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Mitoepigenetics and Its Emerging Roles in Cancer

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Review

Mitoepigenetics and Its Emerging Roles in Cancer

Zhen Dong et al. Front Cell Dev Biol.

Abstract

In human beings, there is a ∼16,569 bp circular mitochondrial DNA (mtDNA) encoding 22 tRNAs, 12S and 16S rRNAs, 13 polypeptides that constitute the central core of ETC/OxPhos complexes, and some non-coding RNAs. Recently, mtDNA has been shown to have some covalent modifications such as methylation or hydroxylmethylation, which play pivotal epigenetic roles in mtDNA replication and transcription. Post-translational modifications of proteins in mitochondrial nucleoids such as mitochondrial transcription factor A (TFAM) also emerge as essential epigenetic modulations in mtDNA replication and transcription. Post-transcriptional modifications of mitochondrial RNAs (mtRNAs) including mt-rRNAs, mt-tRNAs and mt-mRNAs are important epigenetic modulations. Besides, mtDNA or nuclear DNA (n-DNA)-derived non-coding RNAs also play important roles in the regulation of translation and function of mitochondrial genes. These evidences introduce a novel concept of mitoepigenetics that refers to the study of modulations in the mitochondria that alter heritable phenotype in mitochondria itself without changing the mtDNA sequence. Since mitochondrial dysfunction contributes to carcinogenesis and tumor development, mitoepigenetics is also essential for cancer. Understanding the mode of actions of mitoepigenetics in cancers may shade light on the clinical diagnosis and prevention of these diseases. In this review, we summarize the present study about modifications in mtDNA, mtRNA and nucleoids and modulations of mtDNA/nDNA-derived non-coding RNAs that affect mtDNA translation/function, and overview recent studies of mitoepigenetic alterations in cancer.

Keywords: cancer; mitoepigenetics; mtDNA methylation; mtRNA modification; non-coding RNAs.

