Salk scientists show, when telomeres that protect the ends of chromosome become very short, they send RNA messages to the mitochondria to trigger a signalling pathway that activates an inflammatory response to kill the cell before it gets a chance to turn cancerous. This underscores how cells can evading destruction and become cancerous when the pathway is dysfunctional. The findings “Telomere-to-mitochondria signaling by ZBP1 mediates replicative crisis,”  published in Nature on February 8, 2023, could lead to novel methods to prevent and treat cancer and offset the harmful consequences of aging.The study resulted from a collaboration on signaling pathways involved in inflammation, between Jan Karlseder, PhD, and Gerald Shadel, PhD, professors of molecular and cell biology at the Salk Institute. Karlseder’s lab studies how telomeres prevent cancer formation while Shadel’s lab studies the mitochondria’s role in human disease, aging, and the immune system.

“We were excited to discover that telomeres talk to mitochondria,” said Karlseder, holder of the Donald and Darlene Shiley Chair. “They clearly synergize in well-controlled biological processes to initiate cellular pathways that kill cells that could cause cancer.”

“Telomeres, mitochondria, and inflammation are three hallmarks of aging that are most often studied in isolation,” said Shadel, holder of the Audrey Geisel Chair in Biomedical Science and director of the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging. “Our findings showing that stressed telomeres send an RNA message to mitochondria to cause inflammation highlights the need to study interactions between these hallmarks to fully understand aging and perhaps intervene to increase health span in humans.”

During the “replicative crisis” that occurs when telomeres erode to a point where they begin to affect chromosomal genes, cells are programmed to die. This natural death mechanism prevents the destabilization of genomes and the resultant induction of cancer. In earlier studies, Karlseder and Joe Nassour, PhD, a senior research associate in Karlseder’s lab and the first author of the current study, had found cells in crisis are cleared from the body through autophagy, literally “self-eating”.

In this study, the team explored the activation mechanism of autophagy-dependent cell death when telomeres become extremely short. The researchers conducted a genetic screen using human skin cells called fibroblasts, and discovered interdependent immune sensing and inflammatory signaling pathways that are important for cell death during crisis.

Telomeric-repeat-containing RNA (TERRA) molecules are synthesized from dysfunctional telomeres. The researchers found these TERRA, transcribed from short telomeres activate immune sensor proteins called ZBP1 (Z-DNA binding protein 1) and MAVS (mitochondrial antiviral-signaling protein) on the outer surfaces of mitochondria.

“Cancer formation is not a simple process,” says Nassour. “It is a multistep process that requires many alterations and changes throughout the cell. A better understanding of the complex pathways linking telomeres and mitochondria may lead to the development of novel cancer therapeutics in the future.”

In future experiments, the team plans to delve deeper into these pathways and explore the therapeutic potential of targeting these pathways to combat cancer and the ill effects of aging.

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