[{"publisher":"Elsevier","doi":"10.1016/j.isci.2023.107780","article_processing_charge":"Yes","type":"journal_article","date_updated":"2023-12-13T12:27:30Z","_id":"14363","ddc":["570"],"quality_controlled":"1","external_id":{"isi":["001080403500001"],"pmid":["37731609"]},"isi":1,"year":"2023","status":"public","publication":"iScience","date_published":"2023-10-20T00:00:00Z","acknowledgement":"We thank the Scientific Service Units (SSU) of ISTA through resources provided by the Imaging and Optics Facility (IOF), the Lab Support Facility (LSF), and the Pre-Clinical Facility (PCF) team, specifically Sonja Haslinger and Michael Schunn for excellent mouse colony management and support. This research was supported by the FWF Sonderforschungsbereich F83 (to E.E.P). We thank Bálint Nagy, Ryan John A. Cubero, Marco Benevento and all members of the Siegert group for constant feedback on the project and article.","pmid":1,"title":"Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout","oa_version":"Published Version","author":[{"last_name":"Maes","id":"3838F452-F248-11E8-B48F-1D18A9856A87","full_name":"Maes, Margaret E","orcid":"0000-0001-9642-1085","first_name":"Margaret E"},{"full_name":"Colombo, Gloria","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","last_name":"Colombo","first_name":"Gloria","orcid":"0000-0001-9434-8902"},{"first_name":"Florianne E","last_name":"Schoot Uiterkamp","id":"3526230C-F248-11E8-B48F-1D18A9856A87","full_name":"Schoot Uiterkamp, Florianne E"},{"full_name":"Sternberg, Felix","last_name":"Sternberg","first_name":"Felix"},{"full_name":"Venturino, Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","last_name":"Venturino","first_name":"Alessandro","orcid":"0000-0003-2356-9403"},{"full_name":"Pohl, Elena E.","last_name":"Pohl","first_name":"Elena E."},{"orcid":"0000-0001-8635-0877","first_name":"Sandra","last_name":"Siegert","full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87"}],"day":"20","scopus_import":"1","article_type":"original","date_created":"2023-09-24T22:01:11Z","volume":26,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","short":"CC BY (4.0)"},"abstract":[{"lang":"eng","text":"Mitochondrial networks remodel their connectivity, content, and subcellular localization to support optimized energy production in conditions of increased environmental or cellular stress. Microglia rely on mitochondria to respond to these stressors, however our knowledge about mitochondrial networks and their adaptations in microglia in vivo is limited. Here, we generate a mouse model that selectively labels mitochondria in microglia. We identify that mitochondrial networks are more fragmented with increased content and perinuclear localization in vitro vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the injury site after optic nerve crush. Preventing microglial UCP2 increase after injury by selective knockout induces cellular stress. This results in mitochondrial hyperfusion in male microglia, a phenotype absent in females due to circulating estrogens. Our results establish the foundation for mitochondrial network analysis of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects of microglia in other pathologies."}],"intvolume":"        26","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"PreCl"}],"has_accepted_license":"1","publication_identifier":{"eissn":["2589-0042"]},"publication_status":"published","file_date_updated":"2023-11-07T08:53:21Z","month":"10","article_number":"107780","file":[{"file_name":"2023_iScience_Maes.pdf","success":1,"content_type":"application/pdf","access_level":"open_access","relation":"main_file","checksum":"be1a560efdd96d20712311f4fc54aac2","file_size":8197935,"date_created":"2023-11-07T08:53:21Z","creator":"dernst","date_updated":"2023-11-07T08:53:21Z","file_id":"14497"}],"department":[{"_id":"SaSi"}],"language":[{"iso":"eng"}],"oa":1,"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","issue":"10","citation":{"mla":"Maes, Margaret