{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T02:25:41Z","timestamp":1793499941969,"version":"4.5.0"},"reference-count":130,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:00:00Z","timestamp":1623974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Alzheimer\u2019s Disease (AD) is the most common form of dementia, characterised by intra- and extracellular protein aggregation. In AD, the cellular protein quality control (PQC) system is derailed and fails to prevent the formation of these aggregates. Especially the mitochondrial paralogue of the conserved Hsp90 chaperone class, tumour necrosis factor receptor-associated protein 1 (TRAP1), is strongly downregulated in AD, more than other major PQC factors. Here, we review molecular mechanism and cellular function of TRAP1 and subsequently discuss possible links to AD. TRAP1 is an interesting paradigm for the Hsp90 family, as it chaperones proteins with vital cellular function, despite not being regulated by any of the co-chaperones that drive its cytosolic paralogues. TRAP1 encloses late folding intermediates in a non-active state. Thereby, it is involved in the assembly of the electron transport chain, and it favours the switch from oxidative phosphorylation to glycolysis. Another key function is that it ensures mitochondrial integrity by regulating the mitochondrial pore opening through Cyclophilin D. While it is still unclear whether TRAP1 itself is a driver or a passenger in AD, it might be a guide to identify key factors initiating neurodegeneration.<\/jats:p>","DOI":"10.3389\/fmolb.2021.697913","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:33:08Z","timestamp":1623976388000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["The Mitochondrial Hsp90 TRAP1 and Alzheimer\u2019s Disease"],"prefix":"10.3389","volume":"8","author":[{"given":"Fran\u00e7oise A.","family":"Dekker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan G. D.","family":"R\u00fcdiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1158\/1541-7786.mcr-13-0481","article-title":"TRAP1 Regulates Proliferation, Mitochondrial Function, and Has Prognostic Significance in NSCLC","volume":"12","author":"Agorreta","year":"2014","journal-title":"Mol. Cancer Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s12929-017-0379-z","article-title":"Oxidative Toxicity in Diabetes and Alzheimer\u2019s Disease: Mechanisms behind ROS\/RNS Generation","volume":"24","author":"Ahmad","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.bbamcr.2011.08.007","article-title":"Trap-1, the Mitochondrial Hsp90","volume":"1823","author":"Altieri","year":"2012","journal-title":"Biochim. Biophys. Acta (Bba) - Mol. Cel Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1038\/cdd.2011.128","article-title":"TRAP1 and the Proteasome Regulatory Particle TBP7\/RPT3 Interact in the Endoplasmic Reticulum and Control Cellular Ubiquitination of Specific Mitochondrial Proteins","volume":"19","author":"Amoroso","year":"2012","journal-title":"Cell Death Differ"},{"key":"B5","doi-asserted-by":"publisher","first-page":"969","DOI":"10.3892\/ijo.2014.2530","article-title":"TRAP1 Revisited: Novel Localizations and Functions of a \u02bdnext-Generation\u02bc Biomarker (Review)","volume":"45","author":"Amoroso","year":"2014","journal-title":"Int. J. Oncol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1146\/annurev-biochem-060809-095203","article-title":"Regulation of HSF1 Function in the Heat Stress Response: Implications in Aging and Disease","volume":"80","author":"Anckar","year":"2011","journal-title":"Annu. Rev. Biochem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"135","DOI":"10.3390\/biom10010135","article-title":"Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer","volume":"10","author":"Avolio","year":"2020","journal-title":"Biomolecules"},{"key":"B8","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/nature03434","article-title":"Loss of Cyclophilin D Reveals a Critical Role for Mitochondrial Permeability Transition in Cell Death","volume":"434","author":"Baines","year":"2005","journal-title":"Nat."},{"key":"B9","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/978-1-4939-6824-4_11","article-title":"Detection of Dual Targeting and Dual Function of Mitochondrial Proteins in Yeast","volume-title":"Mitochondria","author":"Ben-Menachem","year":"2017"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1517\/14728222.2014.943185","article-title":"Targeting Hsp90 and its Co-chaperones to Treat Alzheimer's Disease","volume":"18","author":"Blair","year":"2014","journal-title":"Expert Opin. Ther. Targets"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1016\/j.celrep.2014.09.042","article-title":"A Chaperome Subnetwork Safeguards Proteostasis in Aging and Neurodegenerative Disease","volume":"9","author":"Brehme","year":"2014","journal-title":"Cell Rep."