Aging, Environment, & DiseaseDNA Methylation and HydroxymethylationHistone Modifications

Mitochondrial epigenetics: Effects beyond the nuclear genome

 

From playing a role in heritable changes to somatic mutations, including associations with diet, exercise, and other lifestyle interventions, epigenetics is progressively becoming implicated in a wide variety of activities and diseases. While the role of epigenetics has been predominately thought of in terms of genomic DNA, a clear role for mitochondria in modulation of epigenetic changes is emerging.

Nuclear genes encode the majority of proteins required for the propagation and function of mitochondria. However, mitochondria also have a small portion of their own DNA, consisting of 37 genes, which are essential for normal mitochondrial function. Many of these genes are involved in oxidative phosphorylation, a process whereby a cells main energy source, ATP is created.

The epigenome is modulated by high-energy intermediates, such as ATP and acetyle-CoA. This suggests that the primary interface between the environment and the epigenome is the bioenergetic system, a key player of which is mitochondria. Until recently, scientists thought that mitochondria only played a role in epigenetics to the extent that they were able to modulate epigenetic mutations in nuclear DNA1. For instance, mitochondria are known to alter nuclear DNA methylation by influencing folate metabolism, leading to the subsequent generation of S-adenosylmethionine (SAM), an important methyl donor. Additionally, alterations in mitochondrial DNA (mtDNA) copy number have been shown to lead to hypo- and hypermethylation of several nuclear genes2.

While mtDNA methylation was first described several decades ago, it was not thought to be a process regularly carried out by mitochondria. This belief was held because mitochondria did not appear to contain histones, a major component of chromatin, and one of the primary sources for epigenetic alterations. Indeed it is this very absence, which was proposed to make mitochondrial mutations relatively common.  However, this idea has recently been unveiled as incorrect, as evidence now exists to show that some types of histones are found in the mitochondrial membrane, albeit at a significantly lower level than that found in the nucleus3. Evidence also suggests that other mitochondrial proteins play a similar role to nuclear histones, essentially forming their own equivalent to chromatin4. Importantly, it was the discovery of mtDNA methyltransferase enzyme 1 (mtDNMT1) and subsequent cytosine methylation in the mitochondria that lead to the realization that mtDNA methylation actively occurs in the mitochondria5. Moreover, dnmt3a, an enzyme involved in methylation, has recently been isolated from mitochondria from the CNS and cerebral cortex. Whereas dnmt1 has not been detected in mitochondria, it has been shown to associate with the outer membrane of the mitochondria, likely playing a similar regulatory role6.

Although it is has not yet been fully elucidated which epigenetic changes can be related specifically to epigenetic changes in the mitochondria, evidence for mitochondrial epigenetic changes currently exist for brain, liver, and muscle cells (beyond epigenetic associations with cancer). For example, SOD1 mice, which serve as a transgenic model of ALS, show the presence of cytosine methylation in mtDNA of adult mouse spinal cord and skeletal muscle, occurring in parallel with loss of myofiber mitochondria6. However, it is likely that these changes are more widespread than currently known, and technologies such as mtDNA-wide bisulphite sequencing will help to improve our understanding of this process.

As with epigenetic changes in nuclear DNA, it is becoming clear that epigenetic changes in mitochondrial DNA can be triggered by disease, aging, chronic stress, certain environmental exposures, and medication use7. For example, studies have shown that mtDNA methylation plays an important role in the molecular changes involved in the transition from steatosis to a more progressed form of liver disease known as steatohepatitis. Hepatic methylation and transcriptional activity of the mitochondrial-encoded NADH dehydrogenase 6 (MT-ND6) have been associated with histological severity of the disease8. Similarly, an increased level of demethylated sites in the D-loop of tumor cells has been strongly associated with increased MT-ND2 expression and mtDNA copy number9. Along with this, hypermethylation of mtDNA has been identified in multiple types of cancer, and has shown to alter mtDNA copy number10,11. Interestingly, most triggers of mitochondrial damage involve oxidative stress, which in itself has shown to influence expression of mitochondrial-encoded NADH dehydrogenase subunits, such as MT-ND312. Importantly, these results suggest that an amplifying feedback loop may exist for mitochondrial methylation.

