1/19/2015

Mitochondria and Your Other DNA

Why read this?
The mitochondrion is, in my opinion, one of the most fascinating and incredible organelles in our cells. Really, I promise that mitochondria are going to surprise you. Stick with me here and I'll try to tell you a story about mitochondria, and about your own body, that you likely have not heard before.

I promise to keep the science talk as colloquial as possible. A very basic knowledge of biology is all that is required to feel very comfortable here, 7th grade biology should cover you. If you don't have that much biology knowledge rattling around in your head, then you will have at least some of it by the end of this article!

Don't skip ahead, and try not to despair over the length. I realize that reading a long story is a big obstacle when it comes to making science seem fun, but this story could easily fall under science fiction if you didn't know any better. Also, long doesn't necessarily mean boring.

At minimum you will think, "Huh, that's pretty neat", but more likely than not, you will spend the rest of the day cleaning your brains off the wall, after this story blows your mind wide open!

The Story:
Those readers who are even superficially familiar with cellular biology will probably remember mitochondria from their 7th grade biology class. You will possibly recall that the mitochondrion is an organelle responsible for manufacturing energy. The so called "Power House" of the cell. You might even remember it looking like the cross section of a kidney bean with a squiggly loop inside, much like the picture below. If you haven't thought about mitochondria since the 7th grade, then your teacher flat out failed to tell you one of the most exciting stories in biology.


Before we get to the really cool part, let's make sure everyone is up to speed on how mitochondria work in our bodies, what they are for, and where they are found.

Yes, this is my best attempt to draw a simplified mitochondrion. Thanks college!



Let's pretend I didn't pay attention to Cell Theory in middle school... where do I keep my mitochondria again?


When biologists talk about multicellular organisms (living critters with more than a single cell), they think about things in order of ascending or descending complexity. As an example let's describe a dog from the most complex structures down to the most fundamental. At the most complex, we are looking at the entire dog. This is a complete multicellular organism, it has lots of parts that need to work together to make the whole thing, that is a 'dog', work. We say that the dog is the cumulative result of many cooperating organ systems like the circulatory system, the nervous system, and the digestive system. Looking deeper, we find that each of these systems is made up of multiple organs. The stomach, the pancreas, the small and large intestine, all of these individual organs make up the more complex 'digestive system'.

Now, what are individual organs made of? 

Starting to get a bit trickier, right?

The answer is that organs are made up of individual types of tissue, each with a function that helps the organ do its job. Tissues can be simple, consisting of just a single type of cell, but often have some added complexity that a single cell acting alone would not exhibit. In the heart you have muscle tissue to contract and pump blood, but you also have fibrous tissue that makes up structures like the valves, and don't forget the nervous tissues that electrochemically conduct rhythm signals to each of the different chambers making your heart beat on time.

Each different type of tissue is made from cells. The muscle tissue of the heart, for example, is made from cardiac muscle cells. Cells are the smallest we can get, any smaller and the parts can't survive alone. This is why we biologists say that the cell is the fundamental (most basic) unit of life. This is a core principle of cell theory. All in all, this is a pretty simple concept, living stuff is made of cells.

Let's stop to think about the profundity of that last paragraph for a second. To you and I it seems obvious that cells build to tissues, to organs, to organ systems, to organisms. This is easy kid stuff. Yet, even a few hundred years ago, this knowledge was hidden from even the most well educated. We had no real concept of the smaller structures that led to tissues until the 1670's CE, after the invention of the microscope. That means the first five and a half thousand years of recorded human history came and went, before a single person knew what a cell was. Take a moment to realize how easy it is to gloss over the importance of something so simple. Think about what it means to have such a firm grasp on a concept that eluded the greatest minds of two hundred generations of people. Think about the fact that just a few beads of glass led to the microscope, that led to the evidence, that led to the cell theory. Glass beads had been available for thousands of years, and jewelers had been setting stone in fine alignment just as long. The only thing that stopped us from discovering cells and microorganisms sooner was that it took a little imagination and a little bit of curiosity, to try looking through a perfect glass bead, rather than at it. It took just one person to put the pieces together, and the world was changed. Bask for a moment in the profound effects that even the silliest of scientific inquiries can induce. "What happens if I look through these two glass spheres?" How much knowledge have we built up from that one simple question?

Let's get back on track.

