Autophagy
·
2024
·
IF 14.6
Zhenchong Xiong,Lin Yang,Chao Zhang,Weiling Huang,Wenjing Zhong,Jiarong Yi,Jikun Feng,Xiazi Zouxu,Libing Song,Xi Wang
During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC cells deal with the glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates BC cell survival under glucose-starvation conditions. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, during glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF’s nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key mitophagy regulator, in the mitochondria. Under conditions of glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, the CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF-PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results highlight the prosurvival role of MANF-mediated mitophagy in BC cells during glucose starvation, suggesting MANF as a potential therapeutic target.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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癌症生物学
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DOI
PubMed
高影响因子
Autophagy
·
2024
·
IF 14.6
Juan Yi,He-Ling Wang,Guang Lu,Hailong Zhang,Lina Wang,Zhen-Yu Li,Liming Wang,Yihua Wu,Dajing Xia,Evandro F. Fang,Han-Ming Shen
Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in Caenorhabditis elegans (C. elegans) in a PINK-1-PDR-1-dependent manner. Functionally, spautin-1 is capable of improving associative learning capability in an Alzheimer disease (AD) C. elegans model. In summary, we report a novel function of spautin-1 in promoting mitophagy via the PINK1-PRKN pathway. As deficiency of mitophagy is closely implicated in the pathogenesis of neurodegenerative disorders, the pro-mitophagy function of spautin-1 might suggest its therapeutic potential in neurodegenerative disorders such as AD.Abbreviations: AD, Alzheimer disease; ATG, autophagy related; BafA1, bafilomycin A1; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; COX4/COX IV, cytochrome c oxidase subunit 4; EBSS, Earle’s balanced salt; ECAR, extracellular acidification rate; GFP, green fluorescent protein; IA, isoamyl alcohol; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MMP, mitochondrial membrane potential; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; O/A, oligomycin-antimycin; OCR, oxygen consumption rate; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; p-Ser65-Ub, phosphorylation of Ub at Ser65; TIMM23, translocase of inner mitochondrial membrane 23; TOMM, translocase of outer mitochondrial membrane; USP10, ubiquitin specific peptidase 10; USP13, ubiquitin specific peptidase 13; VAL, valinomycin; YFP, yellow fluorescent protein.
研究领域:
神经科学
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Autophagy
·
2026
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IF 18.6
Xi Chen,Shuhan Liu,Mengqi Jiang,Mingyu Wei,Shuwan Xu,Jin-Yi Lin,Ze-Bo Huang,Pengxin Xie,Jixiang Cao,Hua Yang,Yun Bai,Guang Lu,Ming Cui
Mitochondrial damage is a pivotal driver of myocardial ischemia-reperfusion (MIR) injury. While PRKN (parkin RBR E3 ubiquitin protein ligase), a key E3 ubiquitin ligase in the PINK1 (PTEN induced kinase 1)-PRKN mitophagy pathway, has been extensively studied, its role and mechanisms in acute MIR injury remain incompletely understood. Here, we demonstrated that PRKN exacerbates MIR injury by promoting cardiomyocyte ferroptosis under hypoxia-reoxygenation (H/R) conditions. Mechanistically, PRKN interacts with and mediates the ubiquitination and proteasomal degradation of IMMT/MIC60 (inner membrane mitochondrial protein), a core mitochondrial inner membrane protein essential for cristae architecture and mitochondrial integrity. This disruption of IMMT facilitates lysosomal degradation of GPX4 (glutathione peroxidase 4), a major ferroptosis suppressor, thereby triggering ferroptosis. Consistent with these findings, cardiac-specific immt knockout mice displayed increased susceptibility to MIR injury in vivo. Our findings establish PRKN-driven IMMT degradation as a key pathological mechanism in MIR injury and identify the PRKN-IMMT axis as a potential therapeutic target for cardioprotection. Abbreviations: ATG5, autophagy related 5; ATP, adenosine triphosphate; CCCP, carbonyl cyanide m-chlorophenylhydrazone; CHX, cycloheximide; cKO, cardiomyocyte-specific knockout; CQ, chloroquine; CRISPR, clustered regularly interspaced short palindromic repeats; EF, ejection fraction; Fer-1, ferrostatin-1; FS, fractional shortening; GO, Gene Ontology; GPX4, glutathione peroxidase 4; GST, glutathione S-transferase; gRNA, guide RNA; hiPSC-CMs, human induced pluripotent stem cell-derived cardiomyocytes; H/R, hypoxia-reoxygenation; IF, immunofluorescence; IHC, immunohistochemistry; IMMT/MIC60, inner membrane mitochondrial protein; IP, immunoprecipitation; LoxP, locus of X-overP1; KO, knockout; KR, lysine residues mutated to arginine; MDA, malondialdehyde; MFN2, mitofusin 2; MIR, myocardial ischemia reperfusion; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mtROS, mitochondrial reactive oxygen species; NAC, N-acetylcysteine; OMM, outer mitochondrial membrane; PRKN, parkin RBR E3 ubiquitin protein ligase; RAB7, RAB7, member RAS oncogene family; RNA-seq, RNA sequencing; UB, ubiquitin; WB, western blot; WT, wild-type.
