Autophagosome biogenesis: From membrane growth to closure

The Journal of Cell Biology, Journal Year: 2020, Volume and Issue: 219(6)

Published: May 1, 2020

Autophagosome biogenesis involves de novo formation of a membrane that elongates to sequester cytoplasmic cargo and closes form double-membrane vesicle (an autophagosome). This process has remained enigmatic since its initial discovery >50 yr ago, but our understanding the mechanisms involved in autophagosome increased substantially during last 20 yr. Several key questions do remain open, however, including, What determines site nucleation? is origin lipid composition membrane? How sequestration regulated under nonselective selective types autophagy? review provides insight into core molecular underlying biogenesis, with specific emphasis on modeling events, highlights recent conceptual advances field.

Language: Английский

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Mitophagy pathways in health and disease

The Journal of Cell Biology, Journal Year: 2020, Volume and Issue: 219(11)

Published: Aug. 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.

Language: Английский

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Mitochondrial metabolism regulates macrophage biology

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 297(1), P. 100904 - 100904

Published: June 23, 2021

Mitochondria are critical for regulation of the activation, differentiation, and survival macrophages other immune cells. In response to various extracellular signals, such as microbial or viral infection, changes mitochondrial metabolism physiology could underlie corresponding state macrophage activation. These include alterations oxidative metabolism, membrane potential, tricarboxylic acid (TCA) cycling, well release reactive oxygen species (mtROS) DNA (mtDNA) transformation ultrastructure. Here, we provide an updated review how in metabolites fumarate, succinate, itaconate coordinate guide activation distinct cellular states, thus clarifying vital link between mitochondria immunity. We also discuss disease settings, dysfunction stress contribute dysregulation inflammatory response. Therefore, a source dynamic signals that regulate biology fine-tune responses. Macrophages safeguard tissue homeostasis To exert these varied functions, show high plasticity adopt different states according stimulus signals. The Th1 cytokine interferon-γ (IFNγ) together with Toll-like receptor (TLR) ligands, including lipopolysaccharide (LPS), promotes classically activated proinflammatory (commonly known M1-like macrophages), which secrete cytokines interleukin-6 (IL-6) IL-1β induce responses fight against infection; generate highly nitrogen intermediates gain efficient microbicidal tumoricidal activities; increase major histocompatibility complex (MHC)-I/II, CD80, CD86 expression (1Orecchioni M. Ghosheh Y. Pramod A.B. Ley K. Macrophage polarization: Different gene signatures M1(LPS+) vs. M2(LPS-) alternatively macrophages.Front. Immunol. 2019; 10: 1084Crossref PubMed Scopus (239) Google Scholar, 2Shapouri-Moghaddam A. Mohammadian S. Vazini H. Taghadosi Esmaeili S.A. Mardani F. Seifi B. Mohammadi Afshari J.T. Sahebkar plasticity, polarization, function health disease.J. Cell Physiol. 2018; 233: 6425-6440Crossref (843) Scholar). However, continuous excessive may lead sustained inflammation accessory damage (3Sica Mantovani vivo veritas.J. Clin. Invest. 2012; 122: 787-795Crossref (3169) can be by stimulating factors states. For example, Th2 interleukin-4 (IL-4) IL-13 alternative M2-like activation) 4Gordon Martinez F.O. Alternative macrophages: Mechanism functions.Immunity. 2010; 32: 593-604Abstract Full Text PDF (2409) attenuate Th1/M1-driven inflammation, facilitate repair remodeling, Th2-driven pathologies, asthma helminth infections. Such express range specific scavenging molecules, mannose galactose receptors enzymes arginase (5Xue J. Schmidt S.V. Sander Draffehn Krebs W. Quester I. De Nardo D. Gohel T.D. Emde Schmidleithner L. Ganesan Nino-Castro Mallmann M.R. Labzin Theis et al.Transcriptome-based network analysis reveals spectrum model human activation.Immunity. 2014; 40: 274-288Abstract (1022) 6Natoli G. Monticelli activation: Glancing into diversity.Immunity. 