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.
Highlights
Epigenetics is the study of mitotically and/or meiotically heritable phenotype alterations that do not entail a change in DNA sequence (Wu and Morris, 2001)
Intra-mitochondrial influencing factors include mutations in the mitochondrial DNA (mtDNA). Most of these mutations in mtDNA do not inhibit energy metabolism in mitochondria but rather change the mitochondrial bioenergetic and biosynthetic state, which can communicate with the nucleus via modulating signaling pathways, transcriptional circuits and/or chromatin structural remodeling to meet the requirements of the cancer cells (Wallace, 2012)
5mC in the 12S rRNA (MT-RNR1) or the displacement loop (D-loop) control region of mtDNA is positively correlated with the level of free thyroid hormones (FT3 and FT4) and mitochondrial DNA copy numbers regulated by these two hormones (Janssen et al, 2017)
Summary
Epigenetics is the study of mitotically and/or meiotically heritable phenotype alterations that do not entail a change in DNA sequence (Wu and Morris, 2001). Mitoepigenetics comprises of four levels: mtDNA methylation/hydroxylmethylation, mitochondrial nucleoid modifications, mtRNA modifications, and mtDNA-derived or nDNA-derived non-coding RNA modulations during mtDNAencoded gene translation/function. PolyA in the 3 -termini can mediate the stability or instability of the transcript possibly depending on additional polyA-binding factors or sequence-specific proteins, which may affect the translation of mt-DNA-encoded genes (Rorbach and Minczuk, 2012).
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