Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression

作者：Vanessa Xavier, Silvia Martinelli, Ryan Corbyn, Rachel Pennie, Kai Rakovic, Ian Powley, Leah Officer-Jones, Vincenzo Ruscica, Alison Galloway, Leo M. Carlin, Victoria H. Cowling, John Le Quesne, Jean‐Claude Martinou, Thomas MacVicar · 发表于：Life Science Alliance · 年份：2024 · DOI：10.26508/lsa.202402764 · 被引用次数：7 · 研究领域：RNA modifications and cancer、Mitochondrial Function and Pathology、Mechanisms of cancer metastasis

Mitochondrial gene expression is a compartmentalised process essential for metabolic function. The replication and transcription of mitochondrial DNA (mtDNA) take place at nucleoids, whereas the subsequent processing and maturation of mitochondrial RNA (mtRNA) and mitoribosome assembly are localised to mitochondrial RNA granules. The bidirectional transcription of circular mtDNA can lead to the hybridisation of polycistronic transcripts and the formation of immunogenic mitochondrial double-stranded RNA (mt-dsRNA). However, the mechanisms that regulate mt-dsRNA localisation and homeostasis are largely unknown. With super-resolution microscopy, we show that mt-dsRNA overlaps with the RNA core and associated proteins of mitochondrial RNA granules but not nucleoids. Mt-dsRNA foci accumulate upon the stimulation of cell proliferation and their abundance depends on mitochondrial ribonucleotide supply by the nucleoside diphosphate kinase, NME6. Consequently, mt-dsRNA foci are profuse in cultured cancer cells and malignant cells of human tumour biopsies. Our results establish a new link between cell proliferation and mitochondrial nucleic acid homeostasis.