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.1158\/1541-7786.mcr-15-0234","article-title":"Maximizing the Therapeutic Potential of HSP90 Inhibitors","volume":"13","author":"Butler","year":"2015","journal-title":"Mol. Cancer Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2603","DOI":"10.3390\/ijms19092603","article-title":"Heat Shock Proteins in Alzheimer's Disease: Role and Targeting","volume":"19","author":"Campanella","year":"2018","journal-title":"Int. J. Mol. Scie."},{"key":"B16","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/nature20412","article-title":"The Road to Restoring Neural Circuits for the Treatment of Alzheimer's Disease","volume":"539","author":"Canter","year":"2016","journal-title":"Nature"},{"key":"B17","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1006\/excr.2000.4983","article-title":"Immunoelectron Microscopy Provides Evidence that Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP-1) Is a Mitochondrial Protein Which Also Localizes at Specific Extramitochondrial Sites","volume":"260","author":"Cechetto","year":"2000","journal-title":"Exp. Cell Res."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00902","article-title":"Mitochondria as Potential Targets in Alzheimer\u2019s Disease Therapy: An Update","volume":"10","author":"Cenini","year":"2019","journal-title":"Front. Pharmacol. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4691","DOI":"10.1128\/mcb.16.9.4691","article-title":"A New Member of the Hsp90 Family of Molecular Chaperones Interacts with the Retinoblastoma Protein during Mitosis and after Heat Shock","volume":"16","author":"Chen","year":"1996","journal-title":"Mol. Cel. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2464","DOI":"10.1523\/jneurosci.0151-13.2014","article-title":"Hsp90 Chaperone Inhibitor 17-AAG Attenuates A -Induced Synaptic Toxicity and Memory Impairment","volume":"34","author":"Chen","year":"2014","journal-title":"J. Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1822","DOI":"10.1016\/j.drudis.2014.06.029","article-title":"Targeting TNF: a Therapeutic Strategy for Alzheimer's Disease","volume":"19","author":"Cheng","year":"2014","journal-title":"Drug Discov. Today"},{"key":"B23","doi-asserted-by":"publisher","first-page":"R12","DOI":"10.1093\/hmg\/ddq160","article-title":"Molecular Mechanisms of Neurodegeneration in Alzheimer's Disease","volume":"19","author":"Crews","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/cdd.2013.189","article-title":"Granzyme M: behind Enemy Lines","volume":"21","author":"De Poot","year":"2014","journal-title":"Cel Death Differ"},{"key":"B25","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1172\/jci29715","article-title":"The High-Affinity HSP90-CHIP Complex Recognizes and Selectively Degrades Phosphorylated Tau Client Proteins","volume":"117","author":"Dickey","year":"2007","journal-title":"J. Clin. Invest."},{"key":"B26","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1111\/tra.12397","article-title":"Human Fumarate Hydratase Is Dual Localized by an Alternative Transcription Initiation Mechanism","volume":"17","author":"Dik","year":"2016","journal-title":"Traffic"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1038\/nm.1868","article-title":"Cyclophilin D Deficiency Attenuates Mitochondrial and Neuronal Perturbation and Ameliorates Learning and Memory in Alzheimer's Disease","volume":"14","author":"Du","year":"2008","journal-title":"Nat. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s40035-018-0107-y","article-title":"Alzheimer\u2019s Disease Hypothesis and Related Therapies","volume":"7","author":"Du","year":"2018","journal-title":"Trans. Neurodegener."