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Remarkably, these organelles are proposed to have evolved from an endosymbiotic association between an alphaproteobacterium and a primitive eukaryotic host cell or an archaeon. This crucial event determined that human cell mitochondria share some features with bacteria, namely cardiolipin, N-formyl peptides, mtDNA and transcription factor A, that can act as mitochondrial-derived damage-associated molecular patterns (DAMPs). The impact of extracellular bacteria on the host act largely through the modulation of mitochondrial activities, and often mitochondria are themselves immunogenic organelles that can trigger protective mechanisms through DAMPs mobilization. In this work, we demonstrate that mesencephalic neurons exposed to an environmental alphaproteobacterium activate innate immunity through toll-like receptor 4 and Nod-like receptor 3. Moreover, we show that mesencephalic neurons increase the expression and aggregation of alpha-synuclein that interacts with mitochondria, leading to their dysfunction. Mitochondrial dynamic alterations also affect mitophagy which favors a positive feedback loop on innate immunity signaling. Our results help to elucidate how bacteria and neuronal mitochondria interact and trigger neuronal damage and neuroinflammation and allow us to discuss the role of bacterial-derived pathogen-associated molecular patterns (PAMPs) in Parkinson\u2019s disease etiology.<\/jats:p>","DOI":"10.3390\/ijms24054339","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T03:59:16Z","timestamp":1677038356000},"page":"4339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Role of Bacteria\u2013Mitochondria Communication in the Activation of Neuronal Innate Immunity: Implications to Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4890-4167","authenticated-orcid":false,"given":"Jo\u00e3o D.","family":"Magalh\u00e3es","sequence":"first","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology and CIBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Ph.D. Programme in Biomedicine and Experimental Biology (PDBEB), Institute for Interdisciplinary Research, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Ana Raquel","family":"Esteves","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology and CIBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Emanuel","family":"Candeias","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology and CIBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Diana F.","family":"Silva","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology and CIBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8938-7560","authenticated-orcid":false,"given":"Nuno","family":"Empadinhas","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology and CIBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2199-0555","authenticated-orcid":false,"given":"Sandra Morais","family":"Cardoso","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology and CIBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","article-title":"Parkinson\u2019s disease","volume":"386","author":"Kalia","year":"2015","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41531-021-00273-9","article-title":"Lewy body disease or diseases with Lewy bodies?","volume":"8","author":"Colosimo","year":"2022","journal-title":"NPJ Park. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41577-022-00684-6","article-title":"Inflammation and immune dysfunction in Parkinson disease","volume":"22","author":"Tansey","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1212\/WNL.38.8.1285","article-title":"Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson\u2019s and Alzheimer\u2019s disease brains","volume":"38","author":"McGeer","year":"1988","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.2174\/138161211798072508","article-title":"The Mitochondrial Cascade Hypothesis for Parkinsons Disease","volume":"17","author":"Cardoso","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1097\/WCO.0b013e3280adc943","article-title":"Therapeutic approaches to inflammation in neurodegenerative disease","volume":"20","author":"Klegeris","year":"2007","journal-title":"Curr. Opin. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"471","DOI":"10.3389\/fphys.2018.00471","article-title":"The Microbiome-Mitochondria Dance in Prodromal Parkinson\u2019s Disease","volume":"9","author":"Cardoso","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4971","DOI":"10.1073\/pnas.1913904117","article-title":"The process of Lewy body formation, rather than simply \u03b1-synuclein fibrillization, is one of the major drivers of neurodegeneration","volume":"117","author":"Burtscher","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5256","DOI":"10.1523\/JNEUROSCI.0984-06.2006","article-title":"Parkinson\u2019s Disease Brain Mitochondrial Complex I Has Oxidatively Damaged Subunits and Is Functionally Impaired and Misassembled","volume":"26","author":"Keeney","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"797833","DOI":"10.3389\/fnmol.2021.797833","article-title":"Mitochondrial Function and Parkinson\u2019s Disease: From the Perspective of the Electron Transport Chain","volume":"14","author":"Li","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1136\/gutjnl-2021-326023","article-title":"Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria","volume":"72","author":"Esteves","year":"2021","journal-title":"Gut"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"27425","DOI":"10.1074\/jbc.M115.667063","article-title":"Rotenone-induced