USP18 enhances dengue virus replication by regulating mitochondrial DNA release DOI Creative Commons
Jenn‐Haung Lai,

De‐Wei Wu,

Chien‐Hsiang Wu

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Nov. 17, 2023

Dengue virus (DENV) infection remains a challenging health threat worldwide. Ubiquitin-specific protease 18 (USP18), which preserves the anti-interferon (IFN) effect, is an ideal target through DENV mediates its own immune evasion. However, much of function and mechanism USP18 in regulating replication incompletely understood. In addition, whether regulates merely by causing IFN hyporesponsiveness not clear. present study, using several different approaches to block signaling, including neutralizing antibodies (Abs), anti-IFN receptor Abs, Janus kinase inhibitors alpha beta subunit 1 (IFNAR1)knockout cells, we showed that may regulate IFN-associated IFN-unassociated manners. Localized mitochondria, regulated release mitochondrial DNA (mtDNA) cytosol affect viral replication, mechanisms such as reactive oxygen species (mtROS) production, changes membrane potential, mobilization calcium into 8-oxoguanine glycosylase (OGG1) expression, oxidation fragmentation mtDNA, opening permeability transition pore (mPTP) were involved USP18-regulated mtDNA cytosol. We therefore identify machineries are association with effects.

Language: Английский

Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke DOI Creative Commons
Xin‐Yuan Guan,

Sitong Zhu,

Jin‐Qian Song

et al.

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(5), P. 101522 - 101522

Published: May 1, 2024

Neuroinflammation plays a significant role in ischemic injury, which can be promoted by oxidized mitochondrial DNA (Ox-mtDNA). Cytidine/uridine monophosphate kinase 2 (CMPK2) regulates mtDNA replication, but its neuroinflammation and injury remains unknown. Here, we report that CMPK2 expression is upregulated monocytes/macrophages microglia post-stroke humans mice, respectively. Microglia/macrophage knockdown using the Cre recombination-dependent adeno-associated virus suppresses inflammatory responses brain, reduces infarcts, improves neurological outcomes CX3CR1Cre/ERT2 mice. Mechanistically, limits newly synthesized Ox-mtDNA formation subsequently blocks NLRP3 inflammasome activation microglia/macrophages. Nordihydroguaiaretic acid (NDGA), as inhibitor, discovered to reduce mice prevent primary human monocytes from patients. Thus, these findings identify promising therapeutic target for stroke other brain disorders associated with neuroinflammation.

Language: Английский

Citations

20
Oxidized mitochondrial DNA activates the cGAS-STING pathway in the neuronal intrinsic immune system after brain ischemia-reperfusion injury DOI Creative Commons

Qingsheng Li,

Lingfei Yang,

Kaixin Wang

et al.

Neurotherapeutics, Journal Year: 2024, Volume and Issue: 21(4), P. e00368 - e00368

Published: April 30, 2024

In the context of stroke and revascularization therapy, brain ischemia-reperfusion injury is a significant challenge that leads to oxidative stress inflammation. Central cell's intrinsic immunity cGAS-STING pathway, which typically activated by unusual DNA structures. The involvement oxidized mitochondrial (ox-mtDNA)-an byproduct-in this type neurological damage has not been fully explored. This study among first examine effect ox-mtDNA on innate neurons following injury. Using rat model transient middle cerebral artery occlusion cellular oxygen-glucose deprivation/reoxygenation, we have discovered activates pathway in neurons. Importantly, pharmacologically limiting release into cytoplasm reduces inflammation improves functions. Our findings suggest targeting may be valuable strategy attenuate therapy for acute ischemic stroke.

Language: Английский

Citations

16
Focusing on mitochondria in the brain: from biology to therapeutics DOI Creative Commons

Nanshan Song,

Shuyuan Mei,

Xiang-Xu Wang

et al.

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: April 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

Language: Английский

Citations

14
Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells DOI Creative Commons
Vanessa López-Polo, Máté Maus, Emmanouil Zacharioudakis

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 27, 2024

The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number inflammatory diseases. Here, we report that release mt-dsRNA is general feature senescent cells and critical driver their secretome, known as senescence-associated secretory phenotype (SASP). Inhibition RNA polymerase, sensors RIGI MDA5, or master signaling protein MAVS, all result in reduced expression SASP, while broadly preserving other hallmarks senescence. Moreover, are hypersensitized mt-dsRNA-driven inflammation due levels PNPT1 ADAR1, two proteins for mitigating accumulation potency dsRNA, respectively. We find mitofusin MFN1, but not MFN2, important activation mt-dsRNA/MAVS/SASP axis and, accordingly, genetic pharmacologic MFN1 inhibition attenuates SASP. Finally, within fibrotic aged tissues present foci, polymerase reduces systemic associated In conclusion, uncover mt-dsRNA/MAVS/MFN1 key SASP identify novel therapeutic strategies authors show

Language: Английский

Citations

12
Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives DOI Creative Commons

Dongxue Hu,

Harshini Sheeja Prabhakaran,

Liang Yu

et al.