E., et al. “Mitochondrial Network Adaptations of Microglia Reveal Sex-Specific Stress Response after Injury and UCP2 Knockout.” <i>IScience</i>, vol. 26, no. 10, 107780, Elsevier, 2023, doi:<a href=\"https://doi.org/10.1016/j.isci.2023.107780\">10.1016/j.isci.2023.107780</a>.","apa":"Maes, M. E., Colombo, G., Schoot Uiterkamp, F. E., Sternberg, F., Venturino, A., Pohl, E. E., &#38; Siegert, S. (2023). Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout. <i>IScience</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.isci.2023.107780\">https://doi.org/10.1016/j.isci.2023.107780</a>","ista":"Maes ME, Colombo G, Schoot Uiterkamp FE, Sternberg F, Venturino A, Pohl EE, Siegert S. 2023. Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout. iScience. 26(10), 107780.","chicago":"Maes, Margaret E, Gloria Colombo, Florianne E Schoot Uiterkamp, Felix Sternberg, Alessandro Venturino, Elena E. Pohl, and Sandra Siegert. “Mitochondrial Network Adaptations of Microglia Reveal Sex-Specific Stress Response after Injury and UCP2 Knockout.” <i>IScience</i>. Elsevier, 2023. <a href=\"https://doi.org/10.1016/j.isci.2023.107780\">https://doi.org/10.1016/j.isci.2023.107780</a>.","short":"M.E. Maes, G. Colombo, F.E. Schoot Uiterkamp, F. Sternberg, A. Venturino, E.E. Pohl, S. Siegert, IScience 26 (2023).","ieee":"M. E. Maes <i>et al.</i>, “Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout,” <i>iScience</i>, vol. 26, no. 10. Elsevier, 2023.","ama":"Maes ME, Colombo G, Schoot Uiterkamp FE, et al. Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout. <i>iScience</i>. 2023;26(10). doi:<a href=\"https://doi.org/10.1016/j.isci.2023.107780\">10.1016/j.isci.2023.107780</a>"}},{"has_accepted_license":"1","intvolume":"        36","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","short":"CC BY (4.0)"},"abstract":[{"text":"Perineuronal nets (PNNs), components of the extracellular matrix, preferentially coat parvalbumin-positive interneurons and constrain critical-period plasticity in the adult cerebral cortex. Current strategies to remove PNN are long-lasting, invasive, and trigger neuropsychiatric symptoms. Here, we apply repeated anesthetic ketamine as a method with minimal behavioral effect. We find that this paradigm strongly reduces PNN coating in the healthy adult brain and promotes juvenile-like plasticity. Microglia are critically involved in PNN loss because they engage with parvalbumin-positive neurons in their defined cortical layer. We identify external 60-Hz light-flickering entrainment to recapitulate microglia-mediated PNN removal. Importantly, 40-Hz frequency, which is known to remove amyloid plaques, does not induce PNN loss, suggesting microglia might functionally tune to distinct brain frequencies. Thus, our 60-Hz light-entrainment strategy provides an alternative form of PNN intervention in the healthy adult brain.","lang":"eng"}],"acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"}],"publication_identifier":{"eissn":["22111247"]},"publication_status":"published","file_date_updated":"2021-07-19T13:32:17Z","author":[{"last_name":"Venturino","full_name":"Venturino, Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2356-9403","first_name":"Alessandro"},{"last_name":"Schulz","full_name":"Schulz, Rouven","id":"4C5E7B96-F248-11E8-B48F-1D18A9856A87","first_name":"Rouven","orcid":"0000-0001-5297-733X"},{"first_name":"Héctor","full_name":"De Jesús-Cortés, Héctor","last_name":"De Jesús-Cortés"},{"orcid":"0000-0001-9642-1085","first_name":"Margaret E","id":"3838F452-F248-11E8-B48F-1D18A9856A87","full_name":"Maes, Margaret