Mitochondrial dysfunctions play major roles in many diseases. However, how mitochondrial stresses are relayed to downstream responses remains unclear. Here we show that the RNA component of mammalian telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53, and then exported back to the cytosol. We found that the import is regulated by PNPASE, and the processing is controlled by mitochondrion-localized RNASET2. Cytosolic TERC-53 levels respond to changes in mitochondrial functions but have no direct effect on these functions. These findings uncover a mitochondrial RNA trafficking pathway and provide a potential mechanism for mitochondria to relay their functional states to other cellular compartments.

Highlights d Liquid-liquid phase separation drives mitotic implantation of transcription factor Pros d Mitotic retention is crucial for Pros to promote terminal neuronal differentiation d Pros condensates and expands H3K9me3 + heterochromatin domains in neurons d Pros recruits and concentrates HP1a into phase-separated condensates

Mammalian mitochondrial genome encodes a small set of tRNAs, rRNAs, and mRNAs. The RNA synthesis process has been well characterized. How the RNAs are degraded, however, is poorly understood. It was long assumed that the degradation happens in the matrix where transcription and translation machineries reside. Here we show that contrary to the assumption, mammalian mitochondrial RNA degradation occurs in the mitochondrial intermembrane space (IMS) and the IMS-localized RNASET2 is the enzyme that degrades the RNAs. This provides a new paradigm for understanding mitochondrial RNA metabolism and transport.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-017-0448-9) contains supplementary material, which is available to authorized users.

Mitochondrial dysfunctions play major roles in ageing. How mitochondrial stresses invoke downstream responses and how specificity of the signaling is achieved, however, remains unclear. We have previously discovered that the RNA component of Telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53 , and then exported back to the cytosol. Cytosolic TERC-53 levels respond to mitochondrial functions, but have no direct effect on these functions, suggesting that cytosolic TERC-53 functions downstream of mitochondria as a signal of mitochondrial functions. Here, we show that cytosolic TERC-53 plays a regulatory role on cellular senescence and is involved in cognition decline in 10 months old mice, independent of its telomerase function. Manipulation of cytosolic TERC-53 levels affects cellular senescence and cognition decline in 10 months old mouse hippocampi without affecting telomerase activity, and most importantly, affects cellular senescence in terc −/− cells. These findings uncover a senescence-related regulatory pathway with a non-coding RNA as the signal in mammals. Electronic supplementary material The online version of this article (10.1007/s13238-019-0612-5) contains supplementary material, which is available to authorized users.