Critical Care, Journal Year: 2024, Volume and Issue: 28(1)

Published: Sept. 3, 2024

Sepsis is a severe medical condition characterized by systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been growing recognition of the pivotal role played mitochondrial damage driving progression sepsis. Various factors contribute to impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, dynamics change, membrane permeabilization. Damaged mitochondria actively participate shaping milieu triggering key signaling pathways, including those mediated Toll-like receptors, NOD-like cyclic GMP-AMP synthase. Consequently, surge interest developing therapeutic strategies targeting mitigate septic pathogenesis. This review aims delve into intricate underpinning sepsis its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated efficacy preclinical models.

Language: Английский

Citations

12
SS-31 inhibits mtDNA–cGAS–STING signaling to improve POCD by activating mitophagy in aged mice DOI

Yelong Ji,

Yuanyuan Ma,

Yimei Ma

et al.

Inflammation Research, Journal Year: 2024, Volume and Issue: 73(4), P. 641 - 654

Published: Feb. 27, 2024

Language: Английский

Citations

10
Elesclomol-Copper Nanoparticles Overcome Multidrug Resistance in Cancer Cells DOI
Qi Wang, Chung-Hui Huang,

Fajar Setyo Wibowo

et al.

ACS Applied Materials & Interfaces, Journal Year: 2024, Volume and Issue: 16(11), P. 13509 - 13524

Published: March 11, 2024

Elesclomol (ES), a copper-binding ionophore, forms an ES–Cu complex with copper ions (Cu(II)). has been proven to induce mitochondrial oxidative stress and copper-dependent cell death (cuprotosis). However, is poorly water-soluble, its delivery various cancer cells challenge. Herein, we designed d-α-tocopherol polyethylene glycol 1000 succinate/chondroitin sulfate-cholic acid (TPGS/CS–CA)-based micellar nanoparticle for delivering the lines demonstrate efficacy as anticancer agent. The nanoparticles exerted high encapsulation efficiency excellent serum stability. of was evaluated in drug-sensitive (DU145, PC3, A549) drug-resistant (DU145TXR, PC3TXR, A549TXR). results showed that potent activities both lines. Western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), molecular docking suggested not substrate P glycoprotein (P-gp), which efflux transporter potentially causing multidrug resistance (MDR) cells. could bypass P-gp without compromising their activity, indicating they may overcome MDR provide novel therapeutic strategy. Additionally, extracellular matrix nanoparticles-pretreated polarize Raw 264.7 macrophages into M1 phenotype. Therefore, our TPGS/CS–CA-based effective method complex, promising strategy therapy potential immune response stimulation.

Language: Английский

Citations

8
GPR35: from enigma to therapeutic target DOI
Graeme Milligan

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(5), P. 263 - 273

Published: March 30, 2023

Language: Английский

Citations

17
Mitochondrial DNA release and sensing in innate immune responses DOI

Jordyn J. VanPortfliet,

Cole Chute,

Yuanjiu Lei

et al.

Human Molecular Genetics, Journal Year: 2024, Volume and Issue: 33(R1), P. R80 - R91

Published: May 22, 2024

Abstract Mitochondria are pleiotropic organelles central to an array of cellular pathways including metabolism, signal transduction, and programmed cell death. also key drivers mammalian immune responses, functioning as scaffolds for innate signaling, governing metabolic switches required activation, releasing agonists that promote inflammation. Mitochondrial DNA (mtDNA) is a potent immunostimulatory agonist, triggering pro-inflammatory type I interferon responses in host types. Here we review recent advances how mtDNA detected by nucleic acid sensors the system upon release into cytoplasm extracellular space. We discuss interplay between sensing impacts endpoints relevant health disease.

Language: Английский

Citations

5
Measuring Interactions Between Proteins and Small Molecules or Nucleic Acids DOI

Angela Lackner,

Yanfei Qiu,

Emy Armanus

et al.

Current Protocols, Journal Year: 2024, Volume and Issue: 4(7)

Published: July 1, 2024

Interactions between proteins and small molecules or nucleic acids play a pivotal role in numerous biological processes critical for human health are fundamental advancing our understanding of systems. Proteins the workhorses cell, executing various functions ranging from catalyzing biochemical reactions to transmitting signals within body. Small molecules, including drugs metabolites, can modulate protein activity, thereby impacting cellular disease pathways. Similarly, acids, such as DNA RNA, regulate synthesis function through intricate interactions. Understanding these interactions is crucial drug discovery development shed light on gene regulation, transcriptional control, RNA processing, providing insights into genetic diseases developmental disorders. Moreover, studying protein-small molecule protein-nucleic acid enhances comprehension mechanisms. A wide array methods study range cost, sensitivity, materials usage, throughput, complexity. Notably last decade, new techniques have been developed that enhance In this review, we aim summarize state-of-the-art detecting well discuss older still hold value today. © 2024 Wiley Periodicals LLC.

Language: Английский

Citations

5