},{"key":"B29","doi-asserted-by":"publisher","first-page":"13717","DOI":"10.1074\/jbc.ra118.003562","article-title":"Calcium Binding to a Remote Site Can Replace Magnesium as Cofactor for Mitochondrial Hsp90 (TRAP1) ATPase Activity","volume":"293","author":"Elnatan","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e25235","DOI":"10.7554\/elife.25235","article-title":"Symmetry Broken and Rebroken during the ATP Hydrolysis Cycle of the Mitochondrial Hsp90 TRAP1","volume":"6","author":"Elnatan","year":"2017","journal-title":"Elife"},{"key":"B31","doi-asserted-by":"publisher","first-page":"113869","DOI":"10.1016\/j.bcp.2020.113869","article-title":"S-nitrosylation Affects TRAP1 Structure and ATPase Activity and Modulates Cell Response to Apoptotic Stimuli","volume":"176","author":"Faienza","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3305","DOI":"10.1074\/jbc.275.5.3305","article-title":"The Hsp90-Related Protein TRAP1 Is a Mitochondrial Protein with Distinct Functional Properties","volume":"275","author":"Felts","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1146\/annurev.biochem.78.081507.101607","article-title":"Recognition and Processing of Ubiquitin-Protein Conjugates by the Proteasome","volume":"78","author":"Finley","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1007\/s12017-014-8294-x","article-title":"Oxidative Stress-Induced Signaling Pathways Implicated in the Pathogenesis of Parkinson's Disease","volume":"16","author":"Gaki","year":"2014","journal-title":"Neuromol. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1074\/jbc.rev118.002806","article-title":"Hsp90 and Hsp70 Chaperones: Collaborators in Protein Remodeling","volume":"294","author":"Genest","year":"2019","journal-title":"J. Biol. Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2779","DOI":"10.2174\/1568026616666160413141154","article-title":"Paralog Specific Hsp90 Inhibitors\u2013A Brief History and a Bright Future","volume":"16","author":"Gewirth","year":"2016","journal-title":"Curr. Top. Med.Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.pharep.2015.07.006","article-title":"Therapeutic Strategies for Alzheimer's Disease in Clinical Trials","volume":"68","author":"Gody\u0144","year":"2016","journal-title":"Pharmacol. Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1126\/science.1132814","article-title":"A century of Alzheimer's Disease","volume":"314","author":"Goedert","year":"2006","journal-title":"Science"},{"key":"B39","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1146\/annurev-med-042915-103753","article-title":"Update on Alzheimer's Disease Therapy and Prevention Strategies","volume":"68","author":"Graham","year":"2017","journal-title":"Annu. Rev. Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.bbamcr.2011.11.018","article-title":"The ER-Mitochondria Interface: The Social Network of Cell Death","volume":"1823","author":"Grimm","year":"2012","journal-title":"Biochim. Biophys. Acta (Bba) - Mol. Cel Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1159\/000076290","article-title":"In Silico analysis Indicates a Similar Gene Expression Pattern between Human Brain and Testis","volume":"103","author":"Guo","year":"2003","journal-title":"Cytogenet. Genome Res."},{"key":"B137","doi-asserted-by":"crossref","first-page":"11897","DOI":"10.18632\/oncotarget.2472","article-title":"Inhibition of Succinate Dehydrogenase by the Mitochondrial Chaperone TRAP1 has Anti-Oxidant and Anti-Apoptotic Effects on Tumor Cells","volume":"5","author":"Guzzo","year":"2014","journal-title":"Oncotarget"},{"key":"B42","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41580-019-0101-y","article-title":"The Proteostasis Network and its Decline in Ageing","volume":"20","author":"Hipp","year":"2019","journal-title":"Nat. Rev. Mol. Cel. Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"3017","DOI":"10.1523\/jneurosci.21-09-03017.2001","article-title":"Mitochondrial Abnormalities in Alzheimer's Disease","volume":"21","author":"Hirai","year":"2001","journal-title":"J. Neurosci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","article-title":"Ageing as a Risk Factor for Neurodegenerative Disease","volume":"15","author":"Hou","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"20553","DOI":"10.1074\/jbc.m703196200","article-title":"Heat Shock Protein 75 (TRAP1) Antagonizes Reactive Oxygen Species Generation and Protects Cells from Granzyme M-Mediated Apoptosis","volume":"282","author":"Hua","year":"2007","journal-title":"J. Biol. Chem."},{"key":"B46","doi-asserted-by":"publisher","first-page":"519","DOI":"10.3892\/br.2016.630","article-title":"Role of Oxidative Stress in Alzheimer's Disease","volume":"4","author":"Huang","year":"2016","journal-title":"Biomed. Rep."},{"key":"B47","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1002\/jcb.21064","article-title":"Iron Chelation Study in a normal Human Hepatocyte Cell Line Suggests that Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) Regulates Production of Reactive Oxygen Species","volume":"100","author":"Im","year":"2007","journal-title":"J. Cel. Biochem."