175-177Abstract (0) kinds environmental stimuli, populations will change their shift phenotype, allow them actively participate resolution progression (7Mosser D.M. Edwards J.P. Exploring full activation.Nat. Rev. 2008; 8: 958-969Crossref (5333) Recent studies indicate shifts (mtROS), cycle, ultrastructure, potential. drive breaks rewire TCA cycle influencing enzymes, IDH (isocitrate dehydrogenase) SDH (succinate dehydrogenase), resulting elevations citrate respectively. augment glycolysis (also Warburg Effect). contrast, IL-4-activated maintain unbroken preferentially engage phosphorylation (OXPHOS) fatty oxidation (FAO) ATP production. OXPHOS is fueled acids glutamine, activates peroxisome proliferator-activated receptor-γ (PPARγ) mediate induction genes regulating functions (8Batista-Gonzalez Vidal R. Criollo Carreño L.J. New insights on role lipid metabolic reprogramming 2993Crossref (5) Glucose oxidation, induced mTORC2-IRF4 signaling axis, contributes IL-4 mediated (9Huang S.C. Smith A.M. Everts Colonna Pearce E.L. Schilling J.D. E.J. Metabolic axis essential 2016; 45: 817-830Abstract (238) Shifts closely linked this review, mechanistic underpinnings differential they biology. type I usually starts when sentinel cells pathogen-associated molecular patterns (PAMPs), cell wall components, nucleic acids, lipoproteins. undergoes during At center mitochondria, not only supplies energy but involved biosynthesis maintaining redox serves platform innate immunological pathways (10Tur Vico T. Lloberas Zorzano Celada mitochondria: A interplay signaling, functional activity.Adv. 2017; 133: 1-36Crossref (21) alter activity electron transport chain (ETC) influence multiple aspects metabolism. They upregulation glucose glutamine utilization toward anabolic pathways. Aerobic glycolysis, LPS-stimulated mammalian target rapamycin (mTOR) hypoxia-inducible factor 1-alpha (HIF-1α) (11Cheng Quintin Cramer R.A. Shepardson K.M. Saeed Kumar V. Giamarellos-Bourboulis Martens J.H. Rao N.A. Aghajanirefah Manjeri G.R. Li Ifrim D.C. Arts R.J. van der Veer B.M. al.mTOR- HIF-1α-mediated aerobic basis trained immunity.Science. 345: 1250684Crossref (741) Scholar), upregulated production while repressed through mechanisms, two cycle. One break results from decreased IDH, enzyme converts α-ketoglutarate (α-KG), allowing cumulation citrate, redirected generating itaconic withdrawn (12Jha A.K. Huang Sergushichev Lampropoulou Ivanova Loginicheva E. Chmielewski Stewart Ashall Driggers E.M. Artyomov M.N. Network integration parallel transcriptional data modules polarization.Immunity. 2015; 42: 419-430Abstract (737) second occurs after novel pathway termed aspartate-arginosuccinate shunt, produce arginine support nitric oxide (NO) NO generated inducible synthase (iNOS) hamper respiration impair anti-inflammatory repolarization, LPS plus IFNγ stimulation inhibit FAO (13Eisner Picard Hajnóczky Mitochondrial dynamics adaptive maladaptive responses.Nat. Biol. 20: 755-765Crossref (161) Consistently, suppressed LPS-tolerant macrophages, no longer able result long-term exposure (14Butcher S.K. O'Carroll C.E. Wells C.A. Carmody tolerance training restimulation 9: 933Crossref (28) Note some characteristics tolerant resemble M2 it would oversimplification equate differ many have more demand glucose, compared rely β-oxidation. increased necessary engaging derived lipolysis triglycerides (15Huang O'Sullivan Nascimento Beatty Love-Gregory Lam W.Y. O'Neill C.M. Yan C. Du Abumrad Urban Jr., J.F. al.Cell-intrinsic lysosomal macrophages.Nat. 15: 846-855Crossref (528) This adaptation proportion NADH FADH2 (nicotinamide adenine dinucleotide flavin dinucleotide) feeds ETC (16Van den Bossche Baardman Otto Velden Neele A.E. Berg S.M. Luque-Martin Chen H.J. Boshuizen M.C. Ahmed Hoeksema M.A. de Vos A.F. Winther M.P. prevents repolarization macrophages.Cell Rep. 17: 684-696Abstract (262) Inhibition sufficient repress phenotype programs (17Johnson A.R. Qin Cozzo A.J. Freemerman M.J. Zhao Sampey B.P. Milner J.J. Beck Damania Rashid N. Galanko J.A. Lee D.P. Edin M.L. Zeldin al.Metabolic protein 1 (FATP1) regulates potential adipose inflammation.Mol. Metab. 5: 506-526Crossref (58) Similar PAMPs, self-encoded damage-associated (DAMPs) N-formyl peptides (NFP) detected leading (18Dela Cruz C.S. Kang associated chronic diseases.Mitochondrion. 41: 37-44Crossref (53) class DAMPs represented oxidized naturally occurring phospholipids, 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (PAPC) collectively oxPAPC, resides membranes lipoproteins PAMPs optimal (19Freigang phospholipids.Eur. 46: 1818-1825Crossref (39) 20Chu L.H. Indramohan Ratsimandresy Gangopadhyay Morris E.P. Monack Dorfleutner Stehlik phospholipid oxPAPC protects septic shock targeting non-canonical inflammasome Commun. 996Crossref (65) OxPAPC modulates upregulating utilization, anaplerotic carbon replenishes intermediates, cytoplasmic levels oxaloacetate (OAA). HIF-1α key transcription numerous proglycolytic IL-1β, its stability tightly regulated OAA, prolyl hydroxylases (PHDs) (21Koivunen P. Hirsilä Remes Hassinen I.E. Kivirikko K.I. Myllyharju (HIF) citric intermediates: Possible links stabilization HIF.J. Chem. 2007; 282: 4524-4532Abstract (361) treatment stabilizes potentiates presence intact (22Di Gioia Spreafico Springstead J.R. Mendelson M.M. Joehanes Levy Zanoni Endogenous phospholipids reprogram boost hyperinflammation.Nat. 2020; 21: 42-53Crossref (33) been shown powerful roles effects pathways, factors, chromatin (23Novakovic Habibi Wang S.Y. R.J.W. Davar Megchelenbrink Kim Kuznetsova Kox Zwaag Matarese Heeringen S.J. Janssen-Megens Sharifi al.