Our cells have developed numerous mechanisms to sense damage and alert the rest of the cell that it is in distress. One key organelle that is able to sense cellular stress is the mitochondria, most widely known as the energy-producing organelle. Cellular stress consists of factors that come from the environment that interfere with the cell’s ability to maintain its regular state. Like the nucleus, the mitochondria contains its own set of DNA, termed mitochondrial DNA (mtDNA), that is packed in a circular form. Unlike the nucleus, the mitochondria does not contain advanced DNA repair mechanisms and is thus extremely susceptible to damage. With the large number of mitochondria present in a cell, this sensitivity to factors that cause damage can be used to alert the cell and trigger pathways within the cell in order to protect itself.
A new research study has further investigated mitochondrial DNA stress signaling and the influences it has on cell behavior. Often times when mtDNA is damaged, it will be released from the mitochondria into the cytoplasm, the water-like fluid that contains all the organelles inside the cell. The researchers found that when exposed to cellular stress, the damaged mtDNA that are released into the cytoplasm served to be a trigger to increase the production of mechanisms involved in nuclear DNA repair. In this case, cellular stress involved exposure to reactive compounds that attack and react with the mtDNA, causing damage that cannot be repaired. In this sense, the mitochondria work as an alarm system and allow the cell to protect itself.
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In response to these findings, the researchers wanted to investigate the influence of mtDNA damage in cancer. The commonly used chemotherapy drug, doxorubicin, is known to target and damage nuclear DNA in order to kill cancer cells. A current issue with this therapy is that people can become resistant to the drug; therefore, the treatment no longer becomes effective. When applying this drug to cultured melanoma cancer cells, the researchers found that the drug leads to an increase in the amount of mtDNA damage and release into the cytoplasm. To further investigate the influence of mtDNA stress signaling on doxorubicin resistance, the researchers edited the melanoma cancer cells in order to make their mitochondria more prone to becoming damaged. This then increased nuclear DNA protection in the cancer cells and they developed resistance to doxorubicin treatment. In this instance, the presence of the mitochondria “alarm system” allowed the cancer cells to be in a protective state, which allowed them to evade the effects of the chemotherapeutic agent. Thus, mitochondrial DNA stress signaling is a mechanism that can work to build resistance to chemotherapy.
These findings are important as they further contribute to our ever-growing understanding of cancer. Since cancer is such an opportunistic disease, it is important to continuously work to find the best and most effective treatment options. Future research on mechanisms to inhibit mtDNA release from cells could potentially prevent the development of doxorubicin resistance and prolong the ability to use this treatment method in patients.
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