Mitochondrial DNA: Epigenetics and environment

Abstract

Maintenance of the mitochondrial genome is essential for proper cellular function. For this purpose, mitochondrial DNA (mtDNA) needs to be faithfully replicated, transcribed, translated, and repaired in the face of constant onslaught from endogenous and environmental agents. Although only 13 polypeptides are encoded within mtDNA, the mitochondrial proteome comprises over 1500 proteins that are encoded by nuclear genes and translocated to the mitochondria for the purpose of maintaining mitochondrial function. Regulation of mtDNA and mitochondrial proteins by epigenetic changes and post-translational modifications facilitate crosstalk between the nucleus and the mitochondria and ultimately lead to the maintenance of cellular health and homeostasis. DNA methyl transferases have been identified in the mitochondria implicating that methylation occurs within this organelle; however, the extent to which mtDNA is methylated has been debated for many years. Mechanisms of demethylation within this organelle have also been postulated, but the exact mechanisms and their outcomes is still an active area of research. Mitochondrial dysfunction in the form of altered gene expression and ATP production, resulting from epigenetic changes, can lead to various conditions including aging-related neurodegenerative disorders, altered metabolism, changes in circadian rhythm, and cancer. Here, we provide an overview of the epigenetic regulation of mtDNA via methylation, long and short noncoding RNAs, and post-translational modifications of nucleoid proteins (as mitochondria lack histones). We also highlight the influence of xenobiotics such as airborne environmental pollutants, contamination from heavy metals, and therapeutic drugs on mtDNA methylation. Environ. Mol. Mutagen., 60:668-682, 2019. © 2019 Wiley Periodicals, Inc.

Keywords: mitochondrial epigenetics; mitochondrial post-translational modifications; mtDNA methylation; noncoding RNAs; xenobiotics.

Figure 1:

Overview of the epigenetic regulation of mtDNA. The 16.569 kbp mitochondrial genome is replicated from 2 origins O_H and O_L found 11 kb apart on the heavy and light strands, respectively. MtDNA encodes for 13 polypeptide sequences, 22 tRNAs, and 2 rRNAs whose transcription is controlled by the heavy strand promoters (HSP1 and HSP2) and the light strand promoter (LSP). Most of these control elements are present within the non-coding region, NCR. The main modifications that regulate gene expression (gene activation or silencing) within the mitochondria include DNA methylation (cytosine or adenine where 5mC is 5-methyl cytosine and 6mA is 6-methyl adenine), non-coding RNAs, and post-translational modifications of nucleoid proteins. In the post-translational modification panel of the figure, the crystal structure of TFAM bound to DNA is indicated (PDB ID:3TQ6, Rubio-Cosials et al. 2011) with the acetylation and phosphorylation sites within the high mobility group 1 domain highlighted by yellow, and red spheres, respectively. The dotted arrow indicates an outcome that is hypothesized for which there is no current evidence. In the non-coding RNA panel, black arrows are representative of cellular processes, green arrows indicate increased regulation, red arrow represents a decrease in regulation, and inhibition is represented with a red line.

Figure 2:

Potential pathways of (de)methylation of cytosine and adenine. A) DNA methyltransferase (DNMT) enzymes 1, 3a, and 3b convert C to 5mC. Oxidation of 5mC by the TET enzymes results in 5hmC, 5fC, and 5caC; in the nucleus, the monofunctional TDG recognizes and catalyzes the removal of 5fC or 5caC, and the resulting abasic sites are converted to cytosine by NEIL-mediated BER. Other possibilities to restore the original cytosine base include active deamination of 5mC, 5hmC, 5fC and 5caC by AID or APOBEC3 to yield thymine, 5hmU, 5fU, and 5caU, respectively, which are excised by a DNA glycosylase and reverted to cytosine by BER. Given that several glycosylases have overlapping substrate preferences, MBD4, NEIL1, NEIL2, NTHL1, TDG, or SMUG1 can facilitate the repair of the deaminated bases. In the mitochondria given that TDG, SMUG1, and MBD4 are not present, 5mC that is deaminated to T yielding a T-G mispair can be repaired via mismatch repair, but this remains unknown (dotted red line). B) In the nucleus, A can be methylated to 6mA by N6AMT1/METTL4, and this process can be reversed by the ALKBH1/4 demethylases. N6-hydroxymethyladenine (6hmA) can also be formed by the oxidation of 6mA by ALKBH1, which may be converted to A via a mechanism that is yet unknown (dotted red line). Proteins that are underlined have been observed in the mitochondria.