The Two DNA Books That Build Your Body

Every cell in your body contains DNA. You can think of DNA like an instruction book that tells your cells how to build everything they need. This instruction book uses only four letters (A, C, T, and G), like a secret code. Using these four letters, your cells can make tiny machines called proteins. These proteins are important to make you, well, you!

Inside each cell, there are actually two instruction books (Figure 1). The first one is called nuclear DNA. It is the big book that contains most of the instructions—more than 90%—to build your body. You get this big book from both your mom and your dad. Scientists have studied it a lot, and it is so big that, when they first “read” it, it took them 13 years!

The second instruction book is much smaller and comes only from your mom. It is called mitochondrial DNA (mtDNA). This little book lives in a tiny part of the cell called the mitochondrion, kind of like a special bean-shaped “room” inside the cell. This mtDNA book is much shorter than the nuclear DNA. It is shaped like a circle, and it is present in multiple copies. mtDNA only has instructions to make 13 proteins, but these proteins are super important because they help the cell make energy to keep you alive and moving.

Repairing Mitochondrial DNA Errors

Imagine you have one copy of the mtDNA book. The book teaches you how to build bricks for a house. To build the house faster, you ask your friends to help. But each friend needs their own copy of the instruction book, so you make lots of copies and give one to each friend.

Unfortunately, you did not notice that one of the instructions has a mistake. Now, your friends will all use the wrong instructions and build faulty bricks! What can you do to fix this? One way is to check every book and fix the mistake one by one. But that would take a long time—by then, your friends might have already built lots of wrong bricks! Another way is to collect all the books and replace them: you find a good book without mistakes, copy it many times, and give the new copies to your friends. This might be faster, but it still takes time to make and share the new books.

How do you know if you still have time to fix the problem? It all depends on how many books have mistakes. If fewer than seven out of 10 books are wrong, you can still fix the problem, using either of the two approaches. But if more than seven books have errors, your house will probably have issues! This is what happens inside your cells: if more than 70% of the mtDNA has mistakes, it can cause a disease. It is completely normal for some mtDNA to have few mistakes. What is important is to find and fix them before they cause trouble. Luckily, your cells are really good at spotting and fixing these mistakes. Plus, each mitochondrion has many copies of mtDNA, so even if one has a mistake, others can still make the right proteins.

Mutations Can Affect Mitochondrial Function

Trouble happens when more and more copies of mtDNA have the same mistake. Scientists call these mistakes mutations. If one of the letters (A, C, T, or G) is in the wrong spot in the mtDNA, it can cause problems when making the 13 proteins produced from the mtDNA. These 13 proteins are important because they help the mitochondria to do their job. They team up with other proteins from the nuclear DNA to build big “machines” called complexes that work together to make energy [1]. If any of these complexes are broken or do not work properly, the cell cannot get enough energy. Without enough energy, cells cannot do their jobs properly and get sick.

A Special Patient’s Story: Cancer in a Healthy Liver

While we were studying a type of cancer that grows in the liver, we found a very special patient. You might already know that cancer happens when some cells stop following the normal rules and only want to survive and grow... and grow... and grow! When these cells grow too much, they form a lump called a tumor. Sometimes tumor cells do not want to stay in one place—they travel around the body to find new spots to grow. This is called metastasis [2]. These traveling cells are very dangerous because they are hard to find and stop.

Our patient was very unique for many reasons. First, he felt perfectly healthy. Usually, when someone has a tumor, their body shows signs they are sick. They may feel tired all the time, have pain, or lose weight. Liver tumors are a bit tricky because the symptoms can take a while to show. But sooner or later, most people notice something is wrong. Our patient found out he had a big tumor by accident, when he was just having a regular check-up with the doctor!

Second, his liver was healthy before the tumor appeared. The kind of liver tumor we studied, called hepatocellular carcinoma, usually grows when the liver is already sick. But his liver started out perfectly fine—no earlier illness could explain why the tumor formed.

