The mitochondrial-derived lncRNA MDL1 mediates a mitochondria-to-nucleus retrograde regulation by inhibiting the nuclear translocation of p53

Abstract

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.