},{"key":"B48","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nrn2967","article-title":"Amyloid-\u03b2 and tau - a toxic pas de deux in Alzheimer's disease","volume":"12","author":"Ittner","year":"2011","journal-title":"Nat. Rev. Neurosci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.brainres.2013.04.059","article-title":"Increased Heat Shock Transcription Factor 1 in the Cerebellum Reverses the Deficiency of Purkinje Cells in Alzheimer's Disease","volume":"1519","author":"Jiang","year":"2013","journal-title":"Brain Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12915-020-0740-7","article-title":"The Mitochondrial Hsp90 Paralog TRAP1 Forms an OXPHOS-Regulated Tetramer and Is Involved in Mitochondrial Metabolic Homeostasis","volume":"18","author":"Joshi","year":"2020","journal-title":"BMC Biol."},{"key":"B51","volume-title":"Primordial Super-enhancers: Heat Shock-Induced Chromatin Organization in Yeast","author":"Kainth","year":"2021"},{"key":"B52","doi-asserted-by":"publisher","first-page":"23","DOI":"10.3389\/fmolb.2014.00023","article-title":"Protein Folding as a Driving Force for Dual Protein Targeting in Eukaryotes","volume":"1","author":"Kalderon","year":"2014","journal-title":"Front. Mol. Biosci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.5483\/bmbrep.2012.45.1.1","article-title":"TRAP1 Regulation of Mitochondrial Life or Death Decision in Cancer Cells and Mitochondria-Targeted TRAP1 Inhibitors","volume":"45","author":"Kang","year":"2012","journal-title":"BMB Rep."},{"key":"B54","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.cell.2007.08.028","article-title":"Regulation of Tumor Cell Mitochondrial Homeostasis by an Organelle-specific Hsp90 Chaperone Network","volume":"131","author":"Kang","year":"2007","journal-title":"Cell"},{"key":"B55","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1016\/j.cell.2014.01.037","article-title":"Hsp90-tau Complex Reveals Molecular Basis for Specificity in Chaperone Action","volume":"156","author":"Karag\u00f6z","year":"2014","journal-title":"Cell"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1002\/2211-5463.12863","article-title":"HSF1 Is Required for Induction of Mitochondrial Chaperones during the Mitochondrial Unfolded Protein Response","volume":"10","author":"Katiyar","year":"2020","journal-title":"FEBS Open bio"},{"key":"B57","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/197192b0","article-title":"Paired Helical Filaments in Electron Microscopy of Alzheimer's Disease","volume":"197","author":"Kidd","year":"1963","journal-title":"Nature"},{"key":"B58","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-018-25404-w","article-title":"Hsp90 Inhibitors Disrupt a Transient Hsp90-HSF1 Interaction and Identify a Noncanonical Model of Hsp90-Mediated HSF1 Regulation","volume":"8","author":"Kijima","year":"2018","journal-title":"Sci. Rep."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1016\/j.cell.2014.04.038","article-title":"Glucocorticoid Receptor Function Regulated by Coordinated Action of the Hsp90 and Hsp70 Chaperone Cycles","volume":"157","author":"Kirschke","year":"2014","journal-title":"Cell"},{"key":"B60","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s10059-012-0100-8","article-title":"PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity","volume":"34","author":"Koh","year":"2012","journal-title":"Mol. Cell"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2020.00214","article-title":"Alzheimer Cells on Their Way to Derailment Show Selective Changes in Protein Quality Control Network","author":"Koopman","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"B62","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1111\/j.1582-4934.2008.00557.x","article-title":"Chaperone Signalling Complexes in Alzheimer's Disease","volume":"13","author":"Koren III","year":"2009","journal-title":"J. Cel. Mol. Med."},{"key":"B63","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1111\/j.1471-4159.2009.06099.x","article-title":"Tumor Necrosis Factor Receptor-Associated Protein 1 Regulates Cell Adhesion and Synaptic Morphology via Modulation of N-Cadherin Expression","volume":"110","author":"Kubota","year":"2009","journal-title":"J. Neurochem."},{"key":"B64","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1016\/j.celrep.2017.10.038","article-title":"Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging","volume":"21","author":"Labbadia","year":"2017","journal-title":"Cel Rep."},{"key":"B65","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1038\/nrn960","article-title":"Calcium Dyshomeostasis and Intracellular Signalling in Alzheimer's Disease","volume":"3","author":"LaFerla","year":"2002","journal-title":"Nat. Rev. Neurosci."