Sirtuins, also known as class III histone deacetylases have been implicated in influencing longevity and in the development of neurodegenerative diseases. Sirtuins have well known effects on mitochondrial biogenesis, as well as oxidative phosphorylation. The first mitochondrial acetylated protein targeted by SIRT3 was recently identified as acetyl-CoA synthetase, indicating a regulatory role of protein acetylation in mitochondrial metabolism13,14. Although there is still much to be learned, it is likely that sirtuins will continue to be implicated in the epigenetic modifications of mitochondria in health and longevity.

Recently, mtDNA methylation status has been offered as a potential biomarker for the detection and diagnosis of certain diseases15. It will be interesting to see whether this plays a role in the newly passed bill in the United Kingdom allowing for a new method of in-vitro fertilization using a mitochdronial DNA surrogate in order to prevent transmission of mitochondrial disease to future offspring.

 

References

1. Wallace DC (2010). Colloquium paper: bioenergetics, the origins of complexity, and the ascent of man. Proceedings of the National Academy of Sciences of the United States of America, 107 Suppl 2, 8947-53 PMID: 20445102

2. Smiraglia, D., Kulawiec, M., Bistulfi, G., Ghoshal, S., & Singh, K. (2014). A novel role for mitochondria in regulating epigenetic modifications in the nucleus Cancer Biology & Therapy, 7 (8), 1182-1190 DOI: 10.4161/cbt.7.8.6215

3. Choi YS, Hoon Jeong J, Min HK, Jung HJ, Hwang D, Lee SW, & Kim Pak Y (2011). Shot-gun proteomic analysis of mitochondrial D-loop DNA binding proteins: identification of mitochondrial histones. Molecular bioSystems, 7 (5), 1523-36 PMID: 21359316

4. Manev H, Dzitoyeva S, & Chen H (2012). Mitochondrial DNA: A Blind Spot in Neuroepigenetics. Biomolecular concepts, 3 (2), 107-115 PMID: 22639700

5. Shock LS, Thakkar PV, Peterson EJ, Moran RG, & Taylor SM (2011). DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proceedings of the National Academy of Sciences of the United States of America, 108 (9), 3630-5 PMID: 21321201

6. Wong M, Gertz B, Chestnut BA, & Martin LJ (2013). Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS. Frontiers in cellular neuroscience, 7 PMID: 24399935

7. Iacobazzi V, Castegna A, Infantino V, & Andria G (2013). Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool. Molecular genetics and metabolism, 110 (1-2), 25-34 PMID: 23920043

8. Pirola CJ, Gianotti TF, Burgueño AL, Rey-Funes M, Loidl CF, Mallardi P, Martino JS, Castaño GO, & Sookoian S (2013). Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut, 62 (9), 1356-63 PMID: 22879518

9. Feng S, Xiong L, Ji Z, Cheng W, & Yang H (2012). Correlation between increased ND2 expression and demethylated displacement loop of mtDNA in colorectal cancer. Molecular medicine reports, 6 (1), 125-30 PMID: 22505229

10. Maekawa, M. (2004). Methylation of Mitochondrial DNA Is Not a Useful Marker for Cancer Detection Clinical Chemistry, 50 (8), 1480-1481 DOI: 10.1373/clinchem.2004.035139

11. Wen SL, Zhang F, & Feng S (2013). Decreased copy number of mitochondrial DNA: A potential diagnostic criterion for gastric cancer. Oncology letters, 6 (4), 1098-1102 PMID: 24137470

12. Wang HN, Chen HD, Chen KY, Xiao JF, He K, Xiang GA, & Xie X (2014). Highly expressed MT-ND3 positively associated with histological severity of hepatic steatosis. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, 122 (5), 443-51 PMID: 24020820

13. Hallows WC, Lee S, & Denu JM (2006). Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proceedings of the National Academy of Sciences of the United States of America, 103 (27), 10230-5 PMID: 16790548

14. Verdin E, & Ott M (2014). 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nature reviews. Molecular cell biology PMID: 25549891

15. Iacobazzi V, Castegna A, Infantino V, & Andria G (2013). Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool. Molecular genetics and metabolism, 110 (1-2), 25-34 PMID: 23920043

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Brandalyn Riedel

Brandalyn Riedel