bims-iorami Biomed News
on Ionising Radiation and Mitochondria
Issue of 2024‒02‒04
eleven papers selected by
Chenxiao Yu, Soochow University
  1. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.
  2. Cellular senescence and aging at the crossroad between immunity and cancer.
  3. Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte proliferation.
  4. Interplay of immune modulation, adaptive response and hormesis: Suggestive of threshold for clinical manifestation of effects of ionizing radiation at low doses?
  5. Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
  6. Mitochondrial diseases and mtDNA editing.
  7. Stress response silencing by an E3 ligase mutated in neurodegeneration.
  8. Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance.
  9. PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury.
  10. 7-Dehydrocholesterol dictates ferroptosis sensitivity.
  11. Dose-dependent changes in cardiac function, strain and remodelling in a preclinical model of heart base irradiation.
  1. Nat Cancer. 2024 Jan 29.
    Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.
    Mahnoor Mahmood, Eric Minwei Liu, Amy L Shergold, Elisabetta Tolla, Jacqueline Tait-Mulder, Alejandro Huerta-Uribe, Engy Shokry, Alex L Young, Sergio Lilla, Minsoo Kim, Tricia Park, Sonia Boscenco, Javier L Manchon, Crístina Rodríguez-Antona, Rowan C Walters, Roger J Springett, James N Blaza, Louise Mitchell, Karen Blyth, Sara Zanivan, David Sumpton, Edward W Roberts, Ed Reznik, Payam A Gammage.
      The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.
    DOI:  https://doi.org/10.1038/s43018-023-00721-w
  2. Methods Cell Biol. 2024 ;pii: S0091-679X(24)00009-8. [Epub ahead of print]181 xvii-xxiv
    Cellular senescence and aging at the crossroad between immunity and cancer.
    Oliver Kepp, Lorenzo Galluzzi, Giulia Petroni.
      
    DOI:  https://doi.org/10.1016/S0091-679X(24)00009-8
  3. Cell Regen. 2024 Jan 31. 13(1): 2
    Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte proliferation.
    Xinhang Li, Yalin Zhu, Pilar Ruiz-Lozano, Ke Wei.
      The regenerative capacity of the adult mammalian heart remains a formidable challenge in biological research. Despite extensive investigations into the loss of regenerative potential during evolution and development, unlocking the mechanisms governing cardiomyocyte proliferation remains elusive. Two recent groundbreaking studies have provided fresh perspectives on mitochondrial-to-nuclear communication, shedding light on novel factors that regulate cardiomyocyte proliferation. The studies identified two mitochondrial processes, fatty acid oxidation and protein translation, as key players in restricting cardiomyocyte proliferation. Inhibition of these processes led to increased cell cycle activity in cardiomyocytes, mediated by reduction in H3k4me3 levels through accumulated α-ketoglutarate (αKG), and activation of the mitochondrial unfolded protein response (UPRmt), respectively. In this research highlight, we discuss the novel insights into mitochondrial-to-nuclear communication presented in these studies, the broad implications in cardiomyocyte biology and cardiovascular diseases, as well as the intriguing scientific questions inspired by the studies that may facilitate future investigations into the detailed molecular mechanisms of cardiomyocyte metabolism, proliferation, and mitochondrial-to-nuclear communications.
    Keywords:  ATF4; Cardiomyocyte; Cpt1b; FAO; H3k4me3; Mitochondria; Mrps5; Proliferation; UPRmt; αKG
    DOI:  https://doi.org/10.1186/s13619-024-00186-x
  4. Sci Total Environ. 2024 Jan 25. pii: S0048-9697(24)00313-9. [Epub ahead of print] 170178
    Interplay of immune modulation, adaptive response and hormesis: Suggestive of threshold for clinical manifestation of effects of ionizing radiation at low doses?
    R K Chaurasia, B K Sapra, D K Aswal.