},{"key":"B66","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1038\/cr.2017.23","article-title":"PHB2\/prohibitin 2: An Inner Membrane Mitophagy Receptor","volume":"27","author":"Lahiri","year":"2017","journal-title":"Cell Res"},{"key":"B67","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.ygyno.2009.10.078","article-title":"Heat Shock Proteins, Cell Survival and Drug Resistance: the Mitochondrial Chaperone TRAP1, a Potential Novel Target for Ovarian Cancer Therapy","volume":"117","author":"Landriscina","year":"2010","journal-title":"Gynecol. Oncol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.molcel.2013.12.023","article-title":"Structural Asymmetry in the Closed State of Mitochondrial Hsp90 (TRAP1) Supports a Two-step ATP Hydrolysis Mechanism","volume":"53","author":"Lavery","year":"2014","journal-title":"Mol. Cel"},{"key":"B69","doi-asserted-by":"publisher","first-page":"11677","DOI":"10.1074\/jbc.m709516200","article-title":"The ATPase Cycle of the Mitochondrial Hsp90 Analog TRAP1","volume":"283","author":"Leskovar","year":"2008","journal-title":"J. Biol. Chem."},{"key":"B70","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1080\/14728222.2017.1349755","article-title":"TRAP1: a Viable Therapeutic Target for Future Cancer Treatments?","volume":"21","author":"Lettini","year":"2017","journal-title":"Expert Opin. Ther. Targets"},{"key":"B71","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s12929-015-0152-0","article-title":"N-terminal Functional Domain of Gasdermin A3 Regulates Mitochondrial Homeostasis via Mitochondrial Targeting","volume":"22","author":"Lin","year":"2015","journal-title":"J. Biomed. Sci."},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.2210\/pdb6xg6\/pdb","article-title":"Cryo-EM Reveals the Dynamic Interplay between Mitochondrial Hsp90 and SdhB Folding Intermediates","author":"Liu","year":"2020","journal-title":"bioRxiv"},{"key":"B73","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer Disease: an Update on Pathobiology and Treatment Strategies","volume":"179","author":"Long","year":"2019","journal-title":"Cell"},{"key":"B74","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.molcel.2016.02.025","article-title":"Mammalian Heat Shock Response and Mechanisms Underlying its Genome-wide Transcriptional Regulation","volume":"62","author":"Mahat","year":"2016","journal-title":"Mol. Cel"},{"key":"B75","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/j.celrep.2016.12.056","article-title":"Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1","volume":"18","author":"Masgras","year":"","journal-title":"Cel Rep."},{"key":"B76","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3389\/fonc.2017.00058","article-title":"The Chaperone TRAP1 as a Modulator of the Mitochondrial Adaptations in Cancer Cells","volume":"7","author":"Masgras","year":"","journal-title":"Front. Oncol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"42503","DOI":"10.1074\/jbc.m404256200","article-title":"Involvement of Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) in Apoptosis Induced by \u03b2-Hydroxyisovalerylshikonin","volume":"279","author":"Masuda","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B78","first-page":"235","article-title":"New Insights into TRAP1 Pathway","volume":"2","author":"Matassa","year":"2012","journal-title":"Am. J. Cancer Res."},{"key":"B79","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/1742-2094-5-45","article-title":"TNF Signaling Inhibition in the CNS: Implications for normal Brain Function and Neurodegenerative Disease","volume":"5","author":"McCoy","year":"2008","journal-title":"J. Neuroinflammation"},{"key":"B80","doi-asserted-by":"publisher","first-page":"778","DOI":"10.15252\/embj.201489524","article-title":"Compartment\u2010specific Aggregases Direct Distinct Nuclear and Cytoplasmic Aggregate Deposition","volume":"34","author":"Miller","year":"2015","journal-title":"Embo J."},{"key":"B81","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1379\/csc-29r1.1","article-title":"Investigating the Protein-Protein Interactions of the Yeast Hsp90 Chaperone System by Two-Hybrid Analysis: Potential Uses and Limitations of This Approach","volume":"9","author":"Millson","year":"2004","journal-title":"Cell Stress Chaper"},{"key":"B82","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1083\/jcb.200209098","article-title":"Regulation of Cytochrome C Oxidase Activity by C-Src in Osteoclasts","volume":"160","author":"Miyazaki","year":"2003","journal-title":"J. Cel Biol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1038\/s41594-018-0057-1","article-title":"Mapping Interactions with the Chaperone Network Reveals Factors that Protect against Tau Aggregation","volume":"25","author":"Mok","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"5343","DOI":"10.1016\/s0021-9258(18)83551-7","article-title":"Murine 86- and 84-kDa Heat Shock Proteins, cDNA Sequences, Chromosome Assignments, and Evolutionary Origins","volume":"264","author":"Moore","year":"1989","journal-title":"J. Biol. Chem."