DNA damage invokes mitophagy through a pathway involving Spata18
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ABSTRACT:
PROVIDER: PRJNA631700 | ENA |
REPOSITORIES: ENA
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Project description:Mitochondria are vital for cellular energy supply and intracellular signaling after stress. Here, we aimed to investigate how mitochondria respond to acute DNA damage with respect to mitophagy, which is an important mitochondrial quality control process. Our results show that mitophagy increases after DNA damage in primary fibroblasts, murine neurons, and C. elegans neurons. Our results indicate that modulation of mitophagy after DNA damage is independent of the type of DNA damage stimuli used and that the protein Spata18 is an important player in this process. Knockdown of Spata18 suppresses mitophagy, disturbs mitochondrial Ca2+ homeostasis, affects ATP production, and attenuates DNA repair. Importantly, mitophagy after DNA damage is a vital cellular response to maintain mitochondrial functions and DNA repair.
2020-05-27 | GSE150273 | GEO
Project description:Mitochondria are vital for cellular energy supply and intracellular signaling after stress. Here, we aimed to investigate how mitochondria respond to acute DNA damage with respect to mitophagy, which is an important mitochondrial quality control process. Our results show that mitophagy increases after DNA damage in primary fibroblasts, murine neurons and Caenorhabditis elegans neurons. Our results indicate that modulation of mitophagy after DNA damage is independent of the type of DNA damage stimuli used and that the protein Spata18 is an important player in this process. Knockdown of Spata18 suppresses mitophagy, disturbs mitochondrial Ca2+ homeostasis, affects ATP production, and attenuates DNA repair. Importantly, mitophagy after DNA damage is a vital cellular response to maintain mitochondrial functions and DNA repair.
| S-EPMC7337932 | biostudies-literature
Project description:DNA replication is sensitive to damage in the template. To bypass lesions and complete replication, cells activate recombination-mediated (error-free) and translesion synthesis-mediated (error-prone) DNA damage tolerance pathways. Crucial for error-free DNA damage tolerance is template switching, which depends on the formation and resolution of damage-bypass intermediates consisting of sister chromatid junctions. Here we show that a chromatin architectural pathway involving the high mobility group box protein Hmo1 channels replication-associated lesions into the error-free DNA damage tolerance pathway mediated by Rad5 and PCNA polyubiquitylation, while preventing mutagenic bypass and toxic recombination. In the process of template switching, Hmo1 also promotes sister chromatid junction formation predominantly during replication. Its C-terminal tail, implicated in chromatin bending, facilitates the formation of catenations/hemicatenations and mediates the roles of Hmo1 in DNA damage tolerance pathway choice and sister chromatid junction formation. Together, the results suggest that replication-associated topological changes involving the molecular DNA bender, Hmo1, set the stage for dedicated repair reactions that limit errors during replication and impact on genome stability. BrdU and proteins ChIP-chip analyses analysis were carried out as described (Bermejo et al., 2009). Labelled probes were hybridized to Affymetrix S.cerevisiae Tiling 1.0 (P/N 900645) arrays and processed with TAS software.
2014-01-28 | E-GEOD-46260 | biostudies-arrayexpress
Project description:Bladder cancer is one of the most common malignancy in the urinary tract with high recurrence and drug resistance in clinics. Alternative treatments from existing drugs might be a promising strategy. Nitazoxanide (NTZ), an FDA-approved antiprotozoal drug, has got increasingly noticed because of its favorable safety profile and antitumor potential, yet the effects in bladder cancer and underlying mechanisms remain poorly understood. Herein, we find that NTZ induces mitochondrial damage and mitophagy initiation through PINK1-generated phospho-ubiquitin(pS65-Ub) and autophagy receptor-mediated pathway even in the absence of Atg5/Beclin1. Meanwhile, NTZ inhibits lysosomal degradation activity, leading to mitophagy flux impairment at late stage. Mitochondrial reactive oxygen species (ROS) production is critical in this process, as eliminating ROS with N-acetylcysteine (NAC) efficiently inhibits PINK1 signaling-mediated mitophagy initiation and alleviates lysosomal dysfunction. Co-treatment with NTZ and autophagy inhibitor Chloroquine (CQ) to aggravate mitophagy flux impairment promotes NTZ-induced apoptosis, while alleviation of mitophagy flux impairment with ROS scavenger reduced cell death. Moreover, we also discover a similar signaling response in the 3D bladder tumor spheroid after NTZ exposure. In vivo study reveals a significant inhibition of orthotopic bladder tumors with no obvious systemic toxicity. Together, our results uncover the anti-tumor activities of NTZ with the involvement of ROS-mediated mitophagy modulation at different stages and demonstrate it as a potential drug candidate for fighting against bladder tumors.