Figures

FIGURE 1
FIGURE 1
The mtDNA and the processing and function of its encoding genes in the mitochondria. mtDNA with 16,569 nucleotides encodes 22 tRNAs, 2 rRNAs, 13 peptides that constitutes the ETC/OxPhos, and some non-coding RNAs. A, mt-tRNAAla; C, mt-tRNACys; D, mt-tRNAAsp; E, mt-tRNAGlu; F, mt-tRNAPhe; G, mt-tRNAGly; H, mt-tRNAHis; I, mt-tRNAIle; K, mt-tRNALys; L(CUN), mt-tRNALeu(CUN); L(UUR), mt-tRNALeu(UUR); M, mt-tRNAMet; N, mt-tRNAAsn; P, mt-tRNAPro; Q, mt-tRNAGln; R, mt-tRNAArg; S(AGY), mt-tRNASer(AGY); S(UCN), mt-tRNASer(UCN); T, mt-tRNAThr; V, mt-tRNAVal; W, mt-tRNATrp; Y, mt-tRNATyr; ATP6/8, Mitochondrially encoded ATP synthase membrane subunit 6/8; CoQ, Coenzyme Q; COX1/2/3, Mitochondrially encoded cytochrome C oxidase I/II/III; Cytb, Cytochrome b; Cytc, Cytochrome c; ETC, Electron transport chain; FAD, Flavine adenine dinucleotide; FADH2, Flavine adenine dinucleotide, reduced; HSP1/2, H-strand promotor 1/2; H-strand, Heavy strand; LSP, L-strand promotor; L-strand, Light strand; NAD+, Nicotinamide adenine dinucleotide; NADH, Nicotinamide adenine dinucleotide, reduced; ND1/2/3/4/4L/5/6, Mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1/2/3/4/4L/5/6; OL, L-strand origin of replication; OH, H-strand origin of replication; OxPhos, Oxidative phosphorylation.
FIGURE 2
FIGURE 2
DNA methylation and active demethylation. DNA can be methylated by DNMTs and demethylated by active demethylation through oxidizing, deaminating and base-excision repair. Enzymes were marked in green, metabolites were marked in blue, while biological process like BER was marked in red. 5caC, 5-Carboxylcytosine; 5fC, 5-Formylcytosine; 5hmC, 5-Hydroxymethylcytosine; 5hmU, 5-Hydroxymethyluracil; 5-AID, activation induced cytidine deaminase; APOBEC, Apolipoprotein B mRNA editing enzyme catalytic subunit; BER, Base-excision repair; DNMT1/3A/3B, DNA methyltransferase 1/3A/3B; MBD4, Methyl-CpG binding domain 4, DNA glycosylase; NEIL1, Nei like DNA glycosylase 1; SMUG1, Single-strand-selective monofunctional uracil-DNA glycosylase 1; TET1/2/3, Tet methylcytosine dioxygenase 1/2/3; C, Cytosine; TDG, Thymine DNA glycosylase; Thy, Thymine.
FIGURE 3
FIGURE 3
The dynamics of TFAM controlled mitochondrial nucleoid and the constitutions of nucleiod. TFAm can directly bind to mtDNA and functions as a histone-like protein. Its degradation is mediated by LONP1, an AAA + Lon protease. There are more than 50 nucleoid-associated proteins including POLRMT, TFAM, TFB2M and TEFM that initiate the mtDNA transcription, and POLG, Twinkle and mtSSB that initiate the mtDNA replication. There are also some proteins that are related to RNA processing and nucleoid regulation. ANT, Adenine nucleotide translocator; ATAD3, ATPase family AAA domain containing 3; ClpXp, ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial; FASTKD2, FAST kinase domains 2; HSP60, Short heat shock protein 60; LONP1, Lon peptidase 1, mitochondrial; M19, Mitochondrial protein M19; mtSSB, Single-stranded DNA binding protein 1, mitochondrial; POLG, DNA polymerase gamma; POLRMT, RNA polymerase mitochondrial; SUV3, ATP-dependent RNA helicase SUV3, mitochondrial; TEFM, Transcription elongation factor, mitochondrial; TFAM, Transcription factor A, mitochondrial; TFB2M, Transcription factor B2, mitochondrial.
FIGURE 4
FIGURE 4
Non-coding RNAs encoded by the mtDNA identified by four different research groups. (A) ncRNAs obtained from the UCSC Genome Bioinformatics (2016 version). (B) lncRNAs identified by Rackham et al., 2011. (C) lncRNAs indented by researchers from Fundación Ciencia para la Vida, Chile. (D) ncRNAs identified by using PacBio full-length transcriptome data.
FIGURE 5
FIGURE 5
Types of Mitoepigenetics and their functions. Mitoepigenetics constitutes with four different types, including mtDNA modifications, nucleoid modifications, mtRNA modifications, and non-coding RNA modulations. Ac, acetylation; D, Dihydrouridine; f5C, 5-Formylcytosine; 5hmC 5-Hydroxymethylcytosine; 5mC, 5-methylcytosine; i6A, N6-Isopentenyladenosine; m1A, 1-Methyladenosine; m1G, 1-Methylguanosine; m2G, N2-Methylguanosine; m22G, N2,N2-Dimethylguanosine; m3C, 3-Methylcytosine; m4C, N4-Methylcytosine; m5C, 5-Methylcytosine; m5U, 5-Methyluridinep; m6A, N6-Methyladenosine; m62A, N6,N6-Dimethyladenosine; ms2i6A, 2-Methylthio-N6-isopentenyladenosine; P, phosphorylation; Ψ, Pseudouridine; Q, Queosine; t6A, N6-Threonylcarbamoyladenosine; TFAM, Transcription factor A, mitochondrial; τm5U, 5-Taurinomethyluridin; τm5s2U, 5-Taurinomethyl-2-thiouridine, Ub, Ubiquitination.

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