Mitochondrial DNA Hypomethylation Is a Biomarker Associated with Induced Senescence in Human Fetal Heart Mesenchymal Stem Cells

Abstract

Background. Fetal heart can regenerate to restore its normal anatomy and function in response to injury, but this regenerative capacity is lost within the first week of postnatal life. Although the specific molecular mechanisms remain to be defined, it is presumed that aging of cardiac stem or progenitor cells may contribute to the loss of regenerative potential. Methods. To study this aging-related dysfunction, we cultured mesenchymal stem cells (MSCs) from human fetal heart tissues. Senescence was induced by exposing cells to chronic oxidative stress/low serum. Mitochondrial DNA methylation was examined during the period of senescence. Results. Senescent MSCs exhibited flattened and enlarged morphology and were positive for the senescence-associated beta-galactosidase (SA-β-Gal). By scanning the entire mitochondrial genome, we found that four CpG islands were hypomethylated in close association with senescence in MSCs. The mitochondrial COX1 gene, which encodes the main subunit of the cytochrome c oxidase complex and contains the differentially methylated CpG island 4, was upregulated in MSCs in parallel with the onset of senescence. Knockdown of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3B) also upregulated COX1 expression and induced cellular senescence in MSCs. Conclusions. This study demonstrates that mitochondrial CpG hypomethylation may serve as a critical biomarker associated with cellular senescence induced by chronic oxidative stress.

Understanding metabolic changes in aging bone marrow

“…Perturbations of the β-oxidation pathway are known to occur by way of intrinsic (biological aging) and extrinsic factors (toxins) [ 20 – 22 ]. We found an up-regulation of several mitochondrial electron transport genes in the transcriptome of old bone marrow in agreement with increased expression of electron transport genes of mtDNA with aging [ 23 , 24 ]. Disruptions of the electron transport chain in mitochondria can generate reactive oxygen species (ROS), which in turn may cause further deterioration of mitochondrial function, generating an amplifying feedback loop [ 22 ].…”

Mitochondrial peptides modulate mitochondrial function during cellular senescence

“…4A ). We recently reported that several mtDNA CpG sites were methylated during senescence [ 54 ]. Here, we examined the methylation status of CpG sites 1, 2 and 4 in doxorubicin-induced senescence.…”

Markers of T Cell Senescence in Humans

“…Mitochondria can be affected by cellular senescence in several aspects such as caveolin-1 deficiency, which has been shown to induce cellular senescence by affecting the functionality of the mitochondria [ 93 ]. The other aspect is mitochondrial DNA hypomethylation, which is a feature of induced senenscence in human fetal heart mesenchymal stem cells and can be induced by reactive oxidative species [ 94 ]. Lipid and nicotinamide (NAD) metabolism are also two other features of mitochondria that could be associated with cellular senescence as they are correlated with age-related diseases [ 95 , 96 , 97 , 98 ] Besides mitochondria, studies have investigated at the RNA level and assessed the role of non-coding RNA (i.e., micro RNAs, long noncoding RNAa and circular RNAs) with cellular senescence in aging organs/tissue.…”