The mtlncRNA-targeting ASOs used in this study.

A bidirectional nucleus-mitochondria communication is essential for homeostasis and stress. By acting as critical molecules, the nuclear-encoded lncRNAs (nulncRNAs) have been implicated in the nucleus-to-mitochondria anterograde regulation. However, role of mitochondrial-derived lncRNAs (mtlncRNAs) in the mitochondria-to-nucleus retrograde regulation remains elusive. Here, we identify functional implication of the mtlncRNAs MDL1AS, lncND5 and lncCyt b in retrograde regulation. Mediated by HuR and PNPT1 proteins, the mtlncRNAs undergo a mitochondria-to-nucleus traveling and then regulate a network of nuclear genes. Moreover, as an example of the functional consequence, we showed that the nuclear-translocated lncCyt b cooperates with the splicing factor hnRNPA2B1 to influence several aspects of cell metabolism including glycolysis, possibly through their regulatory effect on the post-transcriptional processing of related nuclear genes. This study advances our knowledge in mitochondrial biology and provides new insights into the role of mtlncRNAs in mitochondria-nucleus communications.细胞核与线粒体间的双向通讯对于细胞稳态与应激响应至关重要。作为关键功能分子，核编码长链非编码RNA（nuclear-encoded lncRNAs，以下简称nulncRNAs）已被证实参与细胞核向线粒体的顺行调控过程。然而，线粒体来源长链非编码RNA（mitochondrial-derived lncRNAs，以下简称mtlncRNAs）在线粒体向细胞核的逆行调控中所发挥的作用仍不明晰。本研究鉴定出mtlncRNAs MDL1AS、lncND5及lncCyt b在逆行调控中的功能作用。在HuR蛋白与PNPT1蛋白介导下，mtlncRNAs可完成线粒体向细胞核的转运过程，随后调控一系列核基因的表达网络。此外，作为功能效应的典型案例，我们发现核转位的lncCyt b可与剪接因子异质性细胞核核糖蛋白A2B1（heterogeneous nuclear ribonucleoprotein A2B1，hnRNPA2B1）协同作用，影响细胞代谢的多个环节（包括糖酵解），其潜在调控机制可能是通过干预相关核基因的转录后加工过程。本研究拓展了我们对线粒体生物学的认知，并为阐明mtlncRNAs在细胞核-线粒体通讯中的作用提供了全新的研究视角。