E","last_name":"Maes"},{"first_name":"Balint","full_name":"Nagy, Balint","id":"93C65ECC-A6F2-11E9-8DF9-9712E6697425","last_name":"Nagy"},{"last_name":"Reilly-Andújar","full_name":"Reilly-Andújar, Francis","first_name":"Francis"},{"orcid":"0000-0001-9434-8902","first_name":"Gloria","last_name":"Colombo","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","full_name":"Colombo, Gloria"},{"orcid":"0000-0003-0002-1867","first_name":"Ryan J","last_name":"Cubero","id":"850B2E12-9CD4-11E9-837F-E719E6697425","full_name":"Cubero, Ryan J"},{"last_name":"Schoot Uiterkamp","id":"3526230C-F248-11E8-B48F-1D18A9856A87","full_name":"Schoot Uiterkamp, Florianne E","first_name":"Florianne E"},{"first_name":"Mark F.","last_name":"Bear","full_name":"Bear, Mark F."},{"last_name":"Siegert","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra","first_name":"Sandra","orcid":"0000-0001-8635-0877"}],"day":"06","scopus_import":"1","title":"Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain","oa_version":"Published Version","volume":36,"article_type":"original","date_created":"2021-07-11T22:01:16Z","oa":1,"language":[{"iso":"eng"}],"issue":"1","citation":{"short":"A. Venturino, R. Schulz, H. De Jesús-Cortés, M.E. Maes, B. Nagy, F. Reilly-Andújar, G. Colombo, R.J. Cubero, F.E. Schoot Uiterkamp, M.F. Bear, S. Siegert, Cell Reports 36 (2021).","ieee":"A. Venturino <i>et al.</i>, “Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain,” <i>Cell Reports</i>, vol. 36, no. 1. Elsevier, 2021.","ama":"Venturino A, Schulz R, De Jesús-Cortés H, et al. Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain. <i>Cell Reports</i>. 2021;36(1). doi:<a href=\"https://doi.org/10.1016/j.celrep.2021.109313\">10.1016/j.celrep.2021.109313</a>","mla":"Venturino, Alessandro, et al. “Microglia Enable Mature Perineuronal Nets Disassembly upon Anesthetic Ketamine Exposure or 60-Hz Light Entrainment in the Healthy Brain.” <i>Cell Reports</i>, vol. 36, no. 1, 109313, Elsevier, 2021, doi:<a href=\"https://doi.org/10.1016/j.celrep.2021.109313\">10.1016/j.celrep.2021.109313</a>.","apa":"Venturino, A., Schulz, R., De Jesús-Cortés, H., Maes, M. E., Nagy, B., Reilly-Andújar, F., … Siegert, S. (2021). Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain. <i>Cell Reports</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.celrep.2021.109313\">https://doi.org/10.1016/j.celrep.2021.109313</a>","chicago":"Venturino, Alessandro, Rouven Schulz, Héctor De Jesús-Cortés, Margaret E Maes, Balint Nagy, Francis Reilly-Andújar, Gloria Colombo, et al. “Microglia Enable Mature Perineuronal Nets Disassembly upon Anesthetic Ketamine Exposure or 60-Hz Light Entrainment in the Healthy Brain.” <i>Cell Reports</i>. Elsevier, 2021. <a href=\"https://doi.org/10.1016/j.celrep.2021.109313\">https://doi.org/10.1016/j.celrep.2021.109313</a>.","ista":"Venturino A, Schulz R, De Jesús-Cortés H, Maes ME, Nagy B, Reilly-Andújar F, Colombo G, Cubero RJ, Schoot Uiterkamp FE, Bear MF, Siegert S. 2021. Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain. Cell Reports. 36(1), 109313."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","month":"07","department":[{"_id":"SaSi"}],"file":[{"checksum":"f056255f6d01fd9a86b5387635928173","relation":"main_file","content_type":"application/pdf","access_level":"open_access","file_name":"2021_CellReports_Venturino.pdf","success":1,"file_id":"9693","date_updated":"2021-07-19T13:32:17Z","creator":"cziletti","file_size":56388540,"date_created":"2021-07-19T13:32:17Z"}],"article_number":"109313","ddc":["570"],"quality_controlled":"1","doi":"10.1016/j.celrep.2021.109313","article_processing_charge":"No","publisher":"Elsevier","date_updated":"2023-08-10T14:09:39Z","_id":"9642","type":"journal_article","project":[{"_id":"2564DBCA-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","grant_number":"665385","name":"International