β-Glucan reverses epigenetic LPS-induced tolerance.Cell. 167: 1354-1368.e1314Abstract (206) 24Baardman Licht Van Metabolic-epigenetic crosstalk activation.Epigenomics. 7: 1155-1164Crossref 25Noe Mitchell Tricarboxylic control effector phenotypes.J. Leukoc. 106: 359-367Crossref Because disruptions stimulated LPS, certain itaconate, succinate accumulate play important (Fig. 1). Citrate nuclear-cytosolic pool acetyl coenzyme (Acetyl-CoA), substrate histone acetylation synthesis, both (26Wellen K.E. Hatzivassiliou Sachdeva U.M. Bui T.V. Cross Thompson C.B. ATP-citrate lyase acetylation.Science. 2009; 324: 1076-1080Crossref (1258) 27Covarrubias Aksoylar H.I. Yu Snyder N.W. Worth Iyer S.S. Ben-Sahra Byles Polynne-Stapornkul Espinosa E.C. Lamming Manning B.D. Zhang Blair I.A. al.Akt-mTORC1 Acly integrate input activation.Elife. 5e11612Crossref (196) 28Langston P.K. Nambu Jung Shibata Lei Xu Doan M.T. Jiang MacArthur Gao X. Kong Chouchani E.T. Locasale J.W. al.Glycerol phosphate shuttle GPD2 1186-1195Crossref (37) 29Williams N.C. L.A.J. intermediate immunity inflammation.Front. 141Crossref (150) exported carrier (CIC), followed cleavage acetyl-CoA (ACLY) cytosol. Acetyl-CoA TNFα prostaglandin has fuel at LPS-inducible M1 respectively (27Covarrubias Oxaloacetate needed ROS providing NADPH (30Infantino Pierri C.L. Iacobazzi routes inflammation: therapeutic target.Curr. Med. 26: 7104-7116Crossref (15) addition, acted aconitase 2 (ACO2) cis-aconitate, further decarboxylated synthesis (31Kim Seo H.M. Bhatia Song H.S. Jeon J.M. Choi K.Y. Yoon Y.G. Yang Y.H. Production whole-cell bioconversion cis-aconitate decarboxylase (cadA) Escherichia coli.Sci. 39768Crossref Itaconate acts negative regulator inhibiting (32Lampropoulou Bambouskova Nair Vincent E.E. Cervantes-Barragan Ma Griss Weinheimer C.J. Khader Randolph G.J. Jones R.G. al.Itaconate inhibition dehydrogenase remodeling inflammation.Cell 24: 158-166Abstract findings endow transported crucial via ROS, NO, prostaglandin, (33Infantino Convertini Cucci Panaro Di Noia Calvello Palmieri carrier: new player inflammation.Biochem. 2011; 438: 433-436Crossref (208) 34O'Neill L.A. signalling.Biochem. e5-e6Crossref (64) Scholar) Itaconate, produced matrix metabolite immune-responsive (IRG1) (35Degrandi Hoffmann Beuter-Gunia Pfeffer cytokine-induced IRG1 associates mitochondria.J. Interferon Cytokine Res. 29: 55-67Crossref (60) 36Michelucci Cordes Ghelfi Pailot Reiling Goldmann O. Binz Wegner Tallam Rausell Buttini Linster Medina Balling Hiller Immune-responsive catalyzing production.Proc. Natl. Acad. Sci. U. 2013; 110: 7820-7825Crossref (418) critically growing number reducing 37Mills Ryan D.G. Prag H.A. Dikovskaya Menon Zaslona Z. Jedrychowski Costa A.S.H. Higgins Hams Szpyt Runtsch King M.S. McGouran Fischer Nrf2 alkylation KEAP1.Nature. 556: 113-117Crossref (446) influences suppressing SDH, Complex II ETC. leads accumulation decreases consumption 38O'Neill Itaconate: poster child function.Nat. 19: 273-281Crossref Furthermore, electrophile alkylate cysteine residues KEAP1 (37Mills electrophilic sensor normally drives ubiquitination degradation NF-E2–related (Nrf2) (39Yamamoto Kensler T.W. Motohashi KEAP1-NRF2 system: thiol-based sensor-effector apparatus homeostasis.Physiol. 98: 1169-1203Crossref (386) newly synthesized accumulate, translocate nucleus, initiate antioxidant program. way, actions suggest Nrf2-dependent (40Sun K.A. Meliton A.Y. Woods P.S. Kimmig L.M. Cetin-Atalay Hamanaka R.B. Mutlu G.M. required particulate matter-induced NRF2 response.Elife. 9e54877Crossref (14) reported properties derivatives IκBζ activating 3, selective TLR-inducible (41Bambouskova Gorvel Johnson Korenfeld Mathyer M.E. Duncan Bregman Keskin Santeford Apte R.S. al.Electrophilic IκBζ-ATF3 axis.Nature. 501-504Crossref (202) Finally, there feedback loop interferon signaling. Type interferons enhance Irg1 generation limits repressing cytokines, IL1-β IL6 42Yu X.H. D.W. Zheng X.L. Tang C.K. An emerging determinant macrophages.Immunol. 97: 134-141PubMed It accumulates enhances production, acting signal activate (43Tannahill Curtis Adamik Palsson-McDermott McGettrick Goel Frezza Bernard N.J. Kelly Foley N.H. Gardet Tong Jany Corr al.Succinate induces HIF-1α.Nature. 496: 238-242Crossref (1584) 44Mills Logan Varma Bryant Tourlomousis Däbritz J.H.M. Gottlieb Latorre McManus Jacobs H.T. Szibor supports repurposing macrophages.Cell. 457-470.e413Abstract (681) Succinate (SDH) reverse (RET) PHD inhibition, glycolytic sustaining autocrine called (SUCNR1) enhancing (45Littlewood-Evans Sarret Apfel Loesle Dawson Muller Tigani Kneuer Patel Valeaux Gommermann Rubic-Schneider Junt Carballido GPR91 senses released exacerbates rheumatoid arthritis.J. Exp. 213: 1655-1662Crossref (182) intestinal Tuft gut SUCNR1, microbiota-induced infectious agents (46Murphy reimagined: transducers.Cell. 174: 780-784Abstract Pu

