Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes
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REVIEW
Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes Amanda F. C. Lopes1,2*
Abstract Mitochondria are controlled by the coordination of two genomes: the mitochondrial and the nuclear DNA. As such, variations in nuclear gene expression as a consequence of mutations and epigenetic modifications can affect mito‑ chondrial functionality. Conversely, the opposite could also be true. However, the relationship between mitochondrial dysfunction and epigenetics, such as nuclear DNA methylation, remains largely unexplored.Mitochondria function as central metabolic hubs controlling some of the main substrates involved in nuclear DNA methylation, via the one carbon metabolism, the tricarboxylic acid cycle and the methionine pathway. Here, we review key findings and highlight new areas of focus, with the ultimate goal of getting one step closer to understanding the genomic effects of mitochondrial dysfunction on nuclear epigenetic landscapes. Keywords: DNA methylation, Nucleus, Mitochondria, Metabolism, DNA, Haplogroups Background Mitochondrial diseases and population prevalence
Mitochondria display the distinctive feature of being the only mammalian cellular organelle containing an independent genome, the mitochondrial DNA (mtDNA). This DNA can be found in different copy numbers depending on the cell and tissue type, rendering mtDNA as polyplasmic. Quantities can range from around 1 03 to 104 genomes per cell, yet still only representing 1% of the total cellular DNA [1]. Mammalian mtDNA is a circular double-stranded molecule of approximately 16.6 kb in size [1] that encodes only 37 genes, 13 of which are respiratory chain subunits and 24 being RNA components, such as tRNAs and rRNAs [1, 2]. It is estimated that mitochondria contain approximately 1500 different proteins, indicating that the vast majority of these *Correspondence: amanda.lopes@mrc‑mbu.cam.ac.uk 1 Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK Full list of author information is available at the end of the article
are being encoded by the nuclear genome and imported into mitochondria [1]. Pathogenic mutations can occur in both nuclear DNA (nDNA) and mtDNA, with the mitochondrial genome presenting a mutational rate 100 fold higher than that of the nuclear genome, in turn leading to the heterogenous nature of inheritance of mitochondrial diseases [3]. Varying disease penetrance, as well as the occurrence and accumulation of spontaneous mutations in either genomes, contributes to an ever-expanding phenotypic spectrum [3]. Together, the variance in clinical expression and the multisystemic nature of these diseases has led to poor diagnosis and prognosis of mitochondrial diseases. These disorders cause significant morbidity and mortality, with a total of 1 in 4300 adults presenting with a mitochondrial ailment, and with these conditions being among the commonest inherited forms of neurological diseases [3].
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