Emerging views of mitophagy in immunity and autoimmune diseases

Autophagy, Год журнала: 2019, Номер 16(1), С. 3 - 17

Опубликована: Апрель 5, 2019

Mitophagy is a vital form of autophagy for selective removal dysfunctional or redundant mitochondria. Accumulating evidence implicates elimination mitochondria as powerful means employed by to keep the immune system in check. The process mitophagy may restrict inflammatory cytokine secretion and directly regulate mitochondrial antigen presentation cell homeostasis. In this review, we describe distinctive pathways mammalian highlight recent advances relevant its function immunity. addition, further discuss direct indirect linking inflammation autoimmunity underlying pathogenesis autoimmune diseases including bowel (IBD), systemic lupus erythematosus (SLE) primary biliary cirrhosis (PBC).Abbreviations: AICD: activation induced death; AIM2: absent melanoma 2; ALPL/HOPS: alkaline phosphatase, biomineralization associated; AMA: anti-mitochondrial antibodies; AMFR: autocrine motility factor receptor; ATG: autophagy-related; BCL2L13: BCL2 like 13; BNIP3: interacting protein 3; BNIP3L/NIX: 3 like; CALCOCO2/NDP52: calcium binding coiled-coil domain CARD: caspase recruitment containing; CASP1: 1; CD: Crohn disease; CGAS: cyclic GMP-AMP synthase; CXCL1: C-X-C motif chemokine ligand DEN: diethylnitrosamine; DLAT/PDC-E2: dihydrolipoamide S-acetyltransferase; DNM1L/Drp1: dynamin 1 ESCRT: endosomal sorting complexes required transport; FKBP8: FKBP prolyl isomerase 8; FUNDC1: Fun14 containing GABARAP: GABA type A receptor-associated protein; HMGB1: high mobility group box HPIV3: human parainfluenza virus IBD: diseases; IEC: intestinal epithelial cell; IFN: interferon; IL1B/IL-1β: interleukin beta; iNK: invariant natural killer; IRGM: immunity related GTPase M; LIR: LC3-interacting region; LPS: lipopolysaccharide; LRRK2: leucine rich repeat kinase MAP1LC3/LC3: microtubule associated light chain MARCH5: membrane ring-CH-type finger 5; MAVS: antiviral signaling MDV: mitochondria-derived vesicle; MFN1: mitofusin MHC: major histocompatibility complex; MIF: macrophage migration inhibitory factor; mtAP: presentation; mtDNA: DNA; MTOR: mechanistic target rapamycin kinase; mtROS: ROS; MUL1: E3 ubiquitin ligase NBR1: NBR1 cargo NFKB/NF-ĸB: nuclear kappa B subunit; NK: NLR: NOD-like NLRC4: NLR family CARD 4; NLRP3: pyrin OGDH: oxoglutarate dehydrogenase; OMM: outer membrane; OPTN: optineurin; ox: oxidized; PARK7: Parkinsonism deglycase; PBC: cirrhosis; PEX13: peroxisomal biogenesis PHB/PHB1: prohibitin; PHB2: prohibitin PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit PINK1: PTEN PLEKHM1: pleckstrin homology RUN M1; PRKN/PARK2: parkin RBR ligase; RAB: member RAS oncogene family; RHEB: Ras homolog: mTORC1 binding; RIPK2: receptor serine/threonine RLR: DDX58/RIG-I ROS: reactive oxygen species; SBD: small bile ducts; SLC2A1/GLUT1: solute carrier 2 SLE: erythematosus; SMURF1: SMAD specific SQSTM1/p62: sequestosome TAX1BP1: Tax1 TCR: T TFAM: transcription A: mitochondrial; Th17: helper 17; TLR9: toll 9; TMEM173/STING: transmembrane 173; TNF/TNF-α: tumor necrosis Ub: ubiquitin; UC: ulcerative colitis; ULK1: unc-51 activating WIPI: WD domain: phosphoinositide interacting; ZFYVE1/DFCP1: zinc FYVE-type 1.

