Together against cancer: If an aging cell threatens to degenerate, a multi-stage alarm reaction ensures that the affected cell is destroyed in good time – and thus counteracts the development of cancer. Telomeres, the end caps of the chromosomes, and mitochondria, the cell power plants, are involved in this signaling pathway, as researchers report in “Nature”. This finding sheds new light on cellular protective mechanisms against cancer and could help clarify why this protection sometimes fails.
At the ends of our chromosomes, the so-called telomeres form protective caps that stabilize our genetic material. As the cells age, these protective DNA sequences become shorter and shorter, until a crisis finally occurs: the cells that have become genetically unstable initiate apoptosis, a cellular suicide program. This marks them as “for disposal” to the immune system and at the same time destroys the cell from the inside out. This mechanism prevents the development of cancer.
protective response against cancer
So far, however, it was unknown how the process works in detail and how some cells can escape death and form tumors. A team led by Joe Nassour from the Salk Institute for Biological Studies in La Jolla, California, has now dealt with this. “Our results demonstrate a synergy between critically short telomeres, mitochondria, and the innate immune system that evolved to prevent age-related carcinogenesis in humans,” the authors report.
With the help of genetic screenings on human fibroblasts, i.e. cells of the connective tissue, Nassour and his colleagues found that telomeres that have become too short activate signaling pathways of the innate immune system that are decisive for cell death during the crisis. In doing so, they rely on the help of the mitochondria, the power plants of the cell.
Communication between telomeres and mitochondria
“We were thrilled when we discovered that telomeres communicate with mitochondria,” says Nassour’s colleague Jan Karlseder. It is only when the chromosome ends work together with the cell power plants that cellular pathways are set in motion that kill defective and thus potentially degenerating cells. As long as this signaling pathway works, it can also protect against cancer in old age.
Specifically, the research team demonstrated that telomeres that have become too short send out long RNA molecules that bind to an immune sensor called Z-DNA-binding protein 1 (ZBP1) on the mitochondrial surface. This binding activates the mitochondrial antiviral signaling protein (MAVS), which is part of the innate immune system and is responsible, among other things, for eliminating virus-infected cells. In principle, the telomere alarm signal uses a signaling pathway actually developed against viruses to destroy old, genetically unstable cells before degeneration occurs.
Integrated view of aging
“Telomeres, mitochondria and inflammation are three features of aging that are mostly studied in isolation,” says Nassour’s colleague Gerald Shadel. “Our results show that stressed telomeres send an RNA message to the mitochondria to trigger inflammation. This underscores the need to study the interactions between these traits to fully understand aging and perhaps intervene to extend lifespan in humans.”
In future studies, the researchers want to find out how the processes that have now been discovered can possibly be influenced. “The development of cancer is not a simple process,” says Nassour. “It is a multi-step process that requires many changes in the cell. A better understanding of the complex pathways connecting telomeres and mitochondria could lead to the development of new cancer therapeutics in the future.” (Nature, 2023, two: 10.1038/s41586-023-05710-8)
Those: Salk Institute