A novel role for mitochondria in regulating epigenetic modifications in the nucleus

Abstract

Epigenetic modification in the nuclear genome plays a key role in human tumorigenesis. In this paper, we investigated whether changes in the mtDNA copy number frequently reported to vary in a number of human tumors induce methylation changes in the nucleus. We utilized the Restriction Landmark Genomic Scanning (RLGS) to identify genes that undergo changes in their methylation status in response to the depletion and repletion of mtDNA. Our study demonstrates that depletion of mtDNA results in significant changes in methylation pattern of a number of genes. Furthermore, our study suggests that methylation changes are reversed by the restoration of mtDNA in cells otherwise lacking the entire mitochondrial genome. These studies provide the first direct evidence that mitochondria regulate epigenetic modification in the nucleus that may contribute to tumorigenesis.

Mitochondrial regulation of epigenetics and its role in human diseases

“…One of the regions looked at further in this study was the aberrant promoter methylation of the BC030713 mRNA transcript that had been previously identified using RLGS. 5,85 The study showed that the 5' UTR comprising a CpG island was partially hypo/unmethylated in 143B rho 0 compared with the parental cell line that was completely hypermethylated at this region. The study concluded that this partial loss of genomic DNA methylation could be associated with the loss of mitochondrial DNA (mtDNA) and the mitochondria itself; 5 however, it does not disqualify a perturbed genome-wide methylation profile.…”

“…5,33,34 Epigenetic modifications are known to regulate gene expression either in a permanent or transient manner. 35 These epigenetic mechanisms that alter the rate of gene expression without actually changing the physical sequence of nuclear encoded genomic DNA are categorized into three broad groups.…”

“…The functional state of mitochondria in human cells and the response to spontaneous or induced mtDNA or mitochondrial Smiraglia et al 5 developed and studied cells that were void of functional mitochondria (rho 0 cells), enabling them to gain an insight into the possible role mitochondria might have in regulating or being associated with epigenetic alterations of the nuclear genome in a gene specific or genome-wide manner, particularly at the level of DNA methylation. Depletion of the mitochondrial genome in both chemically generated MCF12A rho 0 or genetically modified 143B rho 0 cell lines resulted in the aberrant methylation of promoter CpG islands (high CG-rich regions), 84 that were previously unmethylated in the parental cell line, 5 measured using restriction landmark genomic scanning (RLGS).…”

Detouring of cisplatin to access mitochondrial genome for overcoming resistance

“…The close proximity of mtDNA to the ROS production site makes this genome vulnerable to oxidative damage. Mitochondrial dysfunction and associated mtDNA depletion possibly reversibly control epigenetic changes in the nucleus that contributes to cancer development (1). Thus, targeting mtDNA could lead to novel and effective therapies for aggressive cancers.…”

Adenine nucleotide translocase family: four isoforms for apoptosis modulation in cancer

“…No information regarding the submitochondrial localization of ANT3 and ANT4 are available to date. In addition, differences in the epigenetic modification of ANT isoformes in cancer could help to better understand the differential roles of the isoforms as discussed for other mitochondrial proteins (Smiraglia et al, 2008). Hence, a complete elucidation of the complex interplay of the various ANT isoforms in cancer cells might have crucial implications for a better understanding of the bioenergetic metabolism of cancer cells and the design of novel mitochondrial-targeted anticancer therapies (Fulda et al, 2010).…”