bims-iorami Biomed News
on Ionising Radiation and Mitochondria
Issue of 2024–03–03
six papers selected by
Chenxiao Yu, Soochow University
  1. Aging STINGs: mitophagy at the crossroads of neuroinflammation.
  2. Mitochondrial DNA leakage triggers inflammation in age-related cardiovascular diseases.
  3. Intratumoral TREX1 induction promotes immune evasion by limiting type I interferon.
  4. Radiotherapy Enhances Metastasis Through Immune Suppression by inducing PD-L1 and MDSC in distal sites.
  5. A guideline on the molecular ecosystem regulating ferroptosis.
  6. Apoptosis dysfunction: unravelling the interplay between ZBP1 activation and viral invasion in innate immune responses.
  1. Autophagy. 2024 Feb 27.
    Aging STINGs: mitophagy at the crossroads of neuroinflammation.
    Juan Ignacio Jiménez-Loygorri, Patricia Boya.
      Loss of proteostasis and dysregulated mitochondrial function are part of the traditional hallmarks of aging, and in their last revision impaired macroautophagy and chronic inflammation are also included. Mitophagy is at the intersection of all these processes but whether it undergoes age-associated perturbations was not known. In our recent work, we performed a systematic and systemic analysis of mitolysosome levels in mice and found that, despite the already-known decrease in non-selective macroautophagy, mitophagy remains stable or increases upon aging in all tissues analyzed and is mediated by the PINK1-PRKN-dependent pathway. Further analyses revealed a concomitant increase in mtDNA leakage into the cytosol and activation of the CGAS-STING1 inflammation axis. Notably, both phenomena are also observed in primary fibroblasts from aged human donors. We hypothesized that mitophagy might be selectively upregulated during aging to improve mitochondrial fitness and reduce mtDNA-induced inflammation. Treatment with the mitophagy inducer urolithin A alleviates age-associated neurological decline, including improved synaptic connectivity, cognitive memory and visual function. Supporting our initial hypothesis, urolithin A reduces the levels of cytosolic mtDNA, CGAS-STING1 activation and neuroinflammation. Finally, using an in vitro model of mitochondrial membrane permeabilization we validated that PINK1-PRKN-mediated mitophagy is essential to resolve cytosolic mtDNA-triggered inflammation. These findings open up an integrative approach to tackle aging and increase healthspan via mitophagy induction.
    Keywords:  Inflammation; PINK1; Parkin; mitochondria; mtDNA; retina
    DOI:  https://doi.org/10.1080/15548627.2024.2322421
  2. Front Cell Dev Biol. 2024 ;12 1287447
    Mitochondrial DNA leakage triggers inflammation in age-related cardiovascular diseases.
    Wanyue Ding, Jingyu Chen, Lei Zhao, Shuang Wu, Xiaomei Chen, Hong Chen.
      Mitochondrial dysfunction is one of the hallmarks of cardiovascular aging. The leakage of mitochondrial DNA (mtDNA) is increased in senescent cells, which are resistant to programmed cell death such as apoptosis. Due to its similarity to prokaryotic DNA, mtDNA could be recognized by cellular DNA sensors and trigger innate immune responses, resulting in chronic inflammatory conditions during aging. The mechanisms include cGAS-STING signaling, TLR-9 and inflammasomes activation. Mitochondrial quality controls such as mitophagy could prevent mitochondria from triggering harmful inflammatory responses, but when this homeostasis is out of balance, mtDNA-induced inflammation could become pathogenic and contribute to age-related cardiovascular diseases. Here, we summarize recent studies on mechanisms by which mtDNA promotes inflammation and aging-related cardiovascular diseases, and discuss the potential value of mtDNA in early screening and as therapeutic targets.
    Keywords:  cardiovasuclar diseases; inflammation; innate immunity; mitochondrial DNA; senescence
    DOI:  https://doi.org/10.3389/fcell.2024.1287447
  3. Cancer Immunol Res. 2024 Feb 26.
    Intratumoral TREX1 induction promotes immune evasion by limiting type I interferon.
    Eléonore Toufektchan, Alexandra Dananberg, Josefine Striepen, James H Hickling, Abraham Shim, Yanyang Chen, Ashley Nichols, Mercedes A Duran Paez, Lisa Mohr, Samuel F Bakhoum, John Maciejowski.
      Chromosomal instability is a hallmark of human cancer that is associated with aggressive disease characteristics. Chromosome mis-segregations help fuel natural selection, but they risk provoking a cGAS-STING immune response through the accumulation of cytosolic DNA. The mechanisms of how tumors benefit from chromosomal instability while mitigating associated risks, such as enhanced immune surveillance, are poorly understood. Here, we identify cGAS-STING-dependent upregulation of the nuclease TREX1 as an adaptive, negative feedback mechanism that promotes immune evasion through digestion of cytosolic DNA. TREX1 loss diminishes tumor growth, prolongs survival of host animals, increases tumor immune infiltration, and potentiates response to immune checkpoint blockade selectively in tumors capable of mounting a type I interferon response downstream of STING. Together, these data demonstrate that TREX1 induction shields chromosomally unstable tumors from immune surveillance by dampening type I interferon production and suggest that TREX1 inhibitors might be used to selectively target tumors that have retained the inherent ability to mount an interferon response downstream of STING.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-1093
  4. Clin Cancer Res. 2024 Mar 01.
    Radiotherapy Enhances Metastasis Through Immune Suppression by inducing PD-L1 and MDSC in distal sites.