Organelles are the small bits of machinery inside a cell. Most are ubiquitous, you will find cytoskeletal structures regardless of the type of cell, because all cells need a framework to work on. You will find ribosomes, the machines that read work orders from the DNA and produce the requested proteins, in every cell because all cells need to make proteins. There are also some specialized machines that go in specific cells. Pancreatic islet cells have special storage granules which hold insulin. They store the hormone until your blood sugar increases and your brain sends the signal to release insulin.

The mitochondrion is a type of non-specific organelle. They are found in nearly every single cell type in your body, because almost all of your cells need energy to do their jobs. Depending on the type of cell there can be more mitochondria, or fewer, packed into said cell. Red blood cells have no mitochondria, because their function does not require a fuel source. A muscle cell will have many hundreds or thousands of mitochondria, due to the high demand for energy.

We are all caught up now, and we all know that mitochondria are located inside your cells as organelles.

What then is this great, exciting, amazing fact about mitochondria?

Oh, it's a good one. It is such a deep level fact, that you aren't ready yet. We need to walk through one quick logic problem, and you will see why the mitochondrion is about to blow your mind.

Let's talk for just a second about how your cells work when they divide. It seems intuitive that your cells split in half in order to replicate, but what do they do with all the organelles? How do you get a second set of machinery to put into the new cell? The cell just grows some new ones right?

Sort of.

All of the blueprints required for making every last part of you are stored in your DNA. Like a gigantic instruction manual or cookbook, your cells have specialized machinery that opens the DNA and reads how to make a new protein. Those proteins get bent and shaped like balloon animals into anything the cell needs. In this way, your cell can produce an entirely new set of organelles to populate the duplicate cell. So far this is probably obvious to you, like you might have guessed, the cell just grows the new parts. Blah, blah, blah... bored!

Get ready, because this is subtle and it may take a second to fully sink in. All of your cells contain the DNA blueprint for your entire body, they can make everything they need: tiny electrically controlled floodgates in nerve cells and molecular ratchet mechanisms in your skeletal muscles. Your DNA contains everything, EVERYTHING, that is required to construct you as a human from scratch.

Except...

Your DNA doesn't contain the blueprint for mitochondria.

The ubiquitous power house for your cells. The refinery that turns oxygen and glucose into the fundamental fuel that your body uses. The organelle that makes fuel 15 times better than your body can do on its own, and without which you could not be a big, fast moving, multicellular life form, is simply not in your blueprint. The mitochondrion at first glance is not just another one of your molecular machines. The mitochondrion is an invader, of sorts, living inside every single one of your cells and supercharging your fuel production!

Let that concept wash over you, because it is so important, and because I think it is so, so cool.

Read it again if you need to, take your time.

And keep reading... because we aren't there yet. This goes so much deeper.

The mitochondrion has its own separate DNA, it has its own internal machinery just like your cells do. The mitochondrion is its own entity, and when one of your cells wants to divide it has to let the mitochondria know to make some copies for the new cell.

Your body cannot make mitochondria, but needs them to function. If you have a curious mind, you are probably already asking the next question.

If you can't make any mitochondria, then how do babies get mitochondria in the first place?

That is a really great question, and it has a very simple and elegant answer.

When non-biologists imagine the conception of a new life, there is usually some vagueness involved which adds a layer of mysticism. A great many people imagine a sperm and an egg sort of coming together and their combination creates a flash or a spark. Maybe some chemical reactions happen, then the fertilized egg starts to divide and divide and divide until it starts to look like a new baby.

This is more or less correct, but it lacks an understanding of what EXACTLY happens with that first cell. Luckily, using a microscope, we can remove that mystical magical fog, and look at exactly how it happens!

The sperm and egg are both cells. Each one has a special shape and function, but they are still just normal cells like any other in each parent's body. They need all the requisite cellular machinery to function, just like any other cell. When your body wants to produce some sperm or egg, it signals the mitochondrion to divide just like in all the other cells it ever produced.

An egg is a dormant factory. It contains one half of a blueprint and all the organelles, including the mitochondrion, needed to start building an organism from the ground up. All the egg needs to start the factory up and to build a human, is a few more chromosomes (the other half of the blueprint).

