What Can Mitochondria Tell us About Cellular Stress?

“The mitochondria is the powerhouse of the cell.” This simple phrase is something every high-school biology student learns, and it was even the subject of an internet meme just a few years ago. It’s true—mitochondria are responsible for generating cellular energy. But that’s not all they do! A new study by the Salk Institute for Biological Studies indicates that mitochondria may also be our body’s first alert system in the event of cellular stress.

The study shows that mitochondria send out alert signals to the immune system when cell DNA is damaged (such as by chemotherapy), triggering an immune response by the body. This is significant for cancer research, and could pave the way for new treatment drugs that attack tumors previously resistant to chemotherapy.

The mitochondrial response

Cell DNA is found in the nucleus of the cell. However, mitochondrial DNA—called mtDNA—exists outside of the nucleus, in the mitochondria itself. mtDNA is passed from mother to offspring, and is now linked to the immune responses mothers pass on as part of childrearing—similar to the benefits of breastfeeding on a baby’s immune system.

mtDNA remains with us for our lifetime, and acts as a trigger in the event of cellular stress. For example, during chemotherapy, cells are bombarded with radiation. mtDNA activates to signal interferon-stimulated genes (ISGs), which protect cell DNA from being harmed by the radiation (or any other catalyst for cellular stress). Unfortunately, this means mtDNA suffers and dies, instead of the DNA of cancerous cells. Moreover, a tumor may subsequently develop immunity to the chemotherapy treatment.

This is why chemotherapy is only so effective for so long. It’s also why the mitochondrial response is being referred to as the “canary in a coal mine,” since it’s an early warning that can’t delay the inevitable.

How can researchers use the mitochondrial response?

Anyone who has had cancer or helped a loved one through it has seen the effect of chemotherapy on the body. To kill the cancerous cells, you literally need to poison the rest of the body. Its why people lose their hair, lose weight and become so prone to illness. The immune system is totally weakened, and any power it has left is being used to repair a body under constant duress. The only positive about chemotherapy is its ability to kill cancerous cells and prevent their regrowth.

But chemotherapy as a scattershot approach has one big drawback. Often, tumors develop a resistance. Resistance to chemotherapy means the treatment is only damaging normal cells and putting the immune system to work fruitlessly. Researchers are hoping the mitochondrial response can help put an end to this prospect.

“It says to me that if you can prevent damage to mitochondrial DNA or its release during cancer treatment, you might prevent this form of chemotherapy resistance,” says Gerald Shadel, a professor in Salk’s Molecular and Cell Biology Laboratory and the Audrey Geisel Chair in Biomedical Science.

Being able to prevent the immune response triggered by mtDNA would prevent cancerous cells from evolving resistance to chemotherapy and make cancer treatments more effective in the short-term. Theoretically, it could also help doctors control the protective action of ISGs, to keep normal cells healthier when faced with chemotherapy.

The research is brand-new

The observation of a mitochondria immune response is very new and the effect of this signal is still being investigated by Salk. Early-stage observations are shedding lots of light on how our body registers and understands cellular stress, and what it does to protect itself. But it will take time for scientists to link these findings to new medicines or therapeutic approaches to fighting cancer.

There’s also the type of cellular stress to consider. The mitochondrial response has only been observed in controlled conditions where cell DNA is under duress. It’s not yet known if other types of cellular damage—such as damage to lipids, proteins or macromolecular damage—will trigger the same response. In simpler terms, a dead canary in coal mine means carbon monoxide is present… but that canary might not be able to warn you about a shaft collapse or an electrical accident. Different kinds of cellular stress may trigger different mitochondrial responses—if any at all.

The observation of mitochondrial signaling to the immune system is a great example of the baby steps that take us closer to a better understanding of the human body’s fight against cancer. There’s still so much we don’t know, but every little piece of the puzzle—no matter how small—gets us closer to impactful innovations that change the course of medicine for the better.

Evan DeMarco

Evan DeMarco is a leading sports medicine and nutrition expert, published author, public speaker and frequent guest on television, radio, and digital platforms.

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