      The health impacts of low-dose ionizing radiation exposures have been a subject of debate over the last three to four decades. While there has been enough evidence of "no adverse observable" health effects at low doses and low dose rates, the hypothesis of "Linear No Threshold" continues to rule and govern the principles of radiation protection and the formulation of regulations and public policies. In adopting this conservative approach, the role of the biological processes underway in the human body is kept at abeyance. This review consolidates the available studies that discuss all related biological pathways and repair mechanisms that inhibit the progression of deleterious effects at low doses and low dose rates of ionizing radiation. It is pertinent that, taking cognizance of these processes, there is a need to have a relook at policies of radiation protection, which as of now are too stringent, leading to undue economic losses and negative public perception about radiation.
    Keywords:  Adaptive response; Antioxidant defense system; Clinical significance of LDR; Immune modulation; Linear No-threshold (LNT) hypothesis; Low dose radiation effects; Radiation hormesis
    DOI:  https://doi.org/10.1016/j.scitotenv.2024.170178
  5. Nat Commun. 2024 Jan 27. 15(1): 830
    Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
    Juan Ignacio Jiménez-Loygorri, Beatriz Villarejo-Zori, Álvaro Viedma-Poyatos, Juan Zapata-Muñoz, Rocío Benítez-Fernández, María Dolores Frutos-Lisón, Francisco A Tomás-Barberán, Juan Carlos Espín, Estela Area-Gómez, Aurora Gomez-Duran, Patricia Boya.
      Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.
    DOI:  https://doi.org/10.1038/s41467-024-45044-1
  6. Genes Dis. 2024 May;11(3): 101057
    Mitochondrial diseases and mtDNA editing.
    Min Song, Lingqun Ye, Yongjin Yan, Xuechun Li, Xinglong Han, Shijun Hu, Miao Yu.
      Mitochondrial diseases are a heterogeneous group of inherited disorders characterized by mitochondrial dysfunction, and these diseases are often severe or even fatal. Mitochondrial diseases are often caused by mitochondrial DNA mutations. Currently, there is no curative treatment for patients with pathogenic mitochondrial DNA mutations. With the rapid development of traditional gene editing technologies, such as zinc finger nucleases and transcription activator-like effector nucleases methods, there has been a search for a mitochondrial gene editing technology that can edit mutated mitochondrial DNA; however, there are still some problems hindering the application of these methods. The discovery of the DddA-derived cytosine base editor has provided hope for mitochondrial gene editing. In this paper, we will review the progress in the research on several mitochondrial gene editing technologies with the hope that this review will be useful for further research on mitochondrial gene editing technologies to optimize the treatment of mitochondrial diseases in the future.
    Keywords:  Gene editing; Mitochondrial DNA mutation; Mitochondrialdisease; Transcription activator-like effector nucleases; Zinc finger nucleases
    DOI:  https://doi.org/10.1016/j.gendis.2023.06.026
  7. Nature. 2024 Jan 31.
    Stress response silencing by an E3 ligase mutated in neurodegeneration.
    Diane L Haakonsen, Michael Heider, Andrew J Ingersoll, Kayla Vodehnal, Samuel R Witus, Takeshi Uenaka, Marius Wernig, Michael Rapé.
      Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1-3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.
    DOI:  https://doi.org/10.1038/s41586-023-06985-7
  8. Nat Cancer. 2024 Jan 30.
    Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance.
    Hao Zheng, Jinming Liu, Qi Cheng, Qianping Zhang, Yaoyao Zhang, Lingyu Jiang, Yan Huang, Wenlei Li, Yanping Zhao, Guo Chen, Fan Yu, Lei Liu, Yanjun Li, Xudong Liao, Lai Xu, Yi Xiao, Zhibo Zheng, Ming Li, Hongyi Wang, Gang Hu, Lei Du, Quan Chen.
      Acquired drug resistance is a major challenge for cancer therapy and is the leading cause of cancer mortality; however, the mechanisms of drug resistance are diverse and the strategy to specifically target drug-resistant cancer cells remains an unmet clinical issue. Here, we established a colorectal cancer-derived organoid biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies revealed that chemoresistant cancer-derived organoids exhibited elevated expression of LGR4 and activation of the Wnt signaling pathway. Further, we generated a monoclonal antibody (LGR4-mAb) that potently inhibited LGR4-Wnt signaling and found that treatment with LGR4-mAb notably sensitized drug-induced ferroptosis. Mechanistically, LGR4-dependent Wnt signaling transcriptionally upregulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Our findings reveal that targeting of Wnt signaling by LGR4-mAb augments ferroptosis when co-administrated with chemotherapeutic agents, demonstrating a potential opportunity to fight refractory and recurrent cancers.
