Mitochondrial epigenetics: Effects beyond the nuclear genome

Mitochondria is one of the major cell organelles and since it is the hub of cellular respiration, this organelle is popularly termed as the powerhouse of the cell. 

Besides, accommodating cellular respiration, mitochondria is also home to many useful structural components like mitochondrial DNA (mtDNA). mtDNA is a special kind of DNA and unlike nuclear DNA, this one encodes genes that are vital for cellular bioenergetic processes. When there are two or more than two types of mtDNA genome, it leads to a serious condition called heteroplasmy.

By using DNA Extraction Kit, it is also been observed that the differences found in mitochondrial DNA give birth to pathogenic mutations which would generate a number of clinical phenotypes.  For instance, it is found in astoundingly high levels of RNA leucine [tRNALeu(UUR)] 3243A > G mutant. This condition is also found in perinatal lethality, degenerative disease, of course, diabetes.

Is healthy mitochondrial DNA the same as pathological DNA?

Although scientists could acquire a liberal amount of evidence, the varying clinical phenotypic conditions are still beyond anyone’s understanding. Considering how little there is to know, in PNAS, Kopinski et al, various studies on mtDNA are taking place. The major aim of these studies is to differentiate between the levels of mtDNA tRNA contained by normal mitochondrial DNA versus the pathological mtDNA tRNA. Such understanding is vital for mutation in a human bone and the hybrid model of osteosarcoma. 

 Because of this reason, scientists have created several cell lines, which have either 100% normal or regular mtDNA tRNA or other 100% pathogenic mtDNA homoplasies. By using these cell lines, various measures of metabolism were performed, including NAD+/NADH ratios, epigenetic changes in the nuclear genome. 

In addition, these homoplasmic and heteroplasmic cell lines also share the same nuclear genome, meaning every observed metabolic change is only because of the differences in mitochondrial genetics. (Fetterman & Ballinger, 2019, #)

How come mitochondria are energetic sites?

Since mitochondria accommodate cellular respiration, cells energy currency molecule i.e. ATP is also produced here. This respiration is called oxidative phosphorylation (OXPHOS),  as there is an addition of phosphorus in Adenosine diphosphate or ADP molecules. This entire process of oxidative phosphorylation is monitored by a couple of important biological molecules, the nuclear genomic DNA (gDNA) and the mitochondrial DNA (mtDNA). 

Besides, respiration mitochondria are also responsible for myriads of other body processes such as ageing, apoptosis and oxidative metabolism. Usually, the function of mitochondria varies with different types of tissues. 

Tissues with relatively high usage of energy, for instance, heart and brain, contain more mitochondria and that is why they are the tissues that are much more susceptible to the effects of aerobic metabolism. Any injury or damage to mitochondria leads to serious dysfunction, that contributes greatly to the pathogenesis of a number of diseases, including cancers and body disorders. 

What happens when mitochondria get infected or damaged?

Due to mitochondrial dysfunction rendered by either bacterial or viral invasion, pathogenic mtDNA is produced. This pathogenic mtDNA further induces defects in mitochondrial respiration and thus the ATP synthesis as well. 

Not too long ago, an immense degree of phenotypic variation has been observed and it is associated with various mitochondrial DNA mutations. However, these are not too easy to reconcile with the defects of oxidative phosphorylation. This implies that there must be some additional mechanisms that are contributing not just to the phenotype, but also to the epigenetic modifications. 

What is meant by epigenetic modification?

The epigenetic modifications are evidently one of the most important factors that monitor and affect gene expression. There are three major categories of epigenetic including the post-translational modification of proteins i.e. histone tails which are found in higher-order chromatin. Also, there is genomic DNA methylation and the regulation of gene expression by one of the most popular RNAs i.e. non-coding RNAs. 

Although Perturbed epigenetic mechanisms or modifications have been greatly associated with a number of human pathologies, there is still a great mystery about their role in human pathogenesis. 

The very significance of epigenome in human pathogenesis is as significant as any other grave disease, that affects the mechanism of epigenetics. As a matter of fact, current cancer studies also proved that defects in human mitochondria are greatly associated with epigenetic alteration inside the nuclear genome. (Jackson et al., 2012)

Bibliography

Fetterman, J. L., & Ballinger, S. W. (2019). Mitochondrial genetics regulate nuclear gene expression through metabolites. Proceedings of the national academy of sciences of the United States of America, 1(1), 15763-15765. https://www.pnas.org/content/116/32/15763

Jackson, D. N., Thesis, A. L., & Theiss, A. L. (2012, April 01). Mitochondrial regulation of epigenetics and its role in human diseases. Epigenetics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368816/