Non-coding RNA Research, Год журнала: 2025, Номер unknown
Опубликована: Май 1, 2025
Язык: Английский
Nature Cell Biology, Год журнала: 2024, Номер 26(9), С. 1434 - 1446
Опубликована: Июнь 20, 2024
Язык: Английский
Процитировано
83
The EMBO Journal, Год журнала: 2024, Номер 43(6), С. 904 - 930
Опубликована: Фев. 9, 2024
Abstract Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown be inherently pro-inflammatory with emerging cellular roles, including its ability elicit anti-tumour immunity. Nonetheless, how triggers inflammation the regulates this remains poorly defined. We find upon MOMP, many proteins localised either inner or mitochondrial membranes are ubiquitylated in a promiscuous manner. This extensive ubiquitylation serves recruit adaptor molecule NEMO, leading of NF-κB signalling. show disruption integrity through different means engagement similar signalling platform. Therefore, directly controls inflammation, such permeabilised mitochondria initiate
Язык: Английский
Процитировано
16
Translational Neurodegeneration, Год журнала: 2024, Номер 13(1)
Опубликована: Апрель 17, 2024
Abstract Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to physiology pathology of many organs tissues, among which brain is particularly prominent. The demands 20% resting metabolic rate holds highly active mitochondrial activities. Considerable research shows that mitochondria function, while defects induce or exacerbate in brain. In this review, we provide comprehensive advances biology involved functions, well mitochondria-dependent cellular events pathology. Furthermore, various perspectives explored better identify roles neurological diseases neurophenotypes diseases. Finally, therapies discussed. Mitochondrial-targeting therapeutics showing great potentials treatment
Язык: Английский
Процитировано
15
Molecular Cell, Год журнала: 2024, Номер 84(13), С. 2410 - 2422
Опубликована: Июнь 26, 2024
Язык: Английский
Процитировано
11
The Journal of Cell Biology, Год журнала: 2024, Номер 223(3)
Опубликована: Фев. 9, 2024
Mitochondria are perhaps best known as the “powerhouse of cell” for their role in ATP production required numerous cellular activities. have emerged an important signaling organelle. Here, we first focus on pathways mediated by mitochondria-nuclear communication that promote protein homeostasis (proteostasis). We examine mitochondrial unfolded response (UPRmt) C. elegans, which is regulated a transcription factor harboring both mitochondrial- and nuclear-targeting sequence, integrated stress mammals, well regulation chromatin metabolites. In second section, explore mitochondria-to-nuclear innate immunity inflammation. Perhaps related to prokaryotic origin, mitochondria harbor molecules also found viruses bacteria. If these accumulate cytosol, they elicit same immune responses viral or bacterial infection.
Язык: Английский
Процитировано
10
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(8), С. 4187 - 4187
Опубликована: Апрель 10, 2024
The etiology underlying most sporadic Parkinson's' disease (PD) cases is unknown. Environmental exposures have been suggested as putative causes of the disease. In cell models and in animal studies, certain chemicals can destroy dopaminergic neurons. However, mechanisms how these cause death neurons not understood. Several agents are mitochondrial toxins that inhibit complex I electron transport chain. Familial PD genes also encode proteins with important functions mitochondria. Mitochondrial dysfunction respiratory chain, combination presence redox active dopamine molecules cells, will lead to accumulation reactive oxygen species (ROS) Here, propose a mechanism regarding ROS may killing specificity for One rarely considered hypothesis produced by defective mitochondria formation oxidative DNA damage nuclear DNA. Many neuron-specific extraordinary long, ranging size from several hundred kilobases well over megabase. It predictable such long contain large numbers damaged bases, example form 8-oxoguanine (8-oxoG), which major type ROS. These lesions slow down or stall progression RNA polymerase II, term referred transcription stress. Furthermore, ROS-induced mutations, even postmitotic cells impaired mutagenesis loss neuronal integrity, eventually leading during human lifetime.
Язык: Английский
Процитировано
9
Journal of Autoimmunity, Год журнала: 2024, Номер 146, С. 103214 - 103214
Опубликована: Апрель 21, 2024
Язык: Английский
Процитировано
9
Frontiers in Pharmacology, Год журнала: 2024, Номер 15
Опубликована: Июль 25, 2024
Neurodegenerative diseases constitute a global health issue and major economic burden. They significantly impair both cognitive motor functions, their prevalence is expected to rise due ageing societies continuous population growth. Conventional therapies provide symptomatic relief, nevertheless, disease-modifying treatments that reduce or halt neuron death malfunction are still largely unavailable. Amongst the common hallmarks of neurodegenerative protein aggregation, oxidative stress, neuroinflammation mitochondrial dysfunction. Transcription factor nuclear factor-erythroid 2-related 2 (NRF2) constitutes central regulator cellular defense mechanisms, including regulation antioxidant, anti-inflammatory pathways, making it highly attractive therapeutic target for disease modification in disorders. Here, we describe role NRF2 neurodegeneration, review current pharmacological interventions challenges activating pathway, present alternative approaches modification.