Язык: Английский

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Mitophagy pathways in health and disease

The Journal of Cell Biology, Год журнала: 2020, Номер 219(11)

Опубликована: Авг. 14, 2020

Mitophagy is an evolutionarily conserved process involving the autophagic targeting and clearance of mitochondria destined for removal. Recent insights into complex nature overlapping pathways regulating mitophagy illustrate mitophagy's essential role in maintaining health mitochondrial network. In this review, we highlight recent studies that have changed way understood, from initiation through lysosomal degradation. We outline numerous mitophagic receptors triggers, with a focus on basal physiologically relevant cues, offering insight why they lead to also explore how maintains homeostasis at organ system levels loss may play diverse group diseases, including cardiovascular, metabolic, neurodegenerative diseases. With disrupted affecting such wide array physiological processes, deeper understanding modulate could provide avenues therapies.

Язык: Английский

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Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis

Cells, Год журнала: 2021, Номер 11(1), С. 30 - 30

Опубликована: Дек. 23, 2021

Mitochondria are multifunctional subcellular organelles essential for cellular energy homeostasis and apoptotic cell death. It is, therefore, crucial to maintain mitochondrial fitness. Mitophagy, the selective removal of dysfunctional mitochondria by autophagy, is critical regulating quality control in many physiological processes, including development differentiation. On other hand, both impaired excessive mitophagy involved pathogenesis different ageing-associated diseases such as neurodegeneration, cancer, myocardial injury, liver disease, sarcopenia diabetes. The best-characterized pathway PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent pathway. However, Parkin-independent pathways also reported mediate tethering autophagy apparatuses, directly activating (mitophagy receptors E3 ligases). In addition, existence molecular mechanisms than PINK1-mediated phosphorylation Parkin activation was proposed. adenosine5′-monophosphate (AMP)-activated protein (AMPK) emerging a key player metabolism mitophagy. Beyond its involvement fission autophagosomal engulfment, interplay with PINK1–Parkin reported. Here, we review recent advances elucidating canonical signaling that regulate mitophagy, focusing on early role spatial specificity AMPK/ULK1 axis.

Язык: Английский

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Advances in Understanding of the Role of Lipid Metabolism in Aging

Cells, Год журнала: 2021, Номер 10(4), С. 880 - 880

Опубликована: Апрель 13, 2021

During aging, body adiposity increases with changes in the metabolism of lipids and their metabolite levels. Considering lipid metabolism, excess increased lipotoxicity leads to various age-related diseases, including cardiovascular disease, cancer, arthritis, type 2 diabetes, Alzheimer’s disease. However, multifaceted nature complexities make it difficult delineate its exact mechanism role during aging. With advances genetic engineering techniques, recent studies have demonstrated that are associated aging diseases. Lipid accumulation impaired fatty acid utilization organs pathophysiological phenotypes Changes adipokine levels contribute by modulating systemic inflammation. Advances lipidomic techniques identified profiles Although remains unclear how is regulated or metabolites impact evidence suggests a dynamic for as active participants signaling pathways regulators gene expression. This review describes our understanding established findings approaches.

Язык: Английский

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Mitophagy and Oxidative Stress: The Role of Aging

Antioxidants, Год журнала: 2021, Номер 10(5), С. 794 - 794

Опубликована: Май 17, 2021

Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by selective type macroautophagy, named mitophagy. One the main factors contributing to aging oxidative stress, one early responses excessive reactive oxygen species (ROS) production induction mitophagy remove damaged mitochondria. However, mitochondrial damage caused at least in part chronic stress can accumulate, autophagic mitophagic pathways become overwhelmed. The imbalance delicate equilibrium among mitophagy, ROS start, drive, or accelerate process, either physiological aging, pathological age-related conditions, such as Alzheimer’s Parkinson’s diseases. It remains be determined which prime mover this imbalance, i.e., whether it that initiates dysregulation thus activating vicious circle leads reduced ability mitochondria, an alteration regulation leading

Язык: Английский

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FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner

Journal of Advanced Research, Год журнала: 2023, Номер 55, С. 45 - 60

Опубликована: Фев. 23, 2023

Liver fibrosis is a life-threatening pathological anomaly which usually evolves into advanced liver cirrhosis and hepatocellular carcinoma although limited therapeutic option readily available. FUN14 domain containing 1 (FUNDC1) mitophagy receptor with little information in fibrosis. This study was designed to examine the role for FUNDC1 carbon tetrachloride (CCl4)-induced injury. GEO database analysis subsequent validation of biological processes including western blot, immunofluorescence, co-immunoprecipitation were applied clarify regulatory on ferroptosis. Our data revealed elevated levels tissues patients fibrotic injury CCl4-challenged mice. deletion protected against CCl4-induced hepatic anomalies Moreover, ameliorated ferroptosis vivo vitro. Mechanically, interacted glutathione peroxidase (GPx4), selenoenzyme neutralize lipid hydroperoxides ferroptosis, via its 96–133 amino acid facilitate GPx4 recruitment mitochondria from cytoplasm. entered through mitochondrial protein import system-the translocase outer membrane/translocase inner membrane (TOM/TIM) complex, prior degradation mainly along ROS-induced damaged mitochondria, resulting hepatocyte Taken together, our favored that promoted binding translocation TOM/TIM where degraded by trigger Targeting may be promising approach

Язык: Английский

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Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth

Metabolism, Год журнала: 2024, Номер 154, С. 155811 - 155811

Опубликована: Фев. 2, 2024

Язык: Английский

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Double deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates acetaminophen-induced liver injury in mice

Redox Biology, Год журнала: 2019, Номер 22, С. 101148 - 101148

Опубликована: Фев. 20, 2019

Mitochondria damage plays a critical role in acetaminophen (APAP)-induced necrosis and liver injury.Cells can adapt protect themselves by removing damaged mitochondria via mitophagy.PINK1-Parkin pathway is one of the major pathways that regulate mitophagy but its APAP-induced injury still elusive.We investigated PINK1-Parkin hepatocyte mice.Wild-type (WT), PINK1 knockout (KO), Parkin KO, double KO (DKO) mice were treated with APAP for different time points.Liver was determined measuring serum alanine aminotransferase (ALT) activity, H&E staining as well TUNEL tissues.Tandem fluorescent-tagged inner mitochondrial membrane protein Cox8 (Cox8-GFP-mCherry) be used to monitor based on pH stability GFP mCherry fluorescent proteins.We overexpressed Cox8-GFP-mCherry mouse livers tail vein injection an adenovirus Cox8-GFP-mCherry.Mitophagy assessed confocal microscopy puncta, electron (EM) analysis mitophagosomes western blot proteins.Parkin improved survival after treatment although levels ALT not significantly among WT mice.We only found mild defects or APAP, could due other functions independent mitophagy.In contrast, impaired DKO mice.PINK1-Parkin had further elevated increased mortality administration.In conclusion, our results demonstrated signaling injury.

Язык: Английский

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Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls

Acta Pharmaceutica Sinica B, Год журнала: 2021, Номер 11(12), С. 3740 - 3755

Опубликована: Сен. 30, 2021

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which safe at therapeutic doses but can cause severe liver injury even failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As result, this clinically relevant frequently to study mechanisms drug-induced more so test potential interventions. However, complexity requires thorough understanding pathophysiology obtain valid results mechanistic information that translatable clinic. many studies using are flawed, jeopardizes scientific clinical relevance. purpose review provide framework where mechanistically sound data be obtained. discussion provides insight into how it including critical roles drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy sterile inflammatory response. In addition, most made mistakes when discussed. Thus, considering these recommendations studying will facilitate discovery

Язык: Английский

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Mitochondrial Dysfunction and Chronic Liver Disease

Current Issues in Molecular Biology, Год журнала: 2022, Номер 44(7), С. 3156 - 3165

Опубликована: Июль 9, 2022

Mitochondria are generally considered the powerhouse of cell, a small subcellular organelle that produces most cellular energy in form adenosine triphosphate (ATP). In addition, mitochondria involved various biological functions, such as biosynthesis, lipid metabolism, oxidative phosphorylation, cell signal transduction, and apoptosis. Mitochondrial dysfunction is manifested different aspects, like increased mitochondrial reactive oxygen species (ROS), DNA (mtDNA) damage, (ATP) synthesis disorder, abnormal mitophagy, well changes morphology structure. related to occurrence development chronic liver diseases, including hepatocellular carcinoma (HCC), viral hepatitis, drug-induced injury (DILI), alcoholic fatty (AFL), non-alcoholic (NAFL). this review, we summarize discuss role mechanisms disease, focusing on discussing some latest studies disease.

Язык: Английский

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