bims-iorami Biomed News
on Ionising Radiation and Mitochondria
Issue of 2023–10–22
eight papers selected by
Chenxiao Yu, Soochow University
  1. Mitochondrial DNA is a key driver in cigarette smoke extract-induced IL-6 expression.
  2. Cultured lymphocytes' mitochondrial genome integrity is not altered by cladribine.
  3. A mitochondrial checkpoint to adaptive anticancer immunity.
  4. Preoperative chemoradiotherapy induces multiple pathways related to anti-tumour immunity in rectal cancer.
  5. Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
  6. CDK4/6 inhibitors induce breast cancer senescence with enhanced anti-tumor immunogenic properties compared with DNA-damaging agents.
  7. Radiating the "Radio-Resistant": The Misunderstood Story of Neuroendocrine Tumors and Radiation.
  8. The crosstalk between DNA repair and immune responses.
  1. Hypertens Res. 2023 Oct 17.
    Mitochondrial DNA is a key driver in cigarette smoke extract-induced IL-6 expression.
    Yusuke Kobayashi, Chiemi Sakai, Takafumi Ishida, Minako Nagata, Yukiko Nakano, Mari Ishida.
      Smoking is an independent risk factor for atherosclerosis, the primary pathogenesis of which is inflammation. We recently reported that cigarette smoke extract (CSE) causes cytosolic and extracellular accumulation of both nuclear (n) and mitochondrial (mt) DNA, which leads to inflammation in human umbilical vein endothelial cells (HUVECs). In this study, we examined whether inflammation induction depends more on cytosolic nDNA or mtDNA, and which chemical constituents of CSE are involved. Acrolein (ACR), methyl vinyl ketone (MVK), and 2-cyclopenten-1-one (CPO) were used in the experiments, as these are the major cytotoxic factors in CSE in various cell types. Stimulation with ACR, MVK, or CPO alone resulted in the accumulation of DNA double-strand breaks (DSBs), but not oxidative DNA damage, accumulation of cytosolic DNA, or increased expression of inflammatory cytokines. Simultaneous administration of all three constituents (ALL) resulted in oxidative DNA damage in both the nucleus and mitochondria, accumulation of DSBs, reduced mitochondrial membrane potential, induction of minority mitochondrial outer membrane permeabilization, accumulation of cytosolic free DNA, and increased expression of inflammatory cytokines such as IL-6 and IL-1α. Treatment with N-acetyl-L-cysteine, a reactive oxygen species scavenger, suppressed oxidative DNA damage and the increased expression of IL-6 and IL-1α induced by ALL or CSE. The ALL- or CSE-induced increase in IL-6 expression, but not that of IL-1α, was suppressed by mtDNA depletion. In conclusion, ACR, MVK, and CPO may strongly contribute to CSE-induced inflammation. More importantly, cytosolic free mtDNA is thought to play an important role in IL-6 expression, a central mediator of inflammation.
    Keywords:  Cytosolic DNA; Endothelial cells; Inflammation; Mitochondrial DNA; Smoking
    DOI:  https://doi.org/10.1038/s41440-023-01463-z
  2. Clin Exp Immunol. 2023 Oct 20. pii: uxad112. [Epub ahead of print]
    Cultured lymphocytes' mitochondrial genome integrity is not altered by cladribine.
    Elina Järvinen, Fumi Suomi, James B Stewart, Dimitri Guala, Miko Valori, Lilja Jansson, Janne Nieminen, Thomas G McWilliams, Pentti J Tienari.