The sperm is able to donate the other half of the blueprint, and little else. The sperm is tailor made for its purpose. It uses every bit of energy it has available, and every single one of its mitochondria, to run a powerful engine called a flagellum. By the time a sperm delivers its half of the blueprint to the egg, it has essentially burnt itself out.

Once the egg integrates the DNA from the sperm, the cellular machinery is automatically turned on and dedicates itself to building whatever thing they have in their DNA blueprints, a new human in this case.

And, all along the way, with every new cell formed, the mitochondria from the egg will replicate and provide the fuel to make it all possible.

As a quick aside, this means that all of your mitochondria come from your mother's side. Your mitochondria will always be essentially 100% like your Mom's and 0% like your Dad's. This means we can take mitochondrial DNA from you, and compare it to your great, great, great grandmother's (all following the maternal side) and it will be exactly the same. You are walking around with identical copies of the same mitochondria that were inside the cells of all your maternal ancestors going as far back as you want to look. It is exactly like holding onto an heirloom passed down from mother to daughter for thousands and thousands of generations!

There are some caveats to this, like the fact that random mutations sneak into the genetic code over time, but the idea is still a profound one I think. The mutations are actually pretty cool too, since we can use them to determine things like how many generations ago you and anyone else share a common ancestor. As a simplified clarification, you and your cousin have a common ancestor two generations away, you both have the same grandmother. We can count the number of mutations to determine how long ago that common ancestor lived between two individuals.

Now you might think to yourself, "Wait a second, if the mitochondria in a new baby come from the mother then how could the original mother have gotten the mitochondria? Isn't this a chicken or the egg type of question?"

You, dear inquisitive reader, are onto a deep, deep question and I cannot applaud that type of critical thinking enough. For this answer we will have to go way back. We have to go much, much, much farther back than your question even implies.

This exact question has been under investigation for more than a hundred years. Scientists started trying to come up with guesses about where mitochondria, and their plant cell counterparts the chloroplasts, could have come since around the turn of the last century. There were observational similarities between the mitochondria and some types of bacteria. Many ideas were proposed, including the Theory of Symbiogenesis. The catch is, the scientific method requires you to test your hypothesis against observable evidence, and at the time these hypothesis were proposed, no one knew how to do that. No one knew how an experiment could be designed to determine which theory worked and which were incorrect.

It would be another forty years before we had the knowledge and understanding to begin looking at the DNA evidence and to narrow down the guesses that didn't match the evidence. After years and years of hard work gathering data, it became more and more apparent that our mitochondria are related to various bacteria. Continuing to hypothesize, experiment, and test their guesses against the evidence, biologists were eventually able to prove a model of endosymbiosis as being the origin of our modern mitochondria. The way endosymbiosis works is another fairly simple and elegant solution to a seemingly complex problem.

Based on microfossil and geochemical evidence we can roughly date the emergence of early eukaryotic cells (the type of cells you have, as opposed to prokaryotes like bacteria). These early cells evolved to live in a world where oxygen levels were very low. They produced energy using the less efficient anaerobic (without oxygen) methods, which are still present in your cells. The rising oxygen in the atmosphere over the millenia acted as a poison to anaerobic life, as well as an opportunity for natural selection. At some point around this time a prokaryote developed the ability to use the now abundant oxygen to convert glucose into energy, and gained a significant advantage over other organisms. This meant that there were lots of these bacteria around, and that they were easy fishing for the eukaryotes. The eukaryotes would eat the bacterial cells, digest them, and turn them into energy using the inefficient anaerobic method of energy production. This would have happened every day, just one animal eating another.

Then one day something went a little weird!

To eat a bacterium, a eukaryotic cell floating around in the water will sort of engulf its prey. They have no mouth, so they just wrap around the food and form a little bubble of themselves into a simple stomach. Then things get broken down and the pieces are turned into fuel. This is the normal process.

One day, that process didn't work exactly right.

We can imagine the thin and delicate invagination of the outer cell membrane of a eukaryotic hunter as it closes in. We can imagine the life and death struggle as the predator engulfs its prey. The small bacteria which have learned to metabolize with oxygen and become so abundant, to our hunter, are a common meal. The battle is over quickly, and the eukaryote begins to ingest the bacterium. It is at this point that something goes wrong. For whatever reason, the bacterium is not digested and manages to end up in the cytoplasm (the liquid interior) of the large eukaryotic cell. This may have happened frequently, there is no way to say, but the bacterium accidentally ending up in the cytoplasm of the eukaryotic cell was important. Then the bacterial cell had to be well suited to live within the eukaryotic cell. Also, the eukaryotic cell had to be incapable of, or unwilling to, attack or remove the now internalized bacterium. Finally, the new union must have provided some advantage. We can guess that the initial advantage was the sharing of the abundant fuel created by the bacterium, coupled with the protection of living within the eukaryotic cell.