    DOI:  https://doi.org/10.1038/s43018-023-00715-8
  9. Nat Chem Biol. 2024 Jan 29.
    PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury.
    Qianping Zhang, Tiantian Sun, Fan Yu, Wei Liu, Jin Gao, Jinyu Chen, Hao Zheng, Jinming Liu, Chenjian Miao, Huanyi Guo, Wu Tian, Meihui Su, Yingjie Guo, Xi Liu, Yandong Pei, Zhuofei Wang, Shang Chen, Chenglong Mu, Sin Man Lam, Guanghou Shui, Zongjin Li, Zhongbo Yu, Yan Zhang, Guo Chen, Congcong Lu, Adam C Midgley, Changhua Li, Xin Bian, Xudong Liao, Yong Wang, Wei Xiong, Hongying Zhu, Yanjun Li, Quan Chen.
      Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.
    DOI:  https://doi.org/10.1038/s41589-023-01528-7
  10. Nature. 2024 Jan 31.
    7-Dehydrocholesterol dictates ferroptosis sensitivity.
    Yaxu Li, Qiao Ran, Qiuhui Duan, Jiali Jin, Yanjin Wang, Lei Yu, Chaojie Wang, Zhenyun Zhu, Xin Chen, Linjun Weng, Zan Li, Jia Wang, Qi Wu, Hui Wang, Hongling Tian, Sihui Song, Zezhi Shan, Qiwei Zhai, Huanlong Qin, Shili Chen, Lan Fang, Huiyong Yin, Hu Zhou, Xuejun Jiang, Ping Wang.
      Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.
    DOI:  https://doi.org/10.1038/s41586-023-06983-9
  11. Radiother Oncol. 2024 Jan 30. pii: S0167-8140(24)00034-3. [Epub ahead of print] 110113
    Dose-dependent changes in cardiac function, strain and remodelling in a preclinical model of heart base irradiation.
    Mihaela Ghita-Pettigrew, Kevin S Edgar, Refik Kuburas, Kathryn H Brown, Gerard M Walls, Cecilia Facchi, David J Grieve, Chris J Watson, Alan McWilliam, Marcel van Herk, Kaye J Williams, Karl T Butterworth.
      BACKGROUND AND PURPOSE: Radiation induced cardiotoxicity (RICT) is as an important sequela of radiotherapy to the thorax for patients. In this study, we aim to investigate the dose and fractionation response of RICT. We propose global longitudinal strain (GLS) as an early indicator of RICT and investigate myocardial deformation following irradiation.METHODS: RICT was investigated in female C57BL/6J mice in which the base of the heart was irradiated under image-guidance using a small animal radiation research platform (SARRP). Mice were randomly assigned to a treatment group: single-fraction dose of 16 Gy or 20 Gy, 3 consecutive fractions of 8.66 Gy, or sham irradiation; biological effective doses (BED) used were 101.3 Gy, 153.3 Gy and 101.3 Gy respectively. Longitudinal transthoracic echocardiography (TTE) was performed from baseline up to 50 weeks post-irradiation to detect structural and functional effects.
    RESULTS: Irradiation of the heart base leads to BED-dependent changes in systolic and diastolic function 50 weeks post-irradiation. GLS showed significant decreases in a BED-dependent manner for all irradiated animals, as early as 10 weeks after irradiation. Early changes in GLS indicate late changes in cardiac function. BED-independent increases were observed in the left ventricle (LV) mass and volume and myocardial fibrosis.
    CONCLUSIONS: Functional features of RICT displayed a BED dependence in this study. GLS showed an early change at 10 weeks post-irradiation. Cardiac remodelling was observed as increases in mass and volume of the LV, further supporting our hypothesis that dose to the base of the heart drives the global heart toxicity.
    Keywords:  cardiac strain; cardiac toxicity; heart base; mouse model; preclinical radiotherapy; small animal radiotherapy
    DOI:  https://doi.org/10.1016/j.radonc.2024.110113
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