Third, the doctors removed the tumor with surgery. After that, our patient had to visit the hospital twice a year to make sure everything was okay. Five years later, he was still healthy: no signs that the cancer had spread anywhere else, which is very rare for such a big tumor! So, what exactly happened to the cells that turned into the tumor? That is the big question we wanted to answer.

The “Good” Mutation: How mtDNA Helped Our Patient

When scientists study cancer, they usually look for mutations in the DNA that might explain why the tumor started. The first thing we checked was the nuclear DNA—the big instruction book of the cell. We read through it carefully, especially the parts that often have mistakes in people with liver cancer. But our patient did not have any mistakes in his nuclear DNA that could explain the origin of the tumor. So, we looked at the other instruction book, the mtDNA. There we found a change: the letter “T” was missing at position 14423.

The missing letter “T” was in a special part of the mitochondrial DNA that helps make a protein called NADH-ubiquinone oxidoreductase chain 6 protein (ND6). Remember how we said each protein made by the mitochondrial DNA is part of a complex? ND6 is a member of the biggest team, called Complex I, which starts the important job of making energy for the cell (Figure 2).

More than 70% of the mitochondrial DNA molecules in our patient were missing that “T”. Because of this, his cells made a shorter, incomplete version of ND6! Missing a “T” in the mtDNA was the equivalent of missing one of the instructions used to prepare a brick. Because ND6 was incomplete, Complex I could not be built properly—like trying to build a house with broken bricks. That meant the cell could not make enough energy.

Even though our patient had this mutation, he did not feel sick or have any symptoms. After the doctors removed the tumor, he was cured! That is very rare. So, what was going on?

We think that because the ND6 protein was shorter, Complex I was not working well enough to give the tumor cells the energy they needed to travel and spread to other parts of the body. Because of this, when doctors removed the tumor (which, in this case, had all the cells with the mtDNA mutation) the cancer did not come back. In a way, our patient was lucky: even though he had cancer, the mutation in his mtDNA was a “good” one: it stopped the tumor cells from spreading (Figure 3).

Looking Ahead: The Future of Cancer Research

Even though we found the missing “T” in the mtDNA, we still do not have the tools to understand what exactly caused the tumor in our patient. Was the mutation the reason the tumor formed? Or did the mutation happen because of the tumor? Also, cancer does not happen just because of one mutation. Many things affect it, like the environment around the cells, what we eat, our lifestyles, and more [3].

Based on what we know, it seems more likely that the ND6 mutation appeared after the tumor began—it probably was not the cause. Cancers need a lot of energy to grow. Why would a mutation that decreases energy production cause cancer? But we cannot be completely sure. Cancer cells are called “crazy cells” for a reason, right?

There is still a lot to learn about cancer. Studies like ours that look closely at patients can help scientists understand cancer better. One day, researchers might use what we learned to design treatments that copy helpful mutations, like those that reduce Complex I activity, to stop cancer cells from spreading. It would be amazing if, in the future, doctors could safely target ND6 to slow down cancer and prevent it from coming back!

The more we learn, the better we can create treatments to help patients, especially those who are not as lucky as our patient and have mutations that are not “good”. And the best part? Every mystery we uncover gives future scientists—maybe even you!—new ideas to explore and new questions to ask.

Glossary

Protein: ↑ A tiny building block that cells make by following DNA instructions. Proteins carry out most of the work inside cells, helping them grow, communicate, and stay healthy.

Mitochondria: ↑ Tiny compartments inside cells that make energy to keep the cell alive and working.

Mutation: ↑ A change or mistake in the DNA instructions.

Tumor: ↑ A group of sick cells that grow too much and form a lump.

Metastasis: ↑ The process in which cancer cells break away from their original location and form new tumors in other parts of the body. Those new tumors are also called metastases.

Hepatocellular Carcinoma: ↑ A specific type of tumor that develops in the liver.

NADH-ubiquinone Oxidoreductase Chain 6 Protein (ND6): ↑ A protein that is an important part of Complex I, helping it to work properly.

Complex I: ↑ A big “machine” inside mitochondria that helps make energy for the cell.

Conflict of Interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgment

This study was funded by MFAG 16780/Associazione Italiana per la Ricerca sul Cancro.

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