ncRNAs: New Players in Mitochondrial Health and Disease?

Abstract

The regulation of mitochondrial proteome is unique in that its components have origins in both mitochondria and nucleus. With the development of OMICS technologies, emerging evidence indicates an interaction between mitochondria and nucleus based not only on the proteins but also on the non-coding RNAs (ncRNAs). It is now accepted that large parts of the non-coding genome are transcribed into various ncRNA species. Although their characterization has been a hot topic in recent years, the function of the majority remains unknown. Recently, ncRNA species microRNA (miRNA) and long-non coding RNAs (lncRNA) have been gaining attention as direct or indirect modulators of the mitochondrial proteome homeostasis. These ncRNA can impact mitochondria indirectly by affecting transcripts encoding for mitochondrial proteins in the cytoplasm. Furthermore, reports of mitochondria-localized miRNAs, termed mitomiRs, and lncRNAs directly regulating mitochondrial gene expression suggest the import of RNA to mitochondria, but also transcription from the mitochondrial genome. Interestingly, ncRNAs have been also shown to hide small open reading frames (sORFs) encoding for small functional peptides termed micropeptides, with several examples reported with a role in mitochondria. In this review, we provide a literature overview on ncRNAs and micropeptides found to be associated with mitochondrial biology in the context of both health and disease. Although reported, small study overlap and rare replications by other groups make the presence, transport, and role of ncRNA in mitochondria an attractive, but still challenging subject. Finally, we touch the topic of their potential as prognosis markers and therapeutic targets.

Subcellular Localization of miRNAs and Implications in Cellular Homeostasis

“…[78,79] Without AGO2, miRNAs may translocate separately into mitochondria through SAM50 and/or TOM. [73,77,80] miR-1 AGO2 and miRNA complex from miRISC is transported into mitochondria after changes of GW182 and/or HDAC4. [81] mitomiR-378 Polynucleotide phosphorylase (PNPase) helps import the AGO2 and miRNA complexes into the mitochondria.…”

The largely unexplored biology of small proteins in pro‐ and eukaryotes

“…Despite their obvious abundance, there is so far no uniform nomenclature for small proteins and many different terms have been used, e.g. smORF-encoded polypeptides (SEPs) [35], small single transmembrane domain proteins (STMD-proteins) [12], micro-peptides [36,37], mini-proteins [38], or micro-proteins [39]. Although these terms highlight their small size as common denominator, they fall short in describing the enormous functional diversity of small proteins in prokaryotes and eukaryotes.…”

Genetic basis of mitochondrial diseases

“…Still, little is known about the variants affecting the genomic loci that encode ncRNAs as their effect may not be as straightforward as for protein-coding genes. Focusing on mitochondria, numerous miRNAs and lncRNAs have been described to target variety of mitochondrial functions by binding not only mRNAs, but also miRNAs and proteins, and even to be encoded by the mtDNA itself [216]. For example, lncRNA Cerox1 has been described as a modulator of OXPHOS, by binding miR-488-3p in the cytoplasm and preventing its inhibitory effect on the complex I transcripts [227].…”

“…For example, lncRNA Cerox1 has been described as a modulator of OXPHOS, by binding miR-488-3p in the cytoplasm and preventing its inhibitory effect on the complex I transcripts [227]. However, the field of ncRNAs in mitochondria is heavily understudied, with disappointingly small study overlap and rare replications of findings, and direct association between ncRNAs and mitochondrial disease is yet to be reported [216] In the last decade, the ribosome profiling data and proteomic analyses identified a surprisingly large number of micropeptides* derived from upstream open reading frames (uORFs*), as well as ORFs corresponding to the lncRNAs [125,[228][229][230][231], arguing for the coding potential of noncoding regions and faults in current genome annotation (Box 3). More than twenty ncRNA-encoded proteins have been characterized in depth [235], including the mtDNA-encoded humanin, MOTS-c, and SHLPs [236][237][238], with roles in mitochondrial bioenergetics and metabolism, and mitoregulin, involved in the formation of OXPHOS supercomplexes, fatty acid oxidation, and Ca 2+ dynamics [239].…”