Low-Dose Non-Targeted Effects and Mitochondrial Control
Abstract
:1. Introduction
2. Low-Dose Radiation Effects
3. Hormesis
4. Adaptive Radiation Response and the Involvement of Mitochondrial Functions
5. Low Dose Hyper-Radiation Sensitivity (HRS) and Induction of Radioresistance (IRR)
5.1. IRR
5.2. Involvement of Immune Functions
5.3. Involvement of Mitochondria
6. Bystander Effects: Short Distance NTEs
7. Long Distance NTEs: Abscopal Effects
8. Genomic Instability
9. Mitochondria and Innate and Adaptive Immunity Induced by IR
9.1. Low-Dose Immune Effects
9.2. Role of mtDNA in Innate and Adaptive Immune Responses
9.3. Immunogenic Effects in Antitumor RT
10. Concluding Remarks
10.1. RIBE and NTE and the Role of Mitochondria
IR Exposure Exp. Device | Biological System | Observation | References |
---|---|---|---|
Low LET photons (γ-rays, X-rays) (0.5, 5 and 7.5 Gy) ICCM | Mammalian cells, Chinese hamster (CHO-K1) Human keratinocytes (HGV-G) Medium transfer | Absence of RIBE in CHO-K1 mutants with nonfunctional glucose-6-phosphate dehydrogenase (G6PD) involved in mitochondrial metabolism in HGV-G by inhibition of apoptosis and lactate metabolism. Alteration of calcium fluxes and loss of mitochondrial membrane potential (MMP). Involvement of mitochondrial ROS. | [318,319,323] |
Low LET IR 5 mGy and 0.5 Gy ICCM | Human keratinocytes (HGV-G) Medium transfer | Reduction of clonogenicity. Induction of increases in mitochondrial mass and low Bcl-2 expression in bystander cells after 5 mGy in ICCM, but increased expression after 5 Gy. Decrease in survival. | [312] |
X-rays 1Gy ICCM | Human hybrids cells: Chinese hamster ovary (CHO) cells GM10115 + human chromosome 4, Medium transfer | IR-induced mitochondrial dysfunction results in persistent high levels of ROS perpetuating genomic instability plus clastogenic and transgenerational effects. | [249,250] |
IR: γ-rays 5 Gy ICCM | Chinese hamster (CHO-K1) Human keratinocytes (HGV-G) Medium transfer | Increase in mitochondrial mass, dysfunctional mitochondria in BE. | [324] |
IR: γ-rays (5 mGy, 0.5 Gy, 5 Gy) ICCM | Chinese hamster (CHO-K1) Human keratinocytes (HGV-G) Medium transfer | Mitochondria are sensitive to LDIR and ICCM, loss of enzymatic functions (OXPHOS), and altered mtDNA-directed protein synthesis. | [325] |
γ-rays or 160 kV X-rays (0.5 Gy) | Human mammary epithelial cells (HMEC); Balb/c mice TGF-β1 +/− and +/+ | Increased centrosome deregulation as a function of time. After IR, clonal expansion CA increased in HMEC, but unstable cells could be deleted by TGF-β1 via p53-dependent apoptosis (involving mitochondrial signaling) TGF-β1 that can also suppress EMT. | [326] |
Microbeam IR with Carbon ions or X-rays | Mammalian cells Murine lymphoma L5178Y in co-culture with irradiated neoplastic epithelial cells. Co-culture experiments | Cytoplasmic and cell irradiation affects mitochondria and calcium fluxes in targeted glioma and fibroblast cells. Cytoplasmic IR involved mitochondrial damage and RIBE response. | [244] |
Microbeam with α−particles | T98G glioma cells and AG01522 fibroblasts ICCM or Co-culture experiments | Calcium signaling occurs early (RIBE). NO and mito-chondrial ROS lead to chromosomal damage (MN). | [243] |
241AM source α-particles (100 mGy) ICCM | Hamster normal AL cells ρ+ and mtDNA-depletedAL cells (ρ0) (donor) and normal human fibroblasts (AG1522) (receptor cells). Medium transfer | Mitochondria-derived NO and O2− play an important role in the initiation and activation of RIBE. IR-induced intracellular factors derived from mitochondria and calcium-dependent mitochondrial NOS. Mitochondria intercellular signaling from irradiated cells participates in ROS-mediated genotoxicity. | [327,328] |
Microbeam IR with 1–10 protons ICCM | Human keratinocytes HGV-G Medium transfer | ROS levels increased in bystander cells. Apoptosis induced was associated with a decrease in MMP and increased intracellular Ca2+ levels. | [242] |
Microbeam IR with α-particles | Cervical cancer cells (HeLa) and mitochondria depleted pseudo-ρ0 cells | No RIBE in the absence of mtDNA. Signaling is inhibited by ROS and RNA inhibitors. Mt-dependent 53BP1 delocalization. BE involves intact mt signaling from targeted cytoplasm to the nucleus. | [196] |
Microbeam IR with 4He ions (120 keV/μm) α-rays | Human fibroblast cells ρ0 and ρ+ | High BE mutagenic response in mtDNA depleted ρ0 cells. BE involved mt-dependent NF-κB/iNOS/NO and NF-κB/COX-2/prostaglandin E2 signaling and NOS and COX2 signaling. | [245] |