This event is the heart of the answer to the last question. If we trace back from mother, to mother, to mother going back a billion or two years. Before we were humans as we know ourselves today. Before we were our early hominid ancestors. Before we were small furry warm blooded animals hiding under the earth. Before we were reptiles, or amphibians. Before we were fish with bony jaws or not. Before we were primitive ocean dwellers. Before we were masses of floating cellular colonies. Before we were even chains of cells working together. If we trace back, mother to mother, a billion or two years, then eventually we will trace directly to that hunter eukaryotic cell that didn't quite eat a bacterium. Your direct ancestor, traceable on your mother's side. Single celled and mother to a new era in the history of life on our planet. This single cell gave rise to you, and to every single animal or bug that has ever lived, and every single one that ever will.

This type of deep understanding of the physical world is profoundly beautiful to me.

Think about the journey of understanding we have come through. From ignorance, through increasingly sophisticated layers of clarity. Each step is small and requires easy to understand, tangible and testable evidence. This is what makes science special, what sets it apart from philosophical proofs.

A side effect of this process is a shift in our collective perspective. Moving from a totally egocentric universe, to the realization that we are not the creatures we imagine ourselves to be: alone, unique and center stage. We have shared our evolution for a billion years hand in hand with a symbiotic bacteria, without which we would still be those simple, single celled, hunters.

As surely as you are a the eukaryotic cells in this story, you too are the prokaryotic endosymbiotic cells. 

I described them earlier as alien invaders, but that frame of reference stemmed from a lack of knowledge, of deeper understanding. Alone, your cells could not function as they do today. You, the eukaryotic brain cells, and muscle cells, and liver cells, you are nothing unless you are also the mitochondria. You are two organisms, and one, at the same time.

I think this is important to understand. To see ourselves, our species, as a single tiny twig on the vastly diverse tree of life, and to truly understand how we got there. Not to guess, or to blindly assume, but to be willing to follow the evidence regardless of our initial beliefs.

As a result of our prolonged symbiosis, the mitochondrion has indeed lost its ability to survive without us. In fact is does not well resemble a bacteria any longer. Much of its original DNA has been transferred over to the main blueprint of our nuclear DNA. The long years of evolution have essentially merged two species into one.

With that in mind think of the millions of species of bacteria living now inside your gut. Already you are dependent on some of these species to allow you to digest your food. Might some of these someday be integrated into our very essence like the humble mitochondrion?

One last thought.

The universe we live in is filled with stories and mysteries, some already told, but most still waiting to be discovered. If this type of story excites or interests you, then I would suggest that you are already perfectly suited to become a scientist, a storyteller of the universe. Anyone who is curious at heart can be a scientist, if they are willing to put in the time and effort. All of us are born scientists, we experiment constantly as children in order to understand the world. Many of us are taught to suppress that curiosity as we grow up, we do not ask questions when we fear looking foolish.

Don't do that.

Ask questions until you understand whatever it is you don't understand. If the teacher tells you that they need to move on, let them, but come back after class and ask questions until you understand. If they can't help you, ask who can. Look your questions up in the Library, always ask a librarian how to research topics you know nothing about. Ask questions like an annoying little kid, because that is how you learn. Eventually you might ask a question no one can answer, at that point you are probably standing on the cutting edge of scientific investigation. When you get there, don't stop! Keep asking questions, and keep looking for answers that make sense. You never have to take an answer to a question on faith. You can always understand the basic principles and test them against what is observable. Why not start now? Check on the facts behind the story you just read. Don't just take my word for it.


Continued Reading:
The Origin of Mitochondria: This is a nice intermediate overview of some of the evidence for Mitochondrial Endosymbiotic Origins. If you find yourself wanting more, check out the references at the bottom of their article. If you do not know how to look up a scientific publication, ask your librarian. Trust me, they will be excited to help you.

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