Language: Английский

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Regulation of PRKN-independent mitophagy

Autophagy, Journal Year: 2021, Volume and Issue: 18(1), P. 24 - 39

Published: Feb. 15, 2021

Mitochondria are dynamic, multifunctional cellular organelles that play a fundamental role in maintaining homeostasis. Keeping the quality of mitochondria check is essential importance for functioning and survival cells. Selective autophagic clearance flawed mitochondria, process termed mitophagy, one most prominent mechanisms through which cells maintain healthy mitochondrial pool. The best-studied pathway mitophagy exerted PINK1-PRKN pathway. However, an increasing number studies have shown existence alternative pathways, where different proteins lipids able to recruit machinery independently PINK1 PRKN. significance PRKN-independent pathways reflected various physiological pathophysiological processes, but many questions regarding regulation interplay between these remain open. Here we review current knowledge recent progress made field mitophagy. Particularly focus on receptors participate targeting impaired autophagosomes PRKN.Abbreviations: AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BH: homology; CCCP: Carbonyl cyanide m-chlorophenylhydrazone; CL: cardiolipin; ER: endoplasmic reticulum; FCCP: carbonyl p-trifluoromethoxyphenylhydrazone; IMM: inner membrane; IMS: intermembrane space; LIR: LC3-interacting region; MDVs: mitochondrial-derived vesicles; MTORC1: mechanistic target rapamycin kinase complex 1; OMM: outer OXPHOS: oxidative phosphorylation; PD: Parkinson disease; PtdIns3K: phosphatidylinositol 3-kinase; RGC: retinal ganglion cell; RING: really interesting new gene; ROS: reactive oxygen species; SUMO: small ubiquitin like modifier; TBI: traumatic brain injury; TM: transmembrane.

