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Effect of Low-Dose Ionizing Radiation on the Expression of Mitochondria-Related Genes in Human Mesenchymal Stem Cells.

ABSTRACT: The concept of hormesis describes a phenomenon of adaptive response to low-dose ionizing radiation (LDIR). Similarly, the concept of mitohormesis states that the adaptive program in mitochondria is activated in response to minor stress effects. The mechanisms of hormesis effects are not clear, but it is assumed that they can be mediated by reactive oxygen species. Here, we studied effects of LDIR on mitochondria in mesenchymal stem cells. We have found that X-ray radiation at a dose of 10 cGy as well as oxidized fragments of cell-free DNA (cfDNA) at a concentration of 50 ng/mL resulted in an increased expression of a large number of genes regulating the function of the mitochondrial respiratory chain complexes in human mesenchymal stem cells (MSC). Several genes remained upregulated within hours after the exposure. Both X-ray radiation and oxidized cfDNA resulted in upregulation of FIS1 and MFN1 genes, which regulated fusion and fission of mitochondria, within 3-24 h after the exposure. Three hours after the exposure, the number of copies of mitochondrial DNA in cells had increased. These findings support the hypothesis that assumes oxidized cell-free DNA as a mediator of MSC response to low doses of radiation.

SUBMITTER: Kostyuk SV

PROVIDER: S-EPMC8745621 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mitochondria are highly dynamic organelles that respond rapidly to a number of stressors to regulate energy transduction, cell death signaling, and reactive oxygen species generation. We hypothesized that mitochondrial remodeling, comprising both structural and functional alterations, following ionizing radiation (IR) may underlie some of the tenets of radiobiology. Mesenchymal stem cells (MSCs) are precursors of bone marrow stroma and are altered in acute myeloid leukemia and by radiation and chemotherapy. Here, we report on changes in mitochondrial remodeling in human MSCs following X-ray IR. Mitochondrial function was significantly increased in MSCs 4 h after IR as measured by mitochondrial oxygen consumption. Consistent with this elevated functional effect, electron transport chain supercomplexes were also increased in irradiated samples. In addition, mitochondria were significantly, albeit modestly, elongated, as measured by high-throughput automated confocal imaging coupled with automated mitochondrial morphometric analyses. We also demonstrate in fibroblasts that mitochondrial remodeling is required for the adaptation of cells to IR. To determine novel mechanisms involved in mitochondrial remodeling, we performed quantitative proteomics on isolated mitochondria from cells following IR. Label-free quantitative mitochondrial proteomics revealed notable changes in proteins in irradiated samples and identified prosaposin, and potentially its daughter protein saposin-B, as a potential candidate for regulating mitochondrial function following IR. Whereas research into the biologic effects of cellular irradiation has long focused on nuclear DNA effects, our experimental work, along with that of others, is finding that mitochondrial effects may have broader implications in the field of stress adaptation and cell death in cancer (including leukemia) and other disease states.-Patten, D. A., Ouellet, M., Allan, D. S., Germain, M., Baird, S. D., Harper, M.-E., Richardson, R. B. Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation.

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Effect of Low-Dose Ionizing Radiation on the Expression of Mitochondria-Related Genes in Human Mesenchymal Stem Cells.

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