The RNA component of mammalian telomerase TERC is processed in mitochondria to TERC-53 and then exported back to the cytosol. The cytosolic TERC-53 levels respond to mitochondrial defects. Zheng et al. show that cytosolic TERC-53 regulates cellular senescence and is involved in cognition decline in mouse hippocampus, without affecting telomerase activities. It functions by interfering with nuclear translocation of a transcriptional factor and subsequently changing nuclear gene expression. These findings uncover a mitochondrial retrograde signaling pathway with a non-coding RNA as the signal. The cover picture is a cartoon depiction of a sick mitochondrion communicating with the nucleus. This image was designed and composed by Geng Wang.