},{"key":"B85","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/j.molcel.2018.03.028","article-title":"Hsp90 Breaks the Deadlock of the Hsp70 Chaperone System","volume":"70","author":"Mor\u00e1n Luengo","year":"2018","journal-title":"Mol. Cel"},{"key":"B86","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.tcb.2018.10.004","article-title":"The Hsp70-Hsp90 Chaperone cascade in Protein Folding","volume":"29","author":"Mor\u00e1n Luengo","year":"2019","journal-title":"Trends Cell Biol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.freeradbiomed.2012.05.009","article-title":"Mitochondrial Respiratory Chain Dysfunction: Implications in Neurodegeneration","volume":"53","author":"Mor\u00e1n","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"B88","article-title":"GR Chaperone Cycle Mechanism Revealed by Cryo-EM: Reactivation of GR by the GR: Hsp90: P23 Client-Maturation Complex","author":"Noddings","year":"2020","journal-title":"bioRxiv"},{"key":"B89","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1042\/bj20120509","article-title":"Mitochondrial C-Src Regulates Cell Survival through Phosphorylation of Respiratory Chain Components","volume":"447","author":"Ogura","year":"2012","journal-title":"Biochem. J."},{"key":"B90","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/s41582-018-0116-6","article-title":"A Critical Appraisal of Amyloid-\u03b2-Targeting Therapies for Alzheimer Disease","volume":"15","author":"Panza","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/s12276-019-0360-x","article-title":"Unleashing the Full Potential of Hsp90 Inhibitors as Cancer Therapeutics through Simultaneous Inactivation of HSP90, GRP94, and TRAP1","volume":"52","author":"Park","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"B92","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1002\/msj.20157","article-title":"Neuropathology of Alzheimer's Disease","volume":"77","author":"Perl","year":"2010","journal-title":"Mt Sinai J. Med."},{"key":"B93","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/978-3-030-40204-4_3","article-title":"Regulation of Hsf1 and the Heat Shock Response","volume":"1243","author":"Pincus","year":"2020","journal-title":"HSF1 Mol. Chaperones Biol. Cancer"},{"key":"B95","doi-asserted-by":"publisher","first-page":"3758","DOI":"10.1016\/j.febslet.2007.05.040","article-title":"Inhibitors of the Heat Shock Response: Biology and Pharmacology","volume":"581","author":"Powers","year":"2007","journal-title":"FEBS Lett."},{"key":"B96","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1177\/153537020322800201","article-title":"Regulation of Signaling Protein Function and Trafficking by the Hsp90\/hsp70-Based Chaperone Machinery","volume":"228","author":"Pratt","year":"2003","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050172","article-title":"PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1","volume":"5","author":"Pridgeon","year":"2007","journal-title":"Plos Biol."},{"key":"B98","doi-asserted-by":"publisher","first-page":"2439","DOI":"10.1042\/bcj20160005","article-title":"Mechanisms of Hsp90 Regulation","volume":"473","author":"Prodromou","year":"2016","journal-title":"Biochem. J."},{"key":"B99","doi-asserted-by":"publisher","first-page":"3029","DOI":"10.1016\/j.jmb.2018.05.026","article-title":"Dancing with the Diva: Hsp90-Client Interactions","volume":"430","author":"Radli","year":"2018","journal-title":"J. Mol. Biol."},{"key":"B100","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.tcb.2014.03.005","article-title":"Mitochondrial Oxidative Phosphorylation TRAP(1)ped in Tumor Cells","volume":"24","author":"Rasola","year":"2014","journal-title":"Trends Cell Biol."},{"key":"B101","doi-asserted-by":"publisher","first-page":"4170","DOI":"10.1158\/0008-5472.can-15-2637","article-title":"S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase","volume":"76","author":"Rizza","year":"2016","journal-title":"Cancer Res."