Язык: Английский
Процитировано
9
Autophagy, Год журнала: 2025, Номер unknown, С. 1 - 21
Опубликована: Янв. 2, 2025
Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of material. Maintenance lysosomal integrity is essential homeostasis membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes repaired or degraded via lysophagy, during which glycans, exposed on ruptured membranes, recognized by galectins leading to K48- K63-linked poly-ubiquitination (poly-Ub) proteins followed recruitment macroautophagic/autophagic machinery degradation. Linear (M1) poly-Ub, catalyzed linear ubiquitin chain assembly complex (LUBAC) E3 ligase removed OTULIN (OTU deubiquitinase with linkage specificity) exerts important functions in immune signaling survival, but role M1 poly-Ub remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged accumulate an OTULIN- K63 Ub-dependent manner. LMP-induced at damaged contributes lysosome degradation, recruits NFKB (nuclear factor kappa B) modulator IKBKG/NEMO locally activates inhibitor kinase (IKK) trigger activation. Inhibition enhances LMP- OTULIN-regulated death, indicating pro-survival LMP potentially lysophagy. Finally, also occurs primary mouse neurons induced pluripotent stem cell-derived human dopaminergic neurons. Our results reveal novel homeostasis, lysosomes, implications signaling, inflammation death.Abbreviation: ATG: autophagy related; BafA1: bafilomycin A1; CALCOCO2/NDP52: calcium binding coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component nuclear B complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA protein 1-WD repeat FYVE containing 1; DGCs: degradative compartments; DIV: days vitro; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting required transport; FBXO27: F-box 27; GBM: glioblastoma multiforme; IKBKB/IKKB: subunit beta; IKBKG/NEMO: regulatory gamma; IKK: kinase; iPSC: cell; KBTBD7: kelch BTB 7; KO: knockout; LAMP1: associated LCD: death; LGALS: galectin; LMP: permeabilization; LLOMe: ester; LOP: loperamide; LUBAC: LRSAM1: leucine rich sterile alpha motif MAP1LC3/LC3: microtubule 1 light 3; MTOR: mechanistic target rapamycin MTORC1: MTOR NBR1: NBR1 cargo receptor; NFKB/NF-κB: B; NFKBIA/IĸBα: polypeptide gene enhancer B-cells alpha; OPTN: optineurin; ORAS: OTULIN-related autoinflammatory syndrome; OTULIN: OTU specificity; RING: really interesting new gene; RBR: RING-in-between-RING; PLAA: phospholipase A2 activating protein; RBCK1/HOIL-1: RANBP2-type C3HC4-type zinc finger RNF31/HOIP: ring 31; SHARPIN: SHANK RH interactor; SQSTM1/p62: sequestosome SR-SIM: super-resolution-structured illumination microscopy; TAX1BP1: Tax1 TBK1: TANK TH: tyrosine hydroxylase; TNF/TNFα: tumor necrosis factor; TNFRSF1A/TNFR1-SC: TNF receptor superfamily member 1A TRIM16: tripartite 16; Ub: ubiquitin; UBE2QL1: conjugating enzyme E2 QL1; UBXN6/UBXD1: UBX 6; VCP/p97: valosin WIPI2: WD domain, phosphoinositide interacting YOD1: YOD1 deubiquitinase.
Язык: Английский
Процитировано
1
Nature Communications, Год журнала: 2023, Номер 14(1)
Опубликована: Дек. 19, 2023
Abstract NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of proteostasis by promoting autophagosomal clearance aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress are vulnerable to challenges. Moreover, patient with mutation the NEMO-encoding IKBKG gene resulting defective binding linear ubiquitin chains, developed widespread mixed brain proteinopathy, including α-synuclein, tau TDP-43 pathology. amplifies ubiquitylation at α-synuclein aggregates promotes local concentration p62 into foci. In vitro, lowers threshold concentrations required for ubiquitin-dependent phase transition p62. summary, reshapes aggregate surface efficient providing mobile interphase favoring co-condensation
Язык: Английский
Процитировано
21