Beyond the Powerhouse of the Cell: Mitochondria’s Newfound Ability Is The Key to New Cancer Treatments

Whether you’re a nerd who finds science memes hilarious or a student who has suffered through memorizing unbearable amounts of material for your biology test, you probably have this sentence drilled into your head: The mitochondria is the powerhouse of the cell. Many people know of the mitochondria’s importance in supplying our cells with energy, but new studies reveal that the generation of adenosine triphosphate (ATP) is not their only purpose. Researchers recently discovered another ability mitochondria possess: sending molecular signals when the body is under stress or exposed to DNA-damaging chemicals. These findings may help scientists create new treatments that prevent cancer cells from becoming resistant to chemotherapy.

Previously, the Salk Institute discovered that stressed mitochondrial DNA (mtDNA) triggers an antiviral immune response. As explained by Gerald Shadel, a professor at the Salk Institute’s Molecular and Cell Biology Laboratory, “Mitochondria are acting as a first line of defense in sensing DNA stress. The mitochondria tell the rest of the cell, ‘Hey, I’m under attack, you better protect yourself.’” Shadel also believes that because mtDNA is so abundant in each cell and has fewer DNA repair pathways than nuclear DNA, it can function as efficient DNA stress detectors.

The mtDNA takes the form of a small, round chromosome in mitochondria. When mtDNA is exposed to intracellular or extracellular stress factors, it becomes improperly packaged. According to the Salk Institute’s research, the cell responds to this by ejecting the malfunctioning mtDNA from the mitochondria into the cytosol, the liquid component of the cell. There, the malfunctioning mtDNA activates a step in the innate immune response that destroys any antigens by triggering the expression of interferon-stimulated genes (ISGs). Normally activated by signaling proteins known as interferons, ISGs direct a cell to raise its swords and shields against viral invaders.

Researchers then concentrated on the molecular pathways activated when damaged mtDNA was released into the cytosol. They realized that the ISGs normally activated by interferons were different from the ones activated due to mtDNA stress. Such genes were a subset of ISGs that, in addition to triggering the antiviral immune response, also strengthened nuclear DNA repair responses.

Salk Institute researchers found that these ISGs were not only present in normal body cells, but also in cancer cells resistant to chemotherapeutic agents that attack their DNA. This phenomenon became evident when Shadel and his team stressed the mtDNA in melanoma cancer cells, causing higher levels of ISG expression and promoting nuclear DNA protection and repair. As a result, the cancer cells became resistant to doxorubicin, a chemical used in chemotherapy to destroy nuclear DNA in cancer cells. Doxorubicin also damages the mtDNA, causing it to be released and activate ISGs.

Researchers plan to focus their research on how mtDNA is damaged and released, as well as the DNA repair pathways activated by ISGs. But with the recent discovery showing great potential in the development and manufacture of new chemotherapy treatments related to mtDNA, scientists will need to determine which chemicals damage, or don’t damage, mtDNA. If there were research devoted to finding chemicals that only damage nuclear DNA and not mtDNA, scientists could use those chemicals in chemotherapy, rather than ones that destroy both. As a result, chemotherapy would become much more effective in treating cancer and raise cancer survival rates by a great deal.

These findings also open the possibility of using chemicals that stress mtDNA to fight viral infections by putting them in medicine or drugs to activate the innate immune response. However, as of now, we understand that a reduction of mtDNA has shown negative impacts on the cell, such as impairment of oxidative phosphorylation, an important step to making ATP. Unless the degree of effectiveness in mtDNA-initiated immune responses is significant, this possibility remains closed.

The Salk Institute’s research has shed light on the mitochondria’s purpose in antiviral immunity and DNA repair. Not only do these powerhouses supply our energy, but they also alert our immune system to DNA-damaging stress, helping our bodies protect and repair themselves. These newly discovered abilities of the mitochondria will aid our ongoing battle against cancer by inspiring the development of drugs that can prevent chemotherapy resistance in cancer cells. They also open the door to several possibilities for other treatments against viral infections, as well as better understanding of how these tiny organelles in our cells help our body function properly and allow us to perform our everyday tasks.