},{"key":"B102","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1016\/j.peptides.2007.03.006","article-title":"TNF-\u03b1 Acts in the Hypothalamus Inhibiting Food Intake and Increasing the Respiratory Quotient-Effects on Leptin and Insulin Signaling Pathways","volume":"28","author":"Romanatto","year":"2007","journal-title":"Peptides"},{"key":"B103","doi-asserted-by":"publisher","first-page":"519","DOI":"10.3233\/jad-132483","article-title":"The Emerging Role of Glutathione in Alzheimer's Disease","volume":"40","author":"Saharan","year":"2014","journal-title":"Jad"},{"key":"B105","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/nrm.2017.20","article-title":"The Hsp90 Chaperone Machinery","volume":"18","author":"Schopf","year":"2017","journal-title":"Nat. Rev. Mol. Cel. Biol."},{"key":"B106","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.cell.2006.09.027","article-title":"Structural Analysis of E. coli Hsp90 Reveals Dramatic Nucleotide-dependent Conformational Rearrangements","volume":"127","author":"Shiau","year":"2006","journal-title":"Cell"},{"key":"B107","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1172\/jci44855","article-title":"Exploiting the Mitochondrial Unfolded Protein Response for Cancer Therapy in Mice and Human Cells","volume":"121","author":"Siegelin","year":"2011","journal-title":"J. Clin. Invest."},{"key":"B108","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.canlet.2013.01.045","article-title":"Inhibition of the Mitochondrial Hsp90 Chaperone Network: a Novel, Efficient Treatment Strategy for Cancer?","volume":"333","author":"Siegelin","year":"2013","journal-title":"Cancer Lett."},{"key":"B109","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/j.bbamcr.2018.03.008","article-title":"Regulation of the Hsp90 System","volume":"1865","author":"Sima","year":"2018","journal-title":"Biochim. Biophys. Acta (Bba) - Mol. Cel Res."},{"key":"B110","doi-asserted-by":"publisher","first-page":"2155","DOI":"10.1093\/hmg\/8.12.2155","article-title":"A Direct Interaction between EXT Proteins and Glycosyltransferases Is Defective in Hereditary Multiple Exostoses","volume":"8","author":"Simmons","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"B111","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.molcel.2016.05.014","article-title":"Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis","volume":"63","author":"Sol\u00eds","year":"2016","journal-title":"Mol. Cell"},{"key":"B112","doi-asserted-by":"publisher","first-page":"3574","DOI":"10.1074\/jbc.270.8.3574","article-title":"Identification of a Protein with Homology to Hsp90 that Binds the Type 1 Tumor Necrosis Factor Receptor","volume":"270","author":"Song","year":"1995","journal-title":"J. Biol. Chem."},{"key":"B114","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.molcel.2011.01.029","article-title":"Substrate Binding Drives Large-Scale Conformational Changes in the Hsp90 Molecular Chaperone","volume":"42","author":"Street","year":"2011","journal-title":"Mol. Cell"},{"key":"B115","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1016\/j.neuint.2011.02.015","article-title":"Mitochondrial TRAP1 Regulates the Unfolded Protein Response in the Endoplasmic Reticulum","volume":"58","author":"Takemoto","year":"2011","journal-title":"Neurochem. Int."},{"key":"B116","doi-asserted-by":"publisher","first-page":"a034116","DOI":"10.1101\/cshperspect.a034116","article-title":"A Chemical Biology Approach to the Chaperome in Cancer-HSP90 and beyond","volume":"12","author":"Taldone","year":"2020","journal-title":"Cold Spring Harb Perspect. Biol."},{"key":"B117","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/nrc2887","article-title":"Targeting the Dynamic Hsp90 Complex in Cancer","volume":"10","author":"Trepel","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"B118","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1080\/10715762.2017.1315114","article-title":"In Vivo ROS Production and Use of Oxidative Stress-Derived Biomarkers to Detect the Onset of Diseases Such as Alzheimer's Disease, Parkinson's Disease, and Diabetes","volume":"51","author":"Umeno","year":"2017","journal-title":"Free Radic. Res."},{"key":"B119","doi-asserted-by":"publisher","first-page":"14a","DOI":"10.1016\/j.bpj.2016.11.108","article-title":"Kinase Regulation through Dramatic Unfolding, as Told by Hsp90:Cdc37:Cdk4 Atomic Cryoem Structure","volume":"112","author":"Verba","year":"2017","journal-title":"Biophysical J."