**1. Introduction**

Mitochondria are eukaryotic cell organelles that represent a universal system in higher organisms which generate most of the cellular energy, in the form of ATP, necessary for different

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

cell processes. However, many other functions have been assigned to this tiny organelle, such as apoptosis, reactive oxidative species (ROS) signaling, inflammation and metastasis. Mitochondria play a central role in apoptosis, principally due to the release of proteins from the mitochondrial inter-membrane space [1], linking mitochondria to cell suicide. Mitochondria also represent a major source of DNA-damaging reactive oxygen species (ROS), mainly as byproducts of oxidative phosphorylation. In comparison to nuclear DNA, mitochondrial DNA (mtDNA) is more susceptible to DNA damage due to the reduced capacity of the cell to repair mtDNA, potentially promoting cancer [2].

In this chapter we discuss the importance of long noncoding mitochondrial RNAs (lncmtRNAs)

Long Noncoding Mitochondrial RNAs (LncmtRNAs) as Targets for Cancer Therapy

http://dx.doi.org/10.5772/intechopen.75453

181

Human mitochondrial DNA (mtDNA) is a circular molecule of 16,569 bp in length [13] which encodes a small subset of 13 proteins required for OxPhos, 22 tRNAs and two ribosomal RNAs, 12S rRNA and 16S rRNA, which form part of the small (28S) and large (39S) subunits of the 55S mitoribosome [14]. All other protein components are encoded by nuclear genes and

Replication and transcription of mtDNA is initiated from the D loop, a small noncoding region, and is regulated by nuclear-encoded proteins imported into mitochondria [15]. Mitochondrial RNAs are transcribed as long polycistronic precursors from both strands, termed heavy (H) and light (L) strands [16]. Except for NADH dehydrogenase 6 (ND6), all the 13-mitochondrial proteins are encoded in the H-strand. Additionally, the H-strand encodes 14 of the 22 tRNAs and the 2 rRNAs. The remaining 8 tRNAs are encoded on the L-strand [17]. The precursor transcripts are processed according to the tRNA punctuation model, whereby 22 interspersed tRNAs are excised at their 5' and 3'ends by RNase P [18] and by RNase Z, elaC homology 2 (ELAC2), respectively, releasing simultaneously individual rRNAs and mRNAs [19]. The RNAs then undergo maturation, involving polyadenilation at the 3'eextremitoess of mRNAs and rRNAs, and specific nucleotide modifications and addition of CCA trinucleotides to the 3'eextremities of tRNAs [20]. The data of several groups indicate that 250–300 nuclear-encoded proteins are dedicated exclusively to serve mitochondrial gene expression. This includes RNA polymerase, endonucleases for RNA processing, translation factors, biogenesis factors for the mitochondrial ribosome, aminoacyl-tRNA synthetases, and other auxiliary factors [21, 22]. However, evidence has accumulated supporting the notion that, besides proteins, many types of RNAs transcribed from the nuclear genome are actively delivered to mitochondria. Among these transcripts are different types of noncoding RNAs, such as tRNAs, 5S rRNA, MRP RNA (RMRP) and RNase P RNA (RPPH1) [23], as well as microRNAs (mitomiRs) [24]. The logical explanation is that, despite their critical function, the handfuls of mitochondrial- and nuclear-

encoded proteins are insufficient to maintain mitochondrial structure or activity.

Noncoding RNAs (ncRNAs) are divided in two major groups according to size, as small noncoding RNAs and long noncoding RNAs. Among the small ncRNAs, microRNAs (miRNAs) are the most-studied class in mammals. These RNAs (20–24 nucleotides in length) negatively regulate gene expression through binding with their target mRNA and have been implicated actively in pathogenic processes of many human diseases [24] and, as such, are important regulators of cancer cell metabolism [25]. The observation of association of miRNAs with/inside mitochondria may have important implications in several cellular processes and suggest that the role of mitochondria clearly extends beyond its role in energy metabolism and other cellular processes. The newfound destination of miRNAs indicates novel roles of mitochondria

in diagnostic and pharmaceutical targeting in cancer.

imported into mitochondria from the cytosol.

in normal and pathological events [25].

**2. Mitochondrial transcripts and noncoding RNAs**

In inflammation, mitochondria mainly serve as a source of various signaling molecules, termed damage-associated molecular patterns or DAMPS, which propagate inflammatory signals and therefore activate inflammation [3].

Cancer death is most often due to secondary tumors or metastasis. This process requires a complex series of events, which include epithelial-to-mesenchymal transition, stromal remodeling, invasion and ultimately migration of cancer cells. In this context, mitochondrial ROS play a key role, leading to angiogenesis and metastasis [4] and promoting the migratory plasticity of cells through activation of two essential factors, Src and protein tyrosine kinase 2 [5]. The basic understanding of the dependence of cancer cells on various mitochondrial roles is already endorsing novel therapeutic approaches in cancer.

Along that line, an expanding group of evidences indicate that the mitochondrial genome is not only responsible for the synthesis of the canonical 13 proteins, 22 tRNAs and two ribosomal RNAs (12S and 16S). Novel and expanding evidence suggest that mtDNA compensates for reduced length by using little known phenomena that potentially increase DNA's protein coding repertoire, such as so called swinger polymerization, that consists of systematic exchanges between nucleotides during DNA or RNA polymerization, producing so-called swinger sequences [6, 7]. These transformations alter gene and mRNA coding properties. Moreover, in human mitochondria systematic deletions of mono- and dinucleotides after each trinucleotide have been reported, producing delRNAs. Recently, an exhaustive analysis of human nanoLc mass spectrometry peptidome data detect numerous tetra- and pentapeptides translated from the human mitogenome, and this peptide subgroup would be the result of the translation of delRNAs. Therefore, non-canonical transcriptions and translations could considerably expand the coding potential of mitochondrial DNA and RNA sequences [8, 9].

Finally, in the field of antisense RNAs and because mitochondrial tRNA mutations are 6.5 times more frequently pathogenic than in other mitochondrial sequences, a potential additional tRNA gene function is that of templating for antisense tRNAs. Most antisense tRNAs probably function routinely in translation and extend the tRNA pool and mutation pathogenicity, probably frequently resulting from a mixture of effects due to sense and antisense tRNA translational activity for many mitochondrial tRNAs [10, 11]. These could link to mitochondrial disorders and cancer.

This small but powerful organelle is also a novel source of noncoding RNAs (ncRNAs), and growing evidence shows that mammalian mitochondria can also import/export ncRNAs, turning this organelle into a pivotal player not only in cellular physiology but also in cancer, representing potential targets for innovative ncRNA-based treatment strategies [12].

In this chapter we discuss the importance of long noncoding mitochondrial RNAs (lncmtRNAs) in diagnostic and pharmaceutical targeting in cancer.