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-19
·
IF 12.6
Ai Li,Liu Zhijuan,Li Ran,Hu Ying,Li Yongxia
Background Lung adenocarcinoma, the most common type of non-small cell lung cancer (NSCLC), is a leading cause of cancer-related deaths globally due to its high incidence and treatment difficulty. Despite recent advancements in treatment methods, the prognosis for patients with advanced disease remains poor. Studies have shown that targeting mitophagy, the selective clearance of damaged mitochondria, can influence the sensitivity of cancer cells to treatment. Methods In this study, we designed and synthesized BPQDs@Lipo-YSA, a novel nanomaterial, aimed at specifically inducing mitophagy in lung adenocarcinoma cells. The nanomaterial was characterized using techniques such as transmission electron microscopy (TEM) and dynamic light scattering (DLS). The ability of BPQDs@Lipo-YSA to induce mitophagy was evaluated using Western blot, immunofluorescence, and flow cytometry. Additionally, in vitro and in vivo experiments were conducted to investigate the impact of BPQDs@Lipo-YSA on lung adenocarcinoma cells through the induction of immunogenic cell death (ICD). Results Experimental results showed that BPQDs@Lipo-YSA effectively induced mitophagy in lung adenocarcinoma cells by activating the PRKN/AKT1 pathway. More importantly, this induction of mitophagy significantly enhanced the cytotoxic effect on lung adenocarcinoma cells. In animal models, BPQDs@Lipo-YSA, by inducing ICD, markedly inhibited tumor growth and extended survival. Conclusions This study reveals the potential value of BPQDs@Lipo-YSA in lung adenocarcinoma treatment through the induction of mitophagy and ICD. This finding provides theoretical and technical support for the development of new therapeutic strategies for lung adenocarcinoma.
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PubMed
高影响因子
Autophagy
·
2021
·
IF 16.016
Yabin Gong,Ning Tang,Panrao Liu,Yingjie Sun,Shanxin Lu,Weiwei Liu,Lei Tan,Cuiping Song,Xusheng Qiu,Ying Liao,Shengqing Yu,Xiufan Liu,Shu-Hai Lin,Chan Ding
Lacking a self-contained metabolism network, viruses have evolved multiple mechanisms for rewiring the metabolic system of their host to hijack the host’s metabolic resources for replication. Newcastle disease virus (NDV) is a paramyxovirus, as an oncolytic virus currently being developed for cancer treatment. However, how NDV alters cellular metabolism is still far from fully understood. In this study, we show that NDV infection reprograms cell metabolism by increasing glucose utilization in the glycolytic pathway. Mechanistically, NDV induces mitochondrial damage, elevated mitochondrial reactive oxygen species (mROS) and ETC dysfunction. Infection of cells depletes nucleotide triphosphate levels, resulting in elevated AMP:ATP ratios, AMP-activated protein kinase (AMPK) phosphorylation, and MTOR crosstalk mediated autophagy. In a time-dependent manner, NDV shifts the balance of mitochondrial dynamics from fusion to fission. Subsequently, PINK1-PRKN-dependent mitophagy was activated, forming a ubiquitin chain with MFN2 (mitofusin 2), and molecular receptor SQSTM1/p62 recognized damaged mitochondria. We also found that NDV infection induces NAD+-dependent deacetylase SIRT3 loss via mitophagy to engender HIF1A stabilization, leading to the switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Overall, these studies support a model that NDV modulates host cell metabolism through PINK1-PRKN-dependent mitophagy for degrading SIRT3.Abbreviations: AMPK: AMP-activated protein kinase; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECAR: extracellular acidification rate; hpi: hours post infection LC-MS: liquid chromatography-mass spectrometry; mito-QC: mCherry-GFP-FIS1[mt101–152]; MFN2: mitofusin 2; MMP: mitochondrial membrane potential; mROS: mitochondrial reactive oxygen species; MOI: multiplicity of infection; 2-NBDG: 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxyglucose; NDV: newcastle disease virus; OCR: oxygen consumption rate; siRNA: small interfering RNA; SIRT3: sirtuin 3; TCA: tricarboxylic acid; TCID50: tissue culture infective doses.
