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Alex S. Woodell
The tale of the canary in the coal mine dates back to 1911, when British miners began carrying caged canaries with them underground as a means of detecting toxic gases. The idea of using canaries as an early indicator is credited to John Scott Haldane, a Scottish physiologist known to some as the “father of oxygen therapy.” He suggested using these birds as surveillants due to their portability and immense need for oxygen. Canaries (and all other birds) have a respiratory system that is different from mammals to accommodate a high oxygen demand. Specialized air sacs in their lungs allow canaries to receive a double dose of air with each breath. If carbon monoxide or other poisonous gases within the mining tunnels rose to toxic levels, the canaries were the first to fall ill or die, thereby providing an early warning sign for miners to evacuate.
You may be wondering, what do canaries and coal mines have to do with mitochondria? As we begin to answer this question, let’s start by reviewing the functions of these cellular organelles.
Each cell in your body contains up to thousands of rod-shaped organelles called mitochondria. Mitochondria are often known as the “power plants” of the cell, converting oxygen and nutrients into adenosine triphosphate (ATP). Following this analogy of a power plant, ATP is the electricity that powers the cell to carry out many of its normal metabolic functions. In addition to ATP production, mitochondria fulfill many other roles within the cell including storage of calcium ions for cellular signaling, heat production, and programmed cell death. Recently, researchers at the Salk Institute for Biological Studies in San Diego, California added to the growing list of mitochondrial functions. Their paper published in Nature Metabolism on December 9, 2019 provides evidence that mitochondria set off molecular alarms when exposed to stress or chemicals that can damage DNA.
Mitochondrial DNA (mtDNA) is normally packaged into DNA-protein assemblies inside of mitochondria called nucleoids. However, when mitochondria are exposed to stress they release their mtDNA into the cytosol. Free-floating mtDNA can then interact with cytosolic DNA sensors. The Salk group identified a subset of these sensors known as interferon-stimulated genes (ISGs), that are typically activated by viral RNA after infection. Notably, these ISGs are also activated in cancer cells that are resistant to doxorubicin, a commonly used DNA-damaging chemotherapy drug.
Doxorubicin targets nuclear DNA (nDNA) – that is, DNA located inside the nucleus that contains the blueprints necessary for most cellular functions. It turns out that doxorubicin also damages mtDNA, causing it to be released and subsequently activate ISGs. The Salk group discovered that these ISGs, once activated, protect nDNA from damage by enhancing DNA repair pathways. Additionally, they found that cancer cells take advantage of this mechanism to shield themselves from the DNA-damaging effects of doxorubicin.
Why is mtDNA such a good DNA stress sensor? It could be related to the large number of mitochondria present in most cells. Or perhaps this phenomenon can be better explained by poor mtDNA repair capacity. Irrespective of the reason, it’s probably a good thing that mtDNA is more vulnerable. In normal cells, mitochondria act like the aforementioned canaries, reacting to harmful chemicals before they can damage nDNA. Unfortunately, cancer cells also carry these sentinels; in doing so, they are able to evade chemotherapy by supercharging their DNA repair pathways. While this may not be an ideal scenario, we can potentially improve the effectiveness of chemotherapy by preventing mtDNA damage and/or mtDNA release into the cytoplasm. In other words, we need to find ways to stop mitochondria from warning cancer cells – like coal miners without a canary.
Edited by Brittany Avin McKelvey
Wu, Z., Oeck, S., West, A.P. et al. Mitochondrial DNA stress signalling protects the nuclear genome. Nat Metab 1, 1209–1218 (2019) doi: 10.1038/s42255-019-0150-8
“Canary in a Coal Mine” by Michael Sonnabend is licensed under CC BY-SA 2.0
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