title: Experimental mitochondria-targeted DNA methylation identifies GpC methylation, not CpG methylation, as potential regulator of mitochondrial gene expression.
abstract: Like the nucleus, mitochondria contain their own DNA and recent reports provide accumulating evidence that also the mitochondrial DNA (mtDNA) is subjective to DNA methylation. This evidence includes the demonstration of mitochondria-localised DNA methyltransferases and demethylases, and the detection of mtDNA methylation as well as hydroxymethylation. Importantly, differential mtDNA methylation has been linked to aging and diseases, including cancer and diabetes. However, functionality of mtDNA methylation has not been demonstrated. Therefore, we targeted DNA methylating enzymes (modifying cytosine in the CpG or GpC context) to the mtDNA. Unexpectedly, mtDNA gene expression remained unchanged upon induction of CpG mtDNA methylation, whereas induction of C-methylation in the GpC context decreased mtDNA gene expression. Intriguingly, in the latter case, the three mtDNA promoters were differentially affected in each cell line, while cellular function seemed undisturbed. In conclusion, this is the first study which directly addresses the potential functionality of mtDNA methylation. Giving the important role of mitochondria in health and disease, unravelling the impact of mtDNA methylation adds to our understanding of the role of mitochondria in physiological and pathophysiological processes.
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.
authors.forename: Monique G P
authors.initials: MG
authors.lastname: van der Wijst
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.
authors.forename: Amanda Y
authors.initials: AY
authors.lastname: van Tilburg
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.
authors.forename: Marcel H J
authors.identifier: 0000-0001-8305-0182
authors.initials: MH
authors.lastname: Ruiters
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713, GZ, Groningen, The Netherlands. m.g.rots@umcg.nl.
authors.forename: Marianne G
authors.initials: MG
authors.lastname: Rots
mesh_terms: D002460:Cell Line; D019175:DNA Methylation; D004272:DNA, Mitochondrial / Q000737:chemistry* / Q000235:genetics; D020862:GC Rich Sequence; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins