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.

Expression of Mitochondrial Long Non-Coding RNAs, MDL1 and MDL1AS, Are Good Prognostic and/or Diagnostic Biomarkers for Several Cancers, Including Colorectal Cancer

“…Non-coding RNAs are well known for regulating a large number of genes rather than having specific targets [ 45 ]. In addition, mitochondrial non-coding RNAs may act directly on mitochondrial genes or travel to the nucleus and impact a large number of unrelated pathways [ 46 ], and both MDL1 and MDL1AS have been shown to translocate to the nucleus [ 25 , 26 ]. Furthermore, a number of small RNAs may be produced from the degradation/processing of the MDL1AS sequence [ 24 , 47 ].…”

“…MDL1 has been shown to translocate into the nucleus where it interacts with a network of nuclear genes, including p53, whose function is compromised as a consequence [25]. The translocation of MDL1AS to the nucleus has been also proposed in a recent preprint [26], although no specific function has been described for this lncRNA. Since not much is known about these mitochondrial lncRNAs, the aim of this study was to better understand their role in cancer biology and their biomarker value in several cancers, including rectal cancer.…”