Low-dose a-particles (0.29 mGy–25 mGy) and γ-rays (2 mGy–50 mGy | 208F and v-src trans-formed 208Fsrc3 rat fibroblast cell lines. Co-culture experiments | Low-dose IR of non-transformed cells can induce apoptosis in precancerous cells through RIBE involving ROS/NOS signaling and cytokines, such as TGF-β. The stimulatory effect saturates at 50 mGy for γ-rays and at 25 mGy for α-particles. | [191] |
1 GeV/u iron ions (LET~151 keV/μm), 600 MeV/u; silicon ions (LET~51 keV/μm), or 1 GeV protons (LET~0.2 keV/μm). | Normal human fibroblasts (AG1522) Test of progeny: co-cultures of cells exposed to low or high doses of high LET IR | RIBE depends on radiation quality and dose, and oxidative stress involving mitochondria. | [186] |
γ-rays (0.05 and 0.5 Gy) ICCM | Human keratinocyte cell line (HaCaT) Medium transfer | Low-dose expression of genes involved in mitochondria-driven intrinsic apoptosis induced in bystander cells at low-dose (50 mGy). | [190] |
γ-rays, α-particles and HZE particles (500 mGy) | Normal human FB (AG1522 cells) co-cultured with a-irradiated HeLa cells (500 mGy) (connexin 32) Co-culturing | Increased induction of MN and GI in bystander cells. | [224] |
Tritium (β-radiation) induced UV biophoton emission | Human colon carcinoma cell line, HCT116 p53 +/+ Biophoton emission involvement in BE Exosomes | Biophoton electromagnetic bystander signaling compromises mitochondrial complex V (ATP production) and may be involved in the human fatigue syndrome. Exosomes extracted from UV-ICCM modulates clonogenic survival and MPP in bystander cells. | [38] |
γ-rays (22 mGy) and biophoton emission | Cells: HCT116 p53 +/+ Test involvement of cellular emissions of biophotons in gamma radiation that is induced bystander cells | Low-dose biophoton emission from irradiated human cells may cause detrimental low-dose RIBE. | [39] |
6 MeV photons (Clinac 600), 2 Gy | Fadu cells derived from HNSCC Secretion of exosomes in RIBE | NTE is propagated by mtDNA and RNA in vesicles similar to exosomes. | [28] |
X-rays (0.1, 0.25, 2 Gy) Extracelluar vesicles (EVs) | C57BL/6 mice Total body IR, Extracellular vesicles (EVs) | A panel of miRNA are involved in EVs bystander effects, differently at low and high dose, IR induced systemic effects. | [329] |
X-rays 4 Gy CCCM/ICCM | Seven-week-old male ICR mice: ELV from irradiated mouse serum and ICCM | Absence of DNA damage in CCCM ELV or ICCM ELV from mt-depleted. ρ0 normal human fibroblasts. Secretion of mtDNA via exosomes is involved in mediating RIBE signals. | [32] |
X-Rays Partial and whole body exposure 2 Gy | C57Bl/6 female mice of eight weeks of age Analysis of ‘Out of field ‘effects partial body IR in mice Exosomes | Deregulation of many proteins and miRNAs. Some miRNA, proteomic changes, and exosomes are involved in anti-apoptotic effects. Injection of exosomes from irradiated mice can prevent apoptosis. | [226,227] |
γ-rays, high doses (2–8 Gy) ICCM | Human HepT2 cells Medium transfer from irradiated cells | Induction of Bax, Bcl2, caspases and γ-H2AX DNA damage in bystander HepT2 cells. | [330] |
200 kV X–rays (6 Gy) |
Human pancreatic cancer cells (MiaPaCa–2), wild–type (wt) and ATM−/− fibroblasts Co-culturing | Healthy ATM+/+ cells modify the DDR of irradiated cells by a microtubule- and ATM-dependent exchange of healthy mitochondria. | [201] |
10.2. Factors Possibly Contributing Adaptive Beneficial and Armful Effects of Low Doses
10.3. LDIR Adaptive Responses
10.4. Immune and Anti-Tumor LDIR Effects
10.5. Biopositive Effects of LDIR
10.6. Biopositive Effects of LDIR on the Immune System
10.7. Bionegative Effects of LDIR
10.8. Low Dose-Rate Effects
10.9. Relationship of LDIR and LDRIR to DDR and Mitochondrial ROS
10.10. Role of Mitochondria in Radioresistance
10.11. Conclusive Thoughts
Funding
Institutional Review Board Statement
Informed Consent statement:
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Averbeck, D. Low-Dose Non-Targeted Effects and Mitochondrial Control. Int. J. Mol. Sci. 2023, 24, 11460. https://doi.org/10.3390/ijms241411460
Averbeck D. Low-Dose Non-Targeted Effects and Mitochondrial Control. International Journal of Molecular Sciences. 2023; 24(14):11460. https://doi.org/10.3390/ijms241411460
Chicago/Turabian StyleAverbeck, Dietrich. 2023. "Low-Dose Non-Targeted Effects and Mitochondrial Control" International Journal of Molecular Sciences 24, no. 14: 11460. https://doi.org/10.3390/ijms241411460