2021-03-31 | GSE171129 | GEO
Project description:Accumulation of damaged mitochondria is a hallmark of human aging and age-related neurodegenerative pathologies, including Alzheimer’s disease (AD). However, the molecular mechanisms of the impaired mitochondrial homeostasis and their relationship to AD are still elusive. Here we provide evidence that mitophagy, a cellular process mediating selective clearance of dysfunctional mitochondria, is impaired in AD patient hippocampus, in iPSC-derived human neurons and in animal AD models. In C. elegans models of AD, pharmacological stimulation of mitophagy reverses memory impairment through a PINK-1, PDR-1 and DCT-1 dependent pathway. Mitophagy induction diminishes the levels of insoluble amyloid-β (Aβ)1-42 and Aβ1-40 peptide isoforms and prevents cognitive impairment in AD mice by a mechanism involving microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Furthermore, mitophagy abolishes AD-related Tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic Tau nematodes. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis. Interventions that stimulate mitophagy therefore have therapeutic potential in the prevention and treatment of AD.
2018-11-26 | GSE111737 | GEO
Project description:DNA replication is sensitive to damage in the template. To bypass lesions and complete replication, cells activate recombination-mediated (error-free) and translesion synthesis-mediated (error-prone) DNA damage tolerance pathways. Crucial for error-free DNA damage tolerance is template switching, which depends on the formation and resolution of damage-bypass intermediates consisting of sister chromatid junctions. Here we show that a chromatin architectural pathway involving the high mobility group box protein Hmo1 channels replication-associated lesions into the error-free DNA damage tolerance pathway mediated by Rad5 and PCNA polyubiquitylation, while preventing mutagenic bypass and toxic recombination. In the process of template switching, Hmo1 also promotes sister chromatid junction formation predominantly during replication. Its C-terminal tail, implicated in chromatin bending, facilitates the formation of catenations/hemicatenations and mediates the roles of Hmo1 in DNA damage tolerance pathway choice and sister chromatid junction formation. Together, the results suggest that replication-associated topological changes involving the molecular DNA bender, Hmo1, set the stage for dedicated repair reactions that limit errors during replication and impact on genome stability.
2014-01-28 | GSE46260 | GEO
Project description:a mtROS-triggered adaptive pathway that coordinates mitophagic induction, in order to protect cells and tissues exposed to pathophysiological stress-induced damage
2024-11-29 | PXD058451 |
Project description:Mitophagy plays a key cellular role for the programmed or damage induced removal of mitochondria, however, precisely how this process is orchestrated in response to different stimuli still requires investigation. In this work we have screened for regulators of PARKIN-independent mitophagy using an siRNA library targeting 200 proteins containing lipid interacting domains. We identify Cyclin-G associated kinase (GAK) and Protein Kinase C Delta (PRKCD) as novel regulators of PARKIN independent mitophagy. We demonstrate that the kinase activity of both GAK and PRKCD are required for efficient mitophagy in vitro, that PRKCD is present on mitochondria, and that PRKCD is required for ULK1/ATG13 recruitment to early autophagic structures. Importantly, we demonstrate in vivo relevance for both kinases in the regulation of basal mitophagy. Knockdown of GAK homologue (gakh-1) in C.elegans or PRKCD homologues in zebrafish led to significant inhibition of mitophagy, highlighting the evolutionary relevance of these kinases in mitophagy
2021-09-29 | PXD022773 | Pride
Project description:The random-pattern skin flap is a crucial technique in reconstructive surgery and flap necrosis caused by ischemia/reperfusion injury is a major postoperative complication. Herein, we investigated the mechanism of mitophagy induced by Melatonin (ML) and its effect on the survival of skin flaps. Our results demonstrated that ML could activate mitophagy, ameliorate oxidative stress and alleviate apoptosis in TBHP-stimulated human umbilical vein endothelial cells in vitro. Inhibiting ML-induced mitophagy considerably abolished its protective effects. Moreover, knockdown of Parkin by siRNA inhibited ML-induced mitophagy, and subsequently exacerbated oxidative stress and apoptosis. Further study demonstrated that inhibition of AMPK reversed these protective effects of ML and downregulated the expression of TFEB. In the vivo study, ML effectively promoted flap survival by activating mitophagy and subsequently ameliorating oxidative stress and mitigating apoptosis. These results established that ML is a potent agent capable for increasing random-pattern skin flap survival by activating Parkin-dependent mitophagy through the AMPK-TFEB signaling pathway.
2022-06-29 | GSE203609 | GEO
Project description:The selective autophagic degradation of mitochondria via mitophagy is essential for preserving mitochondrial homeostasis and thereby disease maintenance and progression in acute myeloid leukemia. The process of mitophagy is orchestrated by a variety of mitophagy receptors whose interplay in AML is not well understood. Here, we established a dual multiplexed CRISPR screen targeting mitophagy receptors to elucidate redundancies and individual contributions of mitophagy receptors and gain a deeper understanding of the functional interactome governing mitophagy in AML.
2023-07-11 | GSE211073 | GEO