Correlation between increased ND2 expression and demethylated displacement loop of mtDNA in colorectal cancer

Abstract

Abstract. Change in cellular glucose metabolism is considered to be a biochemical hallmark in cancer cells. The mitochondrion is the key organelle in which glucose metabolism occurs. However, whether DNA methylation at the displacement loop (D-loop) region of mitochondrial DNA (mtDNA) has an effect on the expression of the rate-limiting enzyme, and, therefore, on oxidative phosphorylation in colorectal cancer remains to be determined. Quantitative change in ND2 (a subunit of NADH) and the methylation status of the D-loop were observed during the initiation and progression of colorectal cancer. Furthermore, the possible correlations with clinicopathological stage were also investigated. Tumor and corresponding non-cancerous tissues were surgically resected from 44 colorectal cancer patients between 2008 and 2009. Cox IV expression was quantified in all of the specimens, and the ND2 expression was calculated. Quantitative changes in ND2 expression exhibited a significant increase. The average relative ratios of ND2 content were 1.67±0.44 in the tumor tissues and 0.89±0.44 in the corresponding non-cancerous tissues (p<0.01). In addition, the D-loop of most corresponding non-cancerous tissues was methylated and the percentage was 79.5%, while this percentage was much smaller in the tumor tissues (11.4%). Following correlation with clinicopathological data, changes in the ND2 expression in the colorectal cancer exhibited a significant association with clinicopathological stage. This increase was significant as early as in stage Ⅰ. Furthermore, the ratios of unmethylated D-loop cases were increased in both tumor and corresponding non-cancerous tissues, and the ND2 expression was also increased from stages Ⅰ to Ⅳ. Our results indicate that demethylation of the D-loop plays a key role in regulating ND2 expression during the initiation and/or progression of colorectal cancer.

The Mitochondrial Epigenome: a Role in Alzheimer’s Disease?

“…The majority of studies have focused on diseases where mitochondrial dysfunction is known to be prevalent, for example in cancer, which has been previously linked with mitochondrial dysfunction [48] and more recently in Down's syndrome, where mitochondrial abnormalities have also been reported [49]. Particularly, for the purpose of this review, mitochondrial dysfunction and mtDNA methylation aberrations in Down's syndrome cells (see Table 1) are interesting given that these patients have an increased likelihood of presenting with AD-like phenotypes throughout aging [50,51] due to possessing an extra copy of APP .…”

Effects of Air Pollution and Blood Mitochondrial DNA Methylation on Markers of Heart Rate Variability

“…Effects of air pollution on mtDNA damage, including copy number variation,7 8‐hydroxy‐2′‐deoxyguanosine formation,8 and heteroplasmy,9 have been reported in human and animal studies. Recently, DNA methylation machinery was found in mitochondria,10 and mtDNA methylation levels have been shown to be associated with mitochondrial gene expression,11 which suggests possible roles for mtDNA methylation in controlling mitochondrial functions and biogenesis. Indeed, mtDNA methylation levels in platelets show a significant difference between CVD patients and healthy persons 12…”

Environmental exposure and mitochondrial epigenetics: study design and analytical challenges

“…Mitochondrial DNA methylation, by means of 5-methylcytosine and 5-hydroxymethylcytosine, has been increasingly well established and has led to several disease related studies (Iacobazzi et al 2013), such as those into neuroepigenetics (Chestnut et al 2011; Manev et al 2012), aging (Dzitoyeva et al 2012), and cervical cancer (Sun et al 2011). While Kanno et al indicated that mtDNA methylation is not useful as a marker for the detection of cancer due to the lack of methylated DNA (Maekawa et al 2004), Yang et al found that decreased methylation on the D-loop promoter area plays a key role in regulating NADH dehydrogenase 2 (ND2) expression during the initiation and/or progression of colorectal cancer (Feng et al 2012). Control regions in the D-loop in mitochondrial DNA show unusual CpG and non-CpG methylation patterns (Bellizzi et al 2013).…”