There's more to metabolism than glucose and ATP

A neuroendocrine tumor cell stained to show the cell’s microtubule structure (green), the cell nucleus (blue), and its many mitochondria (red).

Flashcard flashback

I don’t know about you, but when I was in 9th grade, I had to memorize EVERYTHING about how cells make energy. It was probably one of the scariest topics that I ever studied because there were so many steps in all the pathways and so many details to remember for the final exam.  I covered everything from the definition to the cellular location of glycolysis on over 500 flashcards (don’t worry, I later recycled these). But there was one thing that was missing from my flashcards, and it wasn’t covered on the final exam, either….

A diagram of the major pathways involved in metabolism.

Glycolysis or Mitochondrial metabolism: that is the question!

Cells need energy to do stuff. Pretty straightforward, right? But what I didn’t learn from 9th grade biology is whether all the cells of the human body make energy the same way or if different types of cells have different strategies. As it turns out, the latter is true.

Glycolysis and mitochondrial aerobic metabolism are two pathways for making energy from the simple sugar, glucose. In glycolysis, glucose gets broken down into a molecule called pyruvate. Along the way, energy is generated, in the form of  ATP. ATP is known as the “currency of the cell.” It can be cashed in to fuel many of the cell’s daily tasks.

Now, pyruvate is a pretty cool molecule, because it’s at the crossroads of these two metabolic pathways. It can either be recycled in the cell or it can enter the mitochondria, to be further broken down. In my 9th grade biology class, we called these guys “the powerhouse of the cell”.  Once inside the mitochondria, pyruvate is further broken down to generate even more energy. This second process is known as mitochondrial aerobic metabolism (we’ll just call this mitochondrial metabolism for now). So now that we’ve learned how metabolism works, let’s take a look metabolism in the cells of a pretty cool organ—the brain.

Metabolism in the brain

The brain is one of the body’s most energetically demanding organs. It uses one fourth of the glucose that your body consumes every day (and that’s when it’s NOT studying for a biology exam!). So, what are the cells of the brain doing with all this glucose? Do they just rely on glycolysis? Or, do they also make use of mitochondrial metabolism?

Zheng and colleagues (2018) addressed this very question by studying a gene called PTPMT1. Yeah, I know, that’s a lot of letters.  All you really need to know is that PTPMT1 encodes a protein that helps mitochondria take in pyruvate, so that it can be broken down in mitochondrial metabolism. Without PTPMT1, mitochondrial metabolism is  impaired. However, cells can still perform glycolysis. Because of this fact, these researchers were able to use this gene as a tool. By “knocking it out”, they were able to disrupt mitochondrial metabolism in the cells of the brain and see which cells were most affected.

The energy-hungry brain contains made of many different types of cells, and all of these might have unique strategies for meeting their energy needs.

Impairing mitochondrial metabolism hindered brain development

Before we get down to the brass tacks, we need to cover some basics. First, there are many types of cells in the brain. They all do different things, which means that they could all have different strategies for making energy. There are neurons, which send electrical messages to other neurons in the brain. There are also cells called glia, which perform a variety of roles, like supporting neurons, helping make messages travel faster, or even, helping the brain form its unique structure during development. One last type of cell to mention are stem cells. These cells are important in the developing brain. They have special powers. They can reproduce themselves indefinitely as well as make many other types of cells in the brain.

When Zheng and colleagues impaired mitochondrial metabolism in the developing mouse brain, they found that the brain stem cells weren’t happy with this change. The stem cells that give birth to a special type of glial cell in the part of the brain known as the cerebellum were especially disturbed by the loss of PTPMT1. This disruption had serious consequences. The cerebella of these mice were small and disorganized. Because the cerebellum is the part of the brain that is responsible for coordinating movements, these mice had a difficult time scurrying around and keeping themselves upright.

What is interesting about this study is that other brain cells were mostly unfazed by this change. How is this possible? When mitochondrial metabolism was impaired in these cells, they were either better able to adapt than the brain stem cells were, or they already weren’t reliant on mitochondrial metabolism.

The moral of the story

I think this story nicely illustrates the fact that brain cells are unique - not just in superficial ways, like their shape and in their function, but on deeper level, in their metabolic strategies. Why would cells prefer one pathway over another? It’s complicated, but here are a few things to consider.

First of all, mitochondrial metabolism requires oxygen, whereas glycolysis doesn’t. Some cells live in parts of the body that don’t have access to much oxygen. For those cells, relying on mitochondrial metabolism wouldn't make much sense. Next, there’s the fact that glycolysis makes a little bit of ATP (it’s inefficient), whereas mitochondrial metabolism makes a lot of ATP. If a cell has a high energy demand, then it might favor mitochondrial metabolism over glycolysis.

Mitochondrial metabolism also produces toxic molecules that can damage parts of the cell. Some cells may be more sensitive to these toxic molecules than others, and therefore don’t want to use this pathway. One last thing to consider is the fact that metabolic pathways aren’t just about making energy. They’re important for other things, too - like making the building blocks of the cell (DNA, RNA, proteins, and lipids). Both glycolysis and mitochondrial metabolism feed into different pathways that are important for making the building blocks of the cell. This is particularly important for cells that are dividing to make new cells. Depending on what a cell is building, it might require one or both of these pathways to achieve its “cellular goals.”

The fact that brain stem cells were so sensitive to the loss of mitochondrial metabolism was quite unexpected based on what is known already. Exactly why these cells are so sensitive to loosing mitochondrial metabolism isn’t clear. Two things are certain though: different cells have different metabolic strategies, and there’s much more to metabolism than can fit on 500 flashcards.

Edited by Kristin Muench

Reference:

Zheng, H., Yu, W.-M., Shen, J., Kang, S., Hambardzumyan, D., Li, J. Y., . . . Qu, C.-K. (2018). Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development. Science Advances, 4(10). doi:10.1126/sciadv.aat2681