Regulation of Nuclear Transcription by Mitochondrial RNA

Mitochondrial-nuclear communication is vital for cellular homeostasis and stress response. Mitochondria employ messengers e.g., metabolites, peptides, and Ca2+ to communicate to the nucleus. It remains unclear whether mitochondrial RNAs (mtRNAs), the immediate output of mitochondrial transcription, can serve as a messenger for communication to the nucleus. We show that mtRNAs are attached to the nuclear genome and constitute a subset of the chromatin-associated RNA, and hence termed mt-caRNA. Mt-caRNAs preferentially attach to promoter regions and the attachment levels change in response to cellular stress. In human endothelial cells (ECs), suppression of SncmtRNA, a mitochondrial non-coding RNA associated with chromatins, attenuates stress induction of nuclear-transcribed nascent RNAs, including cell adhesion molecules ICAM1 and VCAM1, and abolishes stressinduced monocyte-EC adhesion. In addition, we show nuclear localization of MT-CYB and MT-ND5 in human ECs, a phenomenon potentiated in ECs from diabetic donors. Collectively, our findings suggest the involvement of mtRNAs in mitochondrial-nuclear communications and that mt-caRNAs may regulate nuclear transcription and cellular function. ### Competing Interest Statement J.S. is a co-founder of Translura, Inc. S.Z. is a founder of Genemo, Inc.