    Yuzhu Hou, Kaiting Yang, Liangliang Wang, Jiaai Wang, Xiaona Huang, Andras Piffko, Sean Z Luo, Xinshuang Yu, Enyu Rao, Carlos Martinez, Jason Bugno, Matthias Mack, Everett E Vokes, Sean P Pitroda, Steven J Chmura, Ralph R Weichselbaum, Hua Laura Liang.
       PURPOSE: Radiotherapy (RT) is a widely employed anti-cancer treatment. Emerging evidence suggests that RT can elicit both tumor-inhibiting and tumor-promoting immune effects. This study is to investigate immune suppressive factors of radiotherapy.
    EXPERIMENTAL DESIGN: We used a heterologous two-tumor model in which adaptive concomitant immunity was eliminated.
    RESULTS: Through analysis of PD-L1 expression and MDSC frequencies using patient PBMC and murine two-tumor and metastasis model, we report that local irradiation can induce a systemic increase in MDSCs, as well as PD-L1 expression on DCs and myeloid cells, and thereby increase the potential for metastatic dissemination in distal, non-irradiated tissue. In a mouse model using two distinct tumors, we found that PD-L1 induction by ionizing radiation (IR) was dependent on elevated chemokine CXCL10 signaling. Inhibiting PD-L1 or MDSCs can potentially abrogate RT-induced metastasis and improve clinical outcomes for patients receiving RT.
    CONCLUSIONS: Blockade of PD-L1/CXCL10 axis or MDSC infiltration during radiation can enhance abscopal tumor control and reduce metastasis.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-3206
  5. Nat Cell Biol. 2024 Feb 29.
    A guideline on the molecular ecosystem regulating ferroptosis.
    Enyong Dai, Xin Chen, Andreas Linkermann, Xuejun Jiang, Rui Kang, Valerian E Kagan, Hülya Bayir, Wan Seok Yang, Ana J Garcia-Saez, Maria S Ioannou, Tobias Janowitz, Qitao Ran, Wei Gu, Boyi Gan, Dmitri V Krysko, Xiaofeng Zhu, Jiayi Wang, Stefan Krautwald, Shinya Toyokuni, Yangchun Xie, Florian R Greten, Qing Yi, Joel Schick, Jiao Liu, Dmitry I Gabrilovich, Jinbao Liu, Herbert J Zeh, Donna D Zhang, Minghua Yang, Juan Iovanna, Manfred Kopf, Timon E Adolph, Jen-Tsan Chi, Changfeng Li, Hidenori Ichijo, Michael Karin, Vijay G Sankaran, Weiping Zou, Lorenzo Galluzzi, Ashley I Bush, Binghui Li, Gerry Melino, Eric H Baehrecke, Michael T Lotze, Daniel J Klionsky, Brent R Stockwell, Guido Kroemer, Daolin Tang.
      Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.
    DOI:  https://doi.org/10.1038/s41556-024-01360-8
  6. Cell Commun Signal. 2024 Feb 24. 22(1): 149
    Apoptosis dysfunction: unravelling the interplay between ZBP1 activation and viral invasion in innate immune responses.
    Jianhao Zhan, Jisheng Wang, Yuqing Liang, Lisha Wang, Le Huang, Shanshan Liu, Xiaoping Zeng, Erming Zeng, Hongmei Wang.
      Apoptosis plays a pivotal role in pathogen elimination and maintaining homeostasis. However, viruses have evolved strategies to evade apoptosis, enabling their persistence within the host. Z-DNA binding protein 1 (ZBP1) is a potent innate immune sensor that detects cytoplasmic nucleic acids and activates the innate immune response to clear pathogens. When apoptosis is inhibited by viral invasion, ZBP1 can be activated to compensate for the effect of apoptosis by triggering an innate immune response. This review examined the mechanisms of apoptosis inhibition and ZBP1 activation during viral invasion. The authors outlined the mechanisms of ZBP1-induced type I interferon, pyroptosis and necroptosis, as well as the crosstalk between ZBP1 and the cGAS-STING signalling pathway. Furthermore, ZBP1 can reverse the suppression of apoptotic signals induced by viruses. Intriguingly, a positive feedback loop exists in the ZBP1 signalling pathway, which intensifies the innate immune response while triggering a cytokine storm, leading to tissue and organ damage. The prudent use of ZBP1, which is a double-edged sword, has significant clinical implications for treating infections and inflammation.
    Keywords:  Apoptosis inhibition; Innate immunity; Viral invasion; ZBP1
    DOI:  https://doi.org/10.1186/s12964-024-01531-y
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