The mitochondrial-generated lncRNAs mediate a mitochondria-to-nucleus retrograde regulation after their nuclear translocation

Abstract Since an intense communication between nucleus and mitochondria is vital for maintaining cellular homeostasis, it is important to characterize biological molecules involved in the inter-compartmental crosstalk. While a number of nuclear-encoded lncRNAs (nulncRNAs) have been implicated in anterograde regulation from the nucleus to mitochondria, the participation of mitochondrial-derived long non-coding RNAs (mtlncRNAs) in retrograde regulation from mitochondria to nucleus remains poorly understood. In this study, we identified three mtlncRNAs, namely MDL1AS, lncND5, and lncCyt b, as retrograde messengers following their translocation to the nucleus. Facilitated by the RNA-binding proteins HuR and PNPT1, these three mtlncRNAs shuttle from the mitochondria to the nucleus, subsequently regulating a network of nuclear genes. Furthermore, we demonstrated the cooperative interaction between the nuclear-localized lncCyt b and the splicing factor hnRNPA2B1, which influences various aspects of cell metabolism, including glycolysis. This effect is potentially mediated through their synergistic impact on the pre-mRNA splicing of related nuclear genes. Moreover, our study expands our understanding of mitochondrial biology and provides novel insights it provides novel insights into the role of mtlncRNAs in mediating the communication between mitochondria-nucleus.