Language: Английский

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Mitophagy and Oxidative Stress: The Role of Aging

Antioxidants, Journal Year: 2021, Volume and Issue: 10(5), P. 794 - 794

Published: May 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

Language: Английский

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Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(8), P. 1501 - 1513

Published: March 31, 2022

Selective autophagy specifically eliminates damaged or superfluous organelles, maintaining cellular health. In this process, a double membrane structure termed an autophagosome captures target organelles proteins and delivers cargo to the lysosome for degradation. The attachment of small protein ubiquitin has emerged as common mechanism initiating organelle capture by machinery. suite ubiquitin-binding receptors function initiate assembly in situ on cargo, thereby providing selectivity capture. Here, we review recent efforts understand biochemical mechanisms principles which are marked with how use conserved structural modules recruit initiation machinery, particular focus mitochondria intracellular bacteria cargo. These emerging provide answers long-standing questions field concerning degradation is achieved.

Language: Английский

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Mitochondrial signalling and homeostasis: from cell biology to neurological disease

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(2), P. 137 - 152

Published: Jan. 10, 2023

Efforts to understand how mitochondrial dysfunction contributes neurodegeneration have primarily focussed on the role of mitochondria in neuronal energy metabolism. However, progress understanding etiological nature emerging functions has yielded new ideas about basis neurological disease. Studies aimed at deciphering signal through interorganellar contacts, vesicular trafficking, and metabolic transmission revealed that regulation immunometabolism, cell death, organelle dynamics, neuroimmune interplay are critical determinants neural health. Moreover, homeostatic mechanisms exist protect health turnover via nanoscale proteostasis lysosomal degradation become integrated within signalling pathways support plasticity stress responses nervous system. This review highlights these distinct converge influence contribute disease pathology.

Language: Английский

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Mitochondrial-derived vesicles in metabolism, disease, and aging

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(1), P. 21 - 35

Published: Jan. 1, 2024

Mitochondria are central hubs of cellular metabolism and tightly connected to signaling pathways. The dynamic plasticity mitochondria fuse, divide, contact other organelles flux metabolites is their function. To ensure bona fide functionality interconnectivity, diverse molecular mechanisms evolved. An ancient long-overlooked mechanism the generation mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes target organelles. Just recently, we gained significant insight into functions MDV transport, ranging from role in quality control immune signaling, thus demonstrating unexpected physiological aspects transport. This review highlights origin MDVs, biogenesis, cargo selection, with a specific focus on contribution transport across cell organ barriers. Additionally, implications MDVs peroxisome neurodegeneration, metabolism, aging, cancer discussed.

Language: Английский

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Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(3), P. 1987 - 2026

Published: March 2, 2024

Mitochondria are thought to have become incorporated within the eukaryotic cell approximately 2 billion years ago and play a role in variety of cellular processes, such as energy production, calcium buffering homeostasis, steroid synthesis, growth, apoptosis, well inflammation ROS production. Considering that mitochondria involved multitude mitochondrial dysfunction has been shown several age-related diseases, including cancers, diabetes (type 2), neurodegenerative although underlying mechanisms not entirely understood. The significant increase lifespan increased incidence diseases over recent decades confirmed necessity understand by which impacts process aging diseases. In this review, we will offer brief overview mitochondria, along with structure function important organelle. We then discuss cause consequence process, particular focus on its inflammation, cognitive decline, Huntington’s disease, Parkinson’s Alzheimer’s disease. insight into therapies interventions currently used preserve or restore functioning during neurodegeneration.

Language: Английский

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Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Aug. 3, 2021

Parkinson’s disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation – key features of autophagy mitochondria, known as mitophagy. Here, we investigated role LRRK2, protein kinase frequently mutated PD, process vivo. Using mitophagy reporter mice, bearing either knockout LRRK2 or expressing pathogenic kinase-activating G2019S mutation, found that basal was specifically altered clinically relevant cells tissues. Our data show inversely correlates activity In support this, use distinct inhibitors increased mitophagy, CNS penetrant inhibitor, GSK3357679A, rescued defects observed mice. This study provides first vivo evidence directly impairs strong to idiopathic disease, demonstrates pharmacological inhibition rational mitophagy-rescue approach potential PD therapy.

Language: Английский

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