Inter-organellar nucleic acid communication by a mitochondrial tRNA regulates nuclear metabolic transcription

Efficient communication between mitochondria and the nucleus underlies homoeostatic metabolic control, though the involved mitochondrial factors and their mechanisms are poorly defined. Here, we report the surprising detection of multiple mitochondrial-derived transfer RNAs (mito-tRNAs) within the nuclei of human cells. Focused studies of nuclear-transported mito-tRNA-asparagine (mtAsn) revealed that its cognate charging enzyme (NARS2) is also present in the nucleus. MtAsn promoted interaction of NARS2 with histone deacetylase 2 (HDAC2), and repressed HDAC2 association with specific chromatin loci. Perturbation of this axis using antisense oligonucleotides promoted nucleotide biogenesis and enhanced breast cancer growth, and RNA and nascent transcript sequencing demonstrated specific alterations in the transcription of nuclear genes. These findings uncover nucleic-acid mediated communication between two organelles and the existence of a machinery for nuclear gene regulation by a mito-tRNA that restricts tumor growth through metabolic control. HighlightsO_LIMultiple mitochondrial-derived tRNAs are detected in human cell nuclei C_LIO_LIMtAsn promotes binding between NARS2 and HDAC2 C_LIO_LIMetabolic alterations driven by mtAsn impact cell proliferation C_LIO_LIMtAsn inhibition releases HDAC2 to bind and transcriptionally regulate multiple nuclear genes C_LI