Regulation of Nuclear Transcription by Mitochondrial RNA

Abstract

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.

Mapping Endothelial-Macrophage Interactions in Diabetic Vasculature: Role of TREM2 in Vascular Inflammation and Ischemic Response

“…4C). In line with the in vivo data, TREM2 expression is also increased (at both mRNA and protein levels) in THP-1-derived human MФs and mouse RAW 264.7 MФs treated by high glucose and TNF-a (HT), which in part mimics DM conditions (21,(23)(24)(25) (Fig. 4D-F).…”

“…We began by profiling the DM-associated transcriptomic changes in vascular cells, through scRNA-seq of human mesenteric arteries from deceased organ donors with or without DM (5 ND and 4 DM) collected between 2019 and 2024, a tissue source we have described before (21)(22)(23)(24)(25)(26) (Fig. 1A, sFig.…”

Spatial detection of mitochondrial DNA and RNA in tissues

“…We present a simple RNAscope ™ application, but depending on the kit and sample, it can be used to visualize up to 48 targets. Its application in the study of mtDNA and mtRNA is somewhat recent but gaining popularity (Blumental-Perry et al, 2020;Lee et al, 2023;Sriram et al, 2024).…”

Mitochondrion-to-nucleus communication mediated by RNA export: a survey of potential mechanisms and players across eukaryotes

“…A recent study by Sriram and colleagues [22] uncovered many chromatin-associated RNAs of mitochondrial origin (mt-caRNAs) attached to the nuclear genome in humans, predominantly in gene promoters. Depletion and induction of specific mt-caRNAs altered transcription levels of nuclear genes; knockdown of a group of mt-caRNAs called Sense (i.e.…”

“…The first sense and antisense (i.e. L-strand mapping) non-coding RNAs (SncmtRNAs and ASncmtRNAs, respectively) of mitochondrial origin, later classified as mt-caRNAs, were long non-coding RNAs characterized in normal human cells [12,13,22]. They were found to be associated with chromatin (preferentially heterochromatin) in the nucleus; moreover, sense RNA expression was strongly correlated with cell proliferation [12].…”