Impairment of Mitochondrial Electron Transport Chain Confers a Selective Priming Signal for NLRP3 Inflammasome Activation","volume":"290","author":"Won","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1007\/s12035-017-0420-y","article-title":"Mitochondrial Metabolism Regulates Microtubule Acetylome and Autophagy Trough Sirtuin-2: Impact for Parkinson\u2019s Disease","volume":"55","author":"Esteves","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.biocel.2016.03.007","article-title":"The novel mechanism of rotenone-induced \u03b1-synuclein phosphorylation via reduced protein phosphatase 2A activity","volume":"75","author":"Wang","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1007\/BF00713525","article-title":"Caudate nucleus pathology in Parkinson\u2019s disease: Ultrastructural and biochemical findings in biopsy material","volume":"83","author":"Lach","year":"1992","journal-title":"Acta Neuropathol."},{"key":"ref_16","first-page":"1","article-title":"ROCK1 induces dopaminergic nerve cell apoptosis via the activation of Drp1-mediated aberrant mitochondrial fission in Parkinson\u2019s disease","volume":"51","author":"Zhang","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4861","DOI":"10.1093\/hmg\/ddq419","article-title":"Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1\/parkin-dependent manner upon induction of mitophagy","volume":"19","author":"Gegg","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"243","DOI":"10.4161\/auto.7.2.14332","article-title":"PINK1-parkin-dependent mitophagy involves ubiquitination of mitofusins 1 and 2: Implications for Parkinson disease pathogenesis","volume":"7","author":"Gegg","year":"2011","journal-title":"Autophagy"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Paradies, G., Paradies, V., Ruggiero, F.M., and Petrosillo, G. (2019). Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects. Cells, 8.","DOI":"10.3390\/cells8070728"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1089\/ars.2019.7997","article-title":"The Mitochondrial Ribosome: A World of Opportunities for Mitochondrial Dysfunction Toward Parkinson\u2019s Disease","volume":"34","author":"Esteves","year":"2021","journal-title":"Antioxidants Redox Signal."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Picca, A., Calvani, R., Coelho-Junior, H., and Marzetti, E. (2021). Cell Death and Inflammation: The Role of Mitochondria in Health and Disease. Cells, 10.","DOI":"10.3390\/cells10030537"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41586-018-0059-5","article-title":"Deep mitochondrial origin outside the sampled alphaproteobacteria","volume":"557","author":"Martijn","year":"2018","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"R1177","DOI":"10.1016\/j.cub.2017.09.015","article-title":"The Origin and Diversification of Mitochondria","volume":"27","author":"Roger","year":"2017","journal-title":"Curr. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9914854","DOI":"10.1155\/2021\/9914854","article-title":"Toll-Like Receptors: General Molecular and Structural Biology","volume":"2021","author":"Behzadi","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"536","DOI":"10.3389\/fimmu.2018.00536","article-title":"Mitochondria: An Organelle of Bacterial Origin Controlling Inflammation","volume":"9","author":"Meyer","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s00401-016-1648-8","article-title":"Toll-like receptor 2 is increased in neurons in Parkinson\u2019s disease brain and may contribute to alpha-synuclein pathology","volume":"133","author":"Dzamko","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8514","DOI":"10.1073\/pnas.1432609100","article-title":"Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway","volume":"100","author":"Lehnardt","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.20517\/2347-8659.2015.28","article-title":"Neuronal toll-like receptors and neuro-immunity in Parkinson\u2019s disease, Alzheimer\u2019s disease and stroke","volume":"3","author":"Rietdijk","year":"2016","journal-title":"Neuroimmunol. Neuroinflammation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.bbi.2018.12.003","article-title":"TLR4 absence reduces neuroinflammation and inflammasome activation in Parkinson\u2019s diseases in vivo model","volume":"76","author":"Campolo","year":"2019","journal-title":"Brain, Behav. Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s41232-020-00137-4","article-title":"Cerebral sterile inflammation in neurodegenerative diseases","volume":"40","author":"Otani","year":"2020","journal-title":"Inflamm. Regen."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"508","DOI":"10.3389\/fimmu.2017.00508","article-title":"Mitochondria-Derived Damage-Associated Molecular Patterns in Neurodegeneration","volume":"8","author":"Wilkins","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1186\/s12974-020-02004-y","article-title":"Microbial BMAA elicits mitochondrial dysfunction, innate immunity activation, and Alzheimer\u2019s disease features in cortical neurons","volume":"17","author":"Silva","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1111\/j.1471-4159.2004.02918.x","article-title":"Cytochrome c release from rat brain mitochondria is proportional to the mitochondrial functional deficit: Implications for apoptosis and neurodegenerative disease","volume":"92","author":"Clayton","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"129400","DOI":"10.1016\/j.bbagen.2019.07.009","article-title":"Cytochrome c can be released into extracellular space and modulate functions of human astrocytes in a toll-like receptor 4-dependent manner","volume":"1863","author":"Wenzel","year":"2019","journal-title":"Biochim. Biophys. Acta (BBA)-Gen. Subj."