      Cladribine tablets are a treatment for multiple sclerosis with effects on lymphocytes, yet its mode of action has not been fully established. Here, we analyzed the effects of cladribine on mitochondrial DNA integrity in lymphocytes. We treated cultured human T-cell lines (CCRF-CEM and Jurkat) with varying concentrations of cladribine to mimic the slow cell depletion observed in treated patients. The CCRF-CEM was more susceptible to cladribine than Jurkat cells. In both cells mitochondrial protein synthesis, mitochondrial DNA copy number and mitochondrial cytochrome-c oxidase-I mRNA mutagenesis was not affected by cladribine, while caspase-3 cleavage was detected in Jurkat cells at 100 nM concentration. Cladribine treatment at concentrations up to 10 nM in CCRF-CEM and 100 nM in Jurkat cells did not induce significant increase in mitochondrial DNA mutations. Peripheral blood mononuclear cells from 8 multiple sclerosis patients and 4 controls were cultured with or without an effective dose of cladribine (5 nM). However, we did not find any differences in mitochondrial DNA somatic mutations in lymphocyte subpopulations (CD4+, CD8+ and CD19+) between treated vs. non-treated cells. The overall mutation rate was similar in patients and controls. When different lymphocyte subpopulations were compared, greater mitochondrial DNA mutation levels were detected in CD8+ (p=0.014) and CD4+ (p=0.038) as compared to CD19+ cells, these differences were independent of cladribine treatment. We conclude that T-cells have more detectable mitochondrial DNA mutations than B-cells, and cladribine has no detectable mutagenic effect on lymphocyte mitochondrial genome nor does it impair mitochondrial function in human T-cell lines.
    Keywords:  cladribine; lymphocytes; mitochondrial DNA; multiple sclerosis
    DOI:  https://doi.org/10.1093/cei/uxad112
  3. Oncoimmunology. 2023 ;12(1): 2271693
    A mitochondrial checkpoint to adaptive anticancer immunity.
    Oliver Kepp, Peng Liu, Guido Kroemer, Lorenzo Galluzzi.
      BCL2 robustly preserves mitochondrial integrity, hence inhibiting innate immune signaling and apoptotic cell death in several cell types. Here, we comment on our recent data demonstrating that BCL2 also limits the ability of dendritic cells to elicit adaptive immune responses, lending support to a universal immunosuppressive function for the mitochondrial immune checkpoint.
    Keywords:  Antigen presentation; CGAS; immune checkpoint inhibitors; immunogenic cell death; mtDNA; type I interferon
    DOI:  https://doi.org/10.1080/2162402X.2023.2271693
  4. Br J Cancer. 2023 Oct 14.
    Preoperative chemoradiotherapy induces multiple pathways related to anti-tumour immunity in rectal cancer.
    Ioannis M Koukourakis, Erasmia Xanthopoulou, Theologos I Sgouras, Maria Kouroupi, Alexandra Giatromanolaki, Vassilios Kouloulias, Dina Tiniakos, Anna Zygogianni.
       BACKGROUND: Rectal cancer treated with preoperative radiotherapy (RT) provides an interesting model to study changes induced on cancer cell immuno-phenotype that could be exploited by immunotherapy interventions to improve prognosis.
    MATERIALS AND METHODS: We assessed the expression of HLA-class-I, β2-microglobulin, TAP1, PD-L1 and STING/IFNβ in preoperative biopsies and respective post-RT surgical specimens from patients with rectal cancer (n = 27). The effect of radiation was further investigated in colorectal adenocarcinoma cell lines HT-29 and Caco-2.
    RESULTS: Rectal carcinomas exhibited extensive loss of expression of HLA-Class-I related molecules, which was restored in post-irradiation surgical specimens (P < 0.0001). RT induced the expression of IFNβ and STING in cancer cells and tumour-infiltrating lymphocytes (P < 0.0001). In in vitro experiments, irradiation with 4 Gy or 10 Gy induced the expression of HLA-class-I protein (P < 0.001). PD-L1 levels were transiently induced for two days (P < 0.001). cGAS, STING, IFNβ and the downstream genes (MX1, MX2, UBE2L6v2, IFI6v2 and IFI44) mRNA levels significantly increased after 3 × 8 Gy or 1 × 20 Gy irradiation (P < 0.001). TREX1 mRNA levels remained unaltered.
    CONCLUSIONS: RT induces the IFN-type-I pathway and the expression of HLA-class-I molecules on rectal carcinoma. The transient induction of PD-L1 expression suggests that long-course daily RT may sustain increased PD-L1 levels. Anti-PD-L1/PD-1 immunotherapy could block this immunosuppressive pathway.
