Non-coding RNA TERC Functions As A Signal For Ageing-related Mitochondria-nucleus Crosstalk

Human mitochondrial dysfunctions have long been implicated in the development of ageing related health problems such as metabolic defects,neurodegenerative diseases,and self-immune diseases.Mitochondria also play an active role in cancer cell metabolism and dedifferentiation.Mutations that alter mitochondrial bioenergetics and biosynthesis are common in cancer cells.They promote oncogenesis by modulating signaling pathways and gene expression through mitochondrial retrograde signaling.Mitochondrial retrograde signaling relays the functional state of mitochondria to the nucleus and other cellular compartments,sometimes even leading to cell fate determination.The major known mitochondrial retrograde signals contain calcium ion,ROS and so on.However,all of these retrograde signals lack specificity,and none could fully explain how mitochondria regulate a cellular process specifically.The roles mitochondria play during ageing are more complicated than originally expected.Mitochondrial dysfunctions contribute to different aspects of ageing including cellular senescence,decline of stem cell activity and inflammation.Mitochondrial impairments trigger mitochondrial unfolded protein responses and mitophagy that also have a protection effect and in turn may extend longevity in model organisms such as C.elegans.These processes are regulated by a complex network of signaling pathways,and the intricate interplay and co-regulation only start to unravel.Initially,we were trying to investigate the import and the mitochondrial function of some lncRNAs.This led to an unexpected finding that one of the RNAs TERC is processed in the mitochondria and then exported out of mitochondria.Partially impairment of mitochondrial function caused an accumulation of the mitochondrion-processed RNA in the cytosol.Overexpression of the processed-form led to an increase of cellular senescence without affecting telomerase activity.In mice,a correlation between the processed mTERC level and the age of the animals was observed and the ageing process was accelerated or decelerated by overexpressing the RNA or the antisense RNA.Both manipulations also caused a broad effect on nuclear gene expression.These findings demonstrate for the first time that a nuclear-encoded non-coding RNA functions as a specific mitochondrial retrograde signal,a potential general mechanism,and provide a new mechanism on how mitochondria contribute to cellular senescence and organismal ageing.