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6820","DOI":"10.4049\/jimmunol.171.12.6820","article-title":"Activation of Toll-Like Receptor 2 on Human Tracheobronchial Epithelial Cells Induces the Antimicrobial Peptide Human \u03b2 Defensin-2","volume":"171","author":"Hertz","year":"2003","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Liu, P.T., Schenk, M., Walker, V.P., Dempsey, P.W., Kanchanapoomi, M., Wheelwright, M., Vazirnia, A., Zhang, X., Steinmeyer, A., and Z\u00fcgel, U. (2009). Convergence of IL-1\u03b2 and VDR Activation Pathways in Human TLR2\/1-Induced Antimicrobial Responses. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005810"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1136\/gutjnl-2018-316844","article-title":"Role of TLR4 in the gut-brain axis in Parkinson\u2019s disease: A translational study from men to mice","volume":"68","author":"Dodiya","year":"2019","journal-title":"Gut"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Rannikko, E.H., Weber, S.S., and Kahle, P.J. (2015). Exogenous \u03b1-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes. BMC Neurosci., 16.","DOI":"10.1186\/s12868-015-0192-0"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1007\/s11481-016-9704-7","article-title":"Extracellular Mitochondria and Mitochondrial Components Act as Damage-Associated Molecular Pattern Molecules in the Mouse Brain","volume":"11","author":"Wilkins","year":"2016","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.bbi.2019.06.042","article-title":"Toll-like receptors and their therapeutic potential in Parkinson\u2019s disease and \u03b1-synucleinopathies","volume":"81","author":"Kouli","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.neuron.2019.07.015","article-title":"Mechanisms of Pathogen Invasion into the Central Nervous System","volume":"103","author":"Cain","year":"2019","journal-title":"Neuron"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101396","DOI":"10.1016\/j.arr.2021.101396","article-title":"The neuromicrobiology of Parkinson\u2019s disease: A unifying theory","volume":"70","author":"Empadinhas","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.3389\/fimmu.2018.01413","article-title":"Recognition of Lipopolysaccharide and Activation of NF-\u03baB by Cytosolic Sensor NOD1 in Teleost Fish","volume":"9","author":"Bi","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e0147134","DOI":"10.1371\/journal.pone.0147134","article-title":"Non-Neuronal Cells Are Required to Mediate the Effects of Neuroinflammation: Results from a Neuron-Enriched Culture System","volume":"11","author":"Hui","year":"2016","journal-title":"PLoS ONE"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"110090","DOI":"10.1016\/j.celrep.2021.110090","article-title":"Alpha synuclein, the culprit in Parkinson disease, is required for normal immune function","volume":"38","author":"Alam","year":"2022","journal-title":"Cell Rep."},{"key":"ref_47","first-page":"693761","article-title":"Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD","volume":"2011","author":"Esteves","year":"2011","journal-title":"Park. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13024-019-0349-x","article-title":"Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway","volume":"15","author":"Park","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"580634","DOI":"10.3389\/fcell.2020.580634","article-title":"The Convergence of Alpha-Synuclein, Mitochondrial, and Lysosomal Pathways in Vulnerability of Midbrain Dopaminergic Neurons in Parkinson\u2019s Disease","volume":"8","author":"Minakaki","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Magalh\u00e3es, J.D., F\u00e3o, L., Vila\u00e7a, R., Cardoso, S.M., and Rego, A.C. (2021). Macroautophagy and Mitophagy in Neurodegenerative Disorders: Focus on Therapeutic Interventions. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111625"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1098\/rsbl.2008.0793","article-title":"The \u03b1-proteobacteria: The Darwin finches of the bacterial world","volume":"5","author":"Ettema","year":"2009","journal-title":"Biol. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Andrieux, P., Chevillard, C., Cunha-Neto, E., and Nunes, J.P.S. (2021). Mitochondria as a Cellular Hub in Infection and Inflammation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111338"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.mito.2017.10.007","article-title":"Innate immunity and tolerance toward mitochondria","volume":"41","author":"Rongvaux","year":"2017","journal-title":"Mitochondrion"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kaul, D., Habbel, P., Derkow, K., Kr\u00fcger, C., Franzoni, E., Wulczyn, F.G., Bereswill, S., Nitsch, R., Schott, E., and Veh, R. (2012). Expression of Toll-Like Receptors in the Developing Brain. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037767"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.neuro.2020.01.014","article-title":"Microglial activation and responses to vasculature that result from an acute LPS exposure","volume":"77","author":"Bowyer","year":"2020","journal-title":"Neurotoxicology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s12974-022-02496-w","article-title":"The role of Toll-like receptors and neuroinflammation in Parkinson\u2019s disease","volume":"19","author":"Heidari","year":"2022","journal-title":"J. Neuroinflamm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jocn.2018.10.079","article-title":"Peripheral blood inflammatory markers in early Parkinson\u2019s disease","volume":"58","author":"Kim","year":"2018","journal-title":"J. Clin. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s12974-019-1528-y","article-title":"Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson\u2019s disease","volume":"16","author":"Lin","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0304-3940(94)90508-8","article-title":"Interleukin-1\u03b2, interleukin-6, epidermal growth factor and transforming growth factor-\u03b1 are elevated in the brain from parkinsonian patients","volume":"180","author":"Mogi","year":"1994","journal-title":"Neurosci. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1523\/JNEUROSCI.19-09-03440.1999","article-title":"Fc\u03b5RII\/CD23 Is Expressed in Parkinson\u2019s Disease and Induces, In Vitro, Production of Nitric Oxide and Tumor Necrosis Factor-\u03b1 in Glial Cells","volume":"19","author":"Hunot","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_61","first-page":"S183","article-title":"Blood and Cerebrospinal Fluid Biomarkers of Inflammation in Parkinson\u2019s Disease","volume":"12","author":"Zimmermann","year":"2022","journal-title":"J. Park. Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s11910-022-01207-5","article-title":"Neurodegeneration and Neuroinflammation in Parkinson\u2019s Disease: A Self-Sustained Loop","volume":"22","author":"Arena","year":"2022","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1007\/s00018-022-04389-w","article-title":"Restricting \u03b1-synuclein transport into mitochondria by inhibition of \u03b1-synuclein\u2013VDAC complexation as a potential therapeutic target for Parkinson\u2019s disease treatment","volume":"79","author":"Rajendran","year":"2022","journal-title":"Cell Mol. Life Sci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Fl\u00f8nes, I.H., Nyland, H., Sandnes, D.-A., Alves, G.W., Tysnes, O.-B., and Tzoulis, C. (2022). Early Forms of \u03b1-Synuclein Pathology Are Associated with Neuronal Complex I Deficiency in the Substantia Nigra of Individuals with Parkinson\u2019s Disease. Biomolecules, 12.","DOI":"10.3390\/biom12060747"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s12035-014-8893-4","article-title":"The Impact of Mitochondrial Fusion and Fission Modulation in Sporadic Parkinson\u2019s Disease","volume":"52","author":"Santos","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"112","DOI":"10.4161\/auto.22443","article-title":"Mitochondria drive autophagy pathology via microtubule disassembly: A new hypothesis for Parkinson disease","volume":"9","author":"Esteves","year":"2013","journal-title":"Autophagy"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"845930","DOI":"10.3389\/fphar.2022.845930","article-title":"Neuroinflammation Upregulated Neuronal Toll-Like Receptors 2 and 4 to Drive Synucleinopathy in Neurodegeneration","volume":"13","author":"Chung","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1038\/s41467-020-15119-w","article-title":"Microglia clear neuron-released \u03b1-synuclein via selective autophagy and prevent neurodegeneration","volume":"11","author":"Choi","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5089","DOI":"10.1016\/j.cell.2021.09.007","article-title":"Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes","volume":"184","author":"Scheiblich","year":"2021","journal-title":"Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1007\/s12035-021-02375-0","article-title":"Gut Microbial Metabolites in Parkinson\u2019s Disease: Implications of Mitochondrial Dysfunction in the Pathogenesis and Treatment","volume":"58","author":"Liang","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1043579","DOI":"10.3389\/fimmu.2022.1043579","article-title":"Hypothesis of a potential BrainBiota and its relation to CNS autoimmune inflammation","volume":"13","author":"Elkjaer","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1096\/fj.03-0203fje","article-title":"Synergistic dopaminergic neurotoxicity of MPTP and inflammogen lipopolysaccharide: Relevance to the etiology of Parkinson\u2019s disease","volume":"17","author":"Gao","year":"2003","journal-title":"FASEB J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4680","DOI":"10.1093\/hmg\/dds309","article-title":"Mitochondrial metabolism in Parkinson\u2019s disease impairs quality control autophagy by hampering microtubule-dependent traffic","volume":"21","author":"Esteves","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/S0006-3495(99)77214-0","article-title":"Measurement of Mitochondrial Membrane Potential Using Fluorescent Rhodamine Derivatives","volume":"76","author":"Scaduto","year":"1999","journal-title":"Biophys. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4339\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:39:01Z","timestamp":1760121541000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4339"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,22]]},"references-count":74,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24054339"],"URL":"https:\/\/doi.org\/10.3390\/ijms24054339","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,22]]}}}