},{"key":"B120","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1126\/science.aaf5023","article-title":"Atomic Structure of Hsp90-Cdc37-Cdk4 Reveals that Hsp90 Traps and Stabilizes an Unfolded Kinase","volume":"352","author":"Verba","year":"2016","journal-title":"Science"},{"key":"B121","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1016\/j.bbadis.2013.10.015","article-title":"Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease","volume":"1842","author":"Wang","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"B122","first-page":"7","article-title":"Current Understanding of Alzheimer\u2019s Disease Diagnosis and Treatment","volume-title":"F1000Res","author":"Weller","year":"2018"},{"key":"B123","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1038\/nm1207-1415","article-title":"Putting the Heat on Cancer","volume":"13","author":"Workman","year":"2007","journal-title":"Nat. Med."},{"key":"B124","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1111\/j.1742-4658.2010.07615.x","article-title":"Mitochondrial Chaperone Tumour Necrosis Factor Receptor-Associated Protein 1 Protects Cardiomyocytes from Hypoxic Injury by Regulating Mitochondrial Permeability Transition Pore Opening","volume":"277","author":"Xiang","year":"2010","journal-title":"FEBS J."},{"key":"B125","doi-asserted-by":"publisher","first-page":"s41038","DOI":"10.1186\/s41038-019-0154-3","article-title":"Tumor Necrosis Factor Receptor-Associated Protein 1 Regulates Hypoxia-Induced Apoptosis through a Mitochondria-dependent Pathway Mediated by Cytochrome C Oxidase Subunit Ii","volume":"7","author":"Xiang","year":"2019","journal-title":"Burns & trauma"},{"key":"B126","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s42003-018-0254-9","article-title":"Regional Protein Expression in Human Alzheimer\u2019s Brain Correlates with Disease Severity","volume":"2","author":"Xu","year":"2019","journal-title":"Commun. Biol."},{"key":"B127","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1038\/jcbfm.2008.125","article-title":"Overexpression of Mitochondrial Hsp70\/hsp75 in Rat Brain Protects Mitochondria, Reduces Oxidative Stress, and Protects from Focal Ischemia","volume":"29","author":"Xu","year":"2009","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B128","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1073\/pnas.96.1.109","article-title":"Maturation of the Tyrosine Kinase C-Src as a Kinase and as a Substrate Depends on the Molecular Chaperone Hsp90","volume":"96","author":"Xu","year":"1999","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B129","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1177\/1756285612461679","article-title":"Current and Future Treatments for Alzheimer's Disease","volume":"6","author":"Yiannopoulou","year":"2013","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"B130","doi-asserted-by":"publisher","first-page":"E1604","DOI":"10.1073\/pnas.1220659110","article-title":"Molecular Chaperone TRAP1 Regulates a Metabolic Switch between Mitochondrial Respiration and Aerobic Glycolysis","volume":"110","author":"Yoshida","year":"2013","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B131","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1007\/978-1-4939-7477-1_29","article-title":"Clinical Evaluation and Biomarker Profiling of Hsp90 Inhibitors","author":"Yuno","year":"2018","journal-title":"Chaperones"},{"key":"B133","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1159\/000430174","article-title":"TRAP1 Provides protection against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction","volume":"36","author":"Zhang","year":"2015","journal-title":"Cell Physiol Biochem"},{"key":"B134","doi-asserted-by":"publisher","first-page":"3099","DOI":"10.1016\/j.celrep.2018.02.083","article-title":"Hsf1 Phosphorylation Generates Cell-To-Cell Variation in Hsp90 Levels and Promotes Phenotypic Plasticity","volume":"22","author":"Zheng","year":"2018","journal-title":"Cell Rep."},{"key":"B135","doi-asserted-by":"publisher","first-page":"e18638","DOI":"10.7554\/elife.18638","article-title":"Dynamic Control of Hsf1 during Heat Shock by a Chaperone Switch and Phosphorylation","volume":"5","author":"Zheng","year":"2016","journal-title":"eLife"},{"key":"B136","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1002\/bip.21292","article-title":"Hsp90 and Co-chaperones Twist the Functions of Diverse Client Proteins","volume":"93","author":"Zuehlke","year":"2010","journal-title":"Biopolymers"}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2021.697913\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:33:15Z","timestamp":1623976395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2021.697913\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,18]]},"references-count":130,"alternative-id":["10.3389\/fmolb.2021.697913"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2021.697913","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,18]]},"article-number":"697913"}}