研究领域:
病毒学
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细胞生物学
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分子生物学
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肿瘤学
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代谢
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DOI
PubMed
高影响因子
Autophagy
·
2022
·
IF 13.391
Yuhua Zhang,Qiaojun Fang,Hongfeng Wang,Jieyu Qi,Shan Sun,Menghui Liao,Yunhao Wu,Yangnan Hu,Pei Jiang,Cheng Cheng,Xiaoyun Qian,Mingliang Tang,Wei Cao,Shang Xiang,Chen Zhang,Jianming Yang,Xia Gao,Zheng Ying,Renjie Chai
Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted mitophagy through transcriptional inhibition of Pink1 expression, the key initiator of mitophagy. Moreover, we found that neomycin impaired mitophagy by inducing ATF3 expression. Importantly, treatment with a mitophagy activator could rescue neomycin-treated hair cells by increasing mitophagy, indicating that genetic modulation or drug intervention in mitophagy may have therapeutic potential for aminoglycoside-induced hearing loss.Abbreviations: AAV: adeno-associated virus; ABR: auditory brainstem response; ATF3: activating transcription factor 3; ATOH1/MATH1: atonal bHLH transcription factor 1; BafA1: bafilomycin A1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; COX4I1/COXIV: cytochrome c oxidase subunit 4I1; CTBP2/RIBEYE: C-terminal binding protein 2; DFP: deferiprone; EGFP: enhanced green fluorescent protein; FOXO3: forkhead box O3; GRIA2/GLUR2: glutamate receptor, ionotropic, AMPA2 (alpha 2); HC: hair cell; HSPD1/HSP60: heat shock protein 1 (chaperonin); IHC: inner hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MYO7A: myosin VIIA; OPTN: optineurin; OMM: outer mitochondrial membrane; PRKN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RT-qPCR: real-time quantitative polymerase chain reaction; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; TUNEL: Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling; USP30: ubiquitin specific peptidase 30; XBP1: X-box binding protein 1.
研究领域:
细胞生物学
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神经科学
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耳科学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Xiaoyuan Yan,Na An,Zeying Zhang,Qiujing Qiu,Di Yang,Penggong Wei,Xiyue Zhang,Lihong Qiu,Jiajie Guo
Background In bone tissue engineering (BTE), cell-laden scaffolds offer a promising strategy for repairing bone defects, particularly when host cell regeneration is insufficient due to age or disease. Exogenous stem cell-based BTE requires bioactive factors to activate these cells. Graphene oxide quantum dots (GOQDs), zero-dimensional derivatives of graphene oxide, have emerged as potential osteogenic nanomedicines. However, constructing biological scaffolds with GOQDs and elucidating their biological mechanisms remain critical challenges.Methods We utilized GOQDs with a particle size of 10 nm, characterized by a surface rich in C–O–H and C–O–C functional groups. We developed a gelatin methacryloyl (GelMA) hydrogel incorporated with GOQDs-treated dental pulp stem cells (DPSCs). These constructs were transplanted into rat calvarial bone defects to estimate the effectiveness of GOQDs-induced DPSCs in repairing bone defects while also investigating the molecular mechanism underlying GOQDs-induced osteogenesis in DPSCs.Results GOQDs at 5 μg/mL significantly enhanced the osteogenic differentiation of DPSCs without toxicity. The GOQDs-induced DPSCs showed active osteogenic potential in three-dimensional cell culture system. In vivo, transplantation of GOQDs-preactivated DPSCs/GelMA composite effectively facilitated calvarial bone regeneration. Mechanistically, GOQDs stimulated mitophagy flux through the phosphatase-and-tensin homolog-induced putative kinase 1 (PINK1)/Parkin E3 ubiquitin ligase (PRKN) pathway. Notably, inhibiting mitophagy with cyclosporin A prevented the osteogenic activity of GOQDs.Conclusion This research presents a well-designed bionic GOQDs/DPSCs/GelMA composite scaffold and demonstrated its ability to promote bone regeneration by enhancing mitophagy. These findings highlight the significant potential of this composite for application in BTE and underscore the crucial role of mitophagy in promoting the osteogenic differentiation of GOQDs-induced stem cells.
研究领域:
生物医学工程
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组织工程
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纳米技术
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干细胞生物学
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材料科学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Juanjuan Zhu,Wenmin Tang,Xian Wu,Mao Mu,Quan Zhang,Xueke Zhao
Tectorigenin (TEC) as a plant extract has the advantage of low side effects on metabolic dysfunction-associated steatohepatitis (MASH) treatment. Our previous study have shown that tRNA-derived RNA fragments (tRFs) associated with autophagy and pyroptosis in MASH, but whether TEC can mitigate MASH through tRFs-mediated mitophagy is not fully understood. This study aims to investigate whether TEC relies on tRFs to adjust the crosstalk of hepatocyte mitophagy with pyroptosis in MASH. Immunofluorescence results of PINK1 and PRKN with MitoTracker Green-labeled mitochondria verified that TEC enhanced mitophagy. Additionally, TEC inhibited pyroptosis, as reflected by the level of GSDME, NLRP3, IL-1β, and IL-18 decreased after TEC treatment, while the effect of pyroptosis inhibition by TEC was abrogated by Pink1 silencing. We found that the upregulation expression of tRF-3040b caused by MASH was suppressed by TEC. The promotion of mitophagy and the suppression of pyroptosis induced by TEC were abrogated by tRF-3040b mimics. TEC reduced lipid deposition, inflammation, and pyroptosis, and promoted mitophagy in mice, but tRF-3040b agomir inhibited these effects. In summary, our findings provided that TEC significantly reduced the expression of tRF-3040b to enhance mitophagy, thereby inhibiting pyroptosis in MASH. We elucidated a powerful theoretical basis and provided safe and effective potential drugs for MASH with the prevention and treatment.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
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