Mitoepigenetics and gliomas: epigenetic alterations to mitochondrial DNA and nuclear DNA alter mtDNA expression and contribute to glioma pathogenicity

Abstract

Epigenetic mechanisms allow cells to fine-tune gene expression in response to environmental stimuli. For decades, it has been known that mitochondria have genetic material. Still, only recently have studies shown that epigenetic factors regulate mitochondrial DNA (mtDNA) gene expression. Mitochondria regulate cellular proliferation, apoptosis, and energy metabolism, all critical areas of dysfunction in gliomas. Methylation of mtDNA, alterations in mtDNA packaging via mitochondrial transcription factor A (TFAM), and regulation of mtDNA transcription via the micro-RNAs (mir 23-b) and long noncoding RNAs [RNA mitochondrial RNA processing (RMRP)] have all been identified as contributing to glioma pathogenicity. Developing new interventions interfering with these pathways may improve glioma therapy.

Keywords: epigenetics; glioblastoma; glioma; methylation; mitochondria; mitoepigenetics; mtDNA; noncoding RNA.

Figure 1

Epigenetic alterations affecting mitochondrial DNA expression in glioblastoma. Methylation of nDNA genes POLG and TOPIMT reduces production of Polymerase γ and Topoisomerase proteins and decreases transport and availability in the mitochondria (anterograde signaling). MiR-23b transcription is reduced in gliomas, increasing the expression of TFAM within the nucleus. Transport of IncRNA RMRP to the mitochondria is increased. Reduced Polymerase γ and Topoisomerase and elevated TFAM and RMRP alter mtDNA copy number and gene expression. Decreases in mtDNA copy number can signal epigenetic modifications of nDNA within the cell nucleus (retrograde signaling). Ultimately, these epigenetic modifications result in reduced oxidative phosphorylation capabilities in the mitochondria. In response, the stem cell adopts glycolytic metabolism and a proliferative glioblastoma phenotype.