    DOI:  https://doi.org/10.1038/s41416-023-02459-9
  5. Cell Rep. 2023 Oct 19. pii: S2211-1247(23)01303-7. [Epub ahead of print]42(10): 113291
    Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
    Xiaowen Ma, Sharon Manley, Hui Qian, Yuan Li, Chen Zhang, Kevin Li, Benjamin Ding, Fengli Guo, Allen Chen, Xing Zhang, Meilian Liu, Meihua Hao, Benjamin Kugler, E Matthew Morris, John Thyfault, Ling Yang, Hiromi Sesaki, Hong-Min Ni, Heidi McBride, Wen-Xing Ding.
      Dysfunctional mitochondria are removed via multiple pathways, such as mitophagy, a selective autophagy process. Here, we identify an intracellular hybrid mitochondria-lysosome organelle (termed the mitochondria-lysosome-related organelle [MLRO]), which regulates mitochondrial homeostasis independent of canonical mitophagy during hepatocyte dedifferentiation. The MLRO is an electron-dense organelle that has either a single or double membrane with both mitochondria and lysosome markers. Mechanistically, the MLRO is likely formed from the fusion of mitochondria-derived vesicles (MDVs) with lysosomes through a PARKIN-, ATG5-, and DRP1-independent process, which is negatively regulated by transcription factor EB (TFEB) and associated with mitochondrial protein degradation and hepatocyte dedifferentiation. The MLRO, which is galectin-3 positive, is reminiscent of damaged lysosome and could be cleared by overexpression of TFEB, resulting in attenuation of hepatocyte dedifferentiation. Together, results from this study suggest that the MLRO may act as an alternative mechanism for mitochondrial quality control independent of canonical autophagy/mitophagy involved in cell dedifferentiation.
    Keywords:  ATG5; CP: Cell biology; DRP1; autophagy; hepatocytes; lysosome; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2023.113291
  6. Mol Oncol. 2023 Oct 19.
    CDK4/6 inhibitors induce breast cancer senescence with enhanced anti-tumor immunogenic properties compared with DNA-damaging agents.
    Dong Hyun Lee, Muhammad Imran, Jae Ho Choi, Yoo Jung Park, Young Hwa Kim, Sunwoo Min, Tae Jun Park, Yong Won Choi.
      Since therapy-induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti-tumor TIS is an important issue. Here, cyclin-dependent kinase4/6 inhibitors (CDK4/6i)-induced senescence was compared to the TIS induced by conventional DNA-damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity (IL6, CXCL8, TGFβ, CD274, CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA-damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti-tumor immunomodulatory proteins related to antigen presentation (MHC-I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i-induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-κB) and p53 activation. These data suggest that in contrast with DNA-damaging agents, which augment the pro-tumorigenic microenvironment via pro-inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins.
    Keywords:  CDK4/6 inhibitors; DNA-damaging agents; SASP; Therapy-induced senescence; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.13541
  7. Int J Radiat Oncol Biol Phys. 2023 Nov 15. pii: S0360-3016(23)00083-4. [Epub ahead of print]117(4): 785
    Radiating the "Radio-Resistant": The Misunderstood Story of Neuroendocrine Tumors and Radiation.
    Jonathan M Loree.
      
    DOI:  https://doi.org/10.1016/j.ijrobp.2023.01.039
  8. Mol Cell. 2023 Oct 19. pii: S1097-2765(23)00749-9. [Epub ahead of print]83(20): 3582-3587
    The crosstalk between DNA repair and immune responses.
    Karlene A Cimprich, Guo-Min Li, Sandra Demaria, Nelson O Gekara, Shan Zha, Qianming Chen.
      In recent years, increasing evidence has highlighted the profound connection between DNA damage repair and the activation of immune responses. We spoke with researchers about their mechanistic interplays and the implications for cancer and other diseases.
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.022
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