff (enzymes, glycoproteins, ion channels, etc.) embedded in them, but for our purposes right now, we only need to know about the phospholipids, so let’s take all the rest of that complicated stuff out of the picture.

The membrane in which the electron transport system is housed looks like the bottom picture here—it contains a mix of saturated and unsaturated fatty acids. So one thing to know right off the bat about mitochondrial structure is that if we want healthy mitochondria, we’ve got to have a good supply of all three types of fatty acids: saturated, monounsaturated, and polyunsaturated. The proper makeup of the membrane ensures that it is able to do what it’s supposed to do—that is has the right permeability, fluidity, etc. It’s neither too rigid, nor too “floppy,” and whatever needs to get in through the membrane can, and whatever needs to get out can, too. (The red “balls” on either end of the membrane represent the phosphate part of “phospholipid.” For our purposes, we are more concerned with the fatty acids. [I just didn’t want you thinking they were clown noses or something.]) So think about this in light of the longstanding recommendations to limit saturated fat as much as possible and load up on polyunsaturated vegetable oils. Dietary imbalances can most certainly lead to imbalances in what gets incorporated into these membranes. (We’ll revisit this down the line.) And structure --> function. If the mitochondrial membrane is not built correctly, it cannot do its job correctly.

I think that is probably way more than enough for now, so that’s it for this one.

Next time, we’ll still be knee-deep in mitochondrial structure & function, and we’ll take a look at a few things that can cause damage to mitochondria. Remember: when a cell’s mitochondria are damaged, its ability to generate energy (ATP) is compromised. This “energy crisis” at the cellular level due to mitochondrial dysfunction is the heart of the metabolic theory of cancer. So I promise you, we are inching closer and closer to the stuff that will blow your mind. In fact, this is probably the most "difficult"/scientifically detailed post of the entire series. So if you've survived this long, cheer up -- it's going to be way easier from here on out!

Continue to the next post: Mitochondrial Dysfunction

P.S. If you are super bored sometime and want to learn more about ATP, the Krebs cycle, electron transport, and all that jazz, this video is EXCELLENT. No, like, seriously, EXCELLENT. (And all you have to do is sit there!)

P.P.S. Anyone out there good with web design? I'd really like to upgrade this site so it doesn't look like I'm some preschooler messing around. I have no idea what I'm doing WRT websites...Please contact me privately if you can help. 

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.