[Frontiers in Bioscience, Landmark, 22, 888-908, January 1, 2017]

Mitochondrial genome and epigenome: two sides of the same coin

Patrizia D’Aquila 1 , Alberto Montesanto 1 , Francesco Guarasci 1 , Giuseppe Passarino 1 , Dina Bellizzi1 1

1Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. mtDNA features
    3.1. The mitochondrial genome: structure, replication and transcription
    3.2. Genetics of mtDNA
4. Mitochondrial DNA epigenetics
    4.1. Mitochondrial DNA methylation and hydroxymethylation
5. mtDNA methylation as biomarker of aging and diseases
    5.1. mtDNA methylation and environmental exposures
    5.2. mtDNA methylation and aging
    5.3. mtDNA methylation and diseases
6. Conclusions and future perspectives
7. Acknowledgement
8. References

1. ABSTRACT

The involvement of mitochondrial content, structure and function as well as of the mitochondrial genome (mtDNA) in cell biology, by participating in the main processes occurring in the cells, has been a topic of intense interest for many years. More specifically, the progressive accumulation of variations in mtDNA of post-mitotic tissues represents a major contributing factor to both physiological and pathological phenotypes. Recently, an epigenetic overlay on mtDNA genetics is emerging, as demonstrated by the implication of the mitochondrial genome in the regulation of the intracellular epigenetic landscape being itself object of epigenetic modifications. Indeed, in vitro and population studies strongly suggest that, similarly to nuclear DNA, also mtDNA is subject to methylation and hydroxymethylation. It follows that the mitochondrial-nucleus cross talk and mitochondrial retrograde signaling in cellular properties require a concerted functional cooperation between genetic and epigenetic changes. The present paper aims to review the current advances in mitochondrial epigenetics studies and the increasing indication of mtDNA methylation status as an attractive biomarker for peculiar pathological phenotypes and environmental exposure.

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Abbreviations: 5-hmC: Cytosine hydroxymethylation, 5-mC: Cytosine methylation, AD: Alzheimer Disease, ALS: Amyotrophic Lateral Sclerosis, COI-III: Cytochrome c oxidase subunits I-III, CSBI-III: Conserved Sequence Blocks I-III, CVD: CardioVascular Disease, Cytb: Cytochrome b, DNMT: DNA MethylTransferase, DS: Down Syndrome, ES cells: Embryonic Stem cells, GSS: Gene Start Site, hMe-DIP: h5-mC immunoprecipitation, HSP: Heavy-Strand Promoter, HVRI-II: Hyper Variable Region I and II, LC-ESI-MS: Liquid chromatography-electrospray ionization tandem mass spectrometry, LSP: Light-Strand Promoter, Me-DIP: 5-mC immunoprecipitation, MT-ATP6: ATP synthase F0 subunit6, MT-ATP8: ATP synthase F0 subunit8, mtDNA: Mitochondrial DNA, mTERF: Mitochondrial Transcription Termination Factor 1, MT-ND1: NADH dehydrogenase subunit1, MT-ND4: NADH dehydrogenase subunit4, MT-ND4L: NADH dehydrogenase subunit4L, MT-ND5: NADH dehydrogenase subunit5, MT-ND6: NADH dehydrogenase subunit6, MT-RNR1:12S Ribosomal RNA, MT-RNR2:16S ribosomal RNA, mtSSB: Mitochondrial Single-Stranded Binding proteins, MT-TF: tRNA Phenylalanine, mitochondrial-encoded, MT-TL1: tRNA Leucine 1, mitochondrial-encoded, NASH: Nonalcoholic fatty liver disease, NGS: Next Generation Sequencing, OXPHOS: Oxidative Phosphorylation, PCOS: PolyCystic Ovarian Syndrome, PD: Parkinson Disease, PM: Particulate Matter, POLG: Mitochondrial DNA Polymerase Gamma, POLRMT: Mitochondrial RNA Polymerase, RFLP: Restriction Fragment Length Polymorphism, RITOLS: RNA Incorporated Throughout the Lagging Strand, ROS: Reactive Oxidative Species, rRNA: Ribosomal RNA, SDM: Strand-Displacement Model, SS: Simple Steatosis, TET:Ten-Eleven Traslocation (TET) enzyme, TFAM: Mitochondrial Transcription Factor A, TFB1M: Mitochondrial Transcription Factor B1, TFB2M: Mitochondrial Transcription Factor B2, tRNA: Trasfer RNA, VPA: Sodium Valproate

Key Words: mtDNA Genetics, mtDNA Epigenetics, mtDNA Methylation, mtDNA Hydroxymethylation, Aging, Diseases, Environmental Factors, Review

Send correspondence to: Dina Bellizzi, Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy, Tel: 390984492930, Fax: 39098493601, E-mail: dina.bellizzi@unical.it