Little evidence for mitochondrial DNA methylation

This 2018 Japanese rodent study used three different techniques to detect mitochondrial DNA methylation:

“Whilst 5-methylcytosine (5mC) is a major epigenetic mark in the nuclear DNA in mammals, whether or not mitochondrial DNA (mtDNA) receives 5mC modification remains controversial.

We used bisulfite sequencing, McrBC digestion analyses and liquid chromatography mass spectrometry, which are distinctly differing methods for detecting 5mC..we analysed mtDNAs from mouse ESCs [embryonic stem cells] and from mouse liver and brain tissues.

Taken together, we propose that 5mC is not present at any specific region(s) of mtDNA and that levels of the methylated cytosine are fairly low, provided the modification occurs. It is thus unlikely that 5mC plays a universal role in mtDNA gene expression or mitochondrial metabolism.”


Bisulfite sequencing infers the presence of CpG (CG above) and non-CpG (CH above) methylation through unconverted residues:

“Synthetic and native mtDNA gave similar patterns, suggesting that the resistance of cytosines to bisulfite conversion is not due to methylation.”


It seems that epigenetic changes to mitochondrial DNA occur primarily through histone modifications. Lysine acetylation is gnarly and dynamic is one paper that detailed aspects of this functionality in mitochondria.

https://www.nature.com/articles/s41598-018-24251-z “Accurate estimation of 5-methylcytosine in mammalian mitochondrial DNA”

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