It has been clear that mitochondria are not just nucleus‐relying entities; instead, they also modulate nuclear events reversely. Long noncoding RNAs (lncRNAs) are classified into nuclear‐encoded and mitochondrial‐derived lncRNAs (nulncRNAs and mtlncRNAs, respectively). Relative to nulncRNAs, the mtlncRNAs are far from being well characterized. Here we report a mtlncRNA, MDL1, that interacts with both p53 and Tid1 proteins and acts as retrograde signaling. MDL1 can regulate a network of nuclear genes, including p53 targets, and functions in cells in a p53‐dependent manner. Mechanistically, MDL1 is necessary for maintenance of the reciprocal interaction between p53 and Tid1, thereby facilitating formation of a ternary MDL1/p53/Tid1 complex that inhibits the nuclear translocation of p53. Since p53 is a canonical transcription factor, the observed inhibition of p53 nuclear translocation would contribute to the MDL1‐mediated mitochondrial retrograde regulation on nuclear genes expression. This study advances our understanding of lncRNA biology, and also sheds new light on the role of mtlncRNAs in mitochondrial‐nuclear functional network and in diverse biological processes.
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.
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