IST Doctoral Program"},{"_id":"260C2330-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","name":"ISTplus - Postdoctoral Fellowships","grant_number":"754411"},{"_id":"25D4A630-B435-11E9-9278-68D0E5697425","name":"Microglia action towards neuronal circuit formation and function in health and disease","grant_number":"715571","call_identifier":"H2020"}],"publication":"Cell Reports","status":"public","pmid":1,"ec_funded":1,"date_published":"2021-07-06T00:00:00Z","acknowledgement":"We thank the scientific service units at IST Austria, especially the IST bioimaging facility, the preclinical facility, and, specifically, Michael Schunn and Sonja Haslinger for excellent support; Plexxikon for the PLX food; the Csicsvari group for advice and equipment for in vivo recording; Jürgen Siegert for the light-entrainment design; Marco Benevento, Soledad Gonzalo Cogno, Pat King, and all Siegert group members for constant feedback on the project and manuscript; Lorena Pantano (PILM Bioinformatics Core) for assisting with sample-size determination for OD plasticity experiments; and Ana Morello from MIT for technical assistance with VEPs recordings. This research was supported by a DOC Fellowship from the Austrian Academy of Sciences at the Institute of Science and Technology Austria to R.S., from the European Union Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions program (grants 665385 to G.C.; 754411 to R.J.A.C.), the European Research Council (grant 715571 to S.S.), and the National Eye Institute of the National Institutes of Health under award numbers R01EY029245 (to M.F.B.) and R01EY023037 (diversity supplement to H.D.J-C.).","isi":1,"year":"2021","external_id":{"isi":["000670188500004"],"pmid":["34233180"]},"related_material":{"link":[{"relation":"press_release","description":"News on IST Homepage","url":"https://ist.ac.at/en/news/the-twinkle-and-the-brain/"}]}},{"publication_status":"published","publication_identifier":{"issn":["00219258"],"eissn":["1083351X"]},"intvolume":"       295","abstract":[{"lang":"eng","text":"Following its evoked release, dopamine (DA) signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT). DAT surface availability is dynamically regulated by endocytic trafficking, and direct protein kinase C (PKC) activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. Ex vivo studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKC-stimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation and that the DAT N terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in bona fide DAergic terminals. "}],"article_type":"original","date_created":"2020-05-24T22:00:59Z","volume":295,"oa_version":"Submitted Version","title":"Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact","author":[{"first_name":"Rita R.","full_name":"Fagan, Rita R.","last_name":"Fagan"},{"last_name":"Kearney","full_name":"Kearney, Patrick J.","first_name":"Patrick J."},{"first_name":"Carolyn G.","last_name":"Sweeney","full_name":"Sweeney, Carolyn G."},{"first_name":"Dino","full_name":"Luethi, Dino","last_name":"Luethi"},{"id":"3526230C-F248-11E8-B48F-1D18A9856A87","full_name":"Schoot Uiterkamp, Florianne E","last_name":"Schoot Uiterkamp","first_name":"Florianne E"},{"first_name":"Klaus","full_name":"Schicker, Klaus","last_name":"Schicker"},{"full_name":"Alejandro, Brian S.","last_name":"Alejandro","first_name":"Brian S."},{"last_name":"O'Connor","full_name":"O'Connor, Lauren C.","first_name":"Lauren C."},{"last_name":"Sitte","full_name":"Sitte, Harald H.","first_name":"Harald H."},{"last_name":"Melikian","full_name":"Melikian, Haley E.","first_name":"Haley E."}],"day":"17","scopus_import":"1","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","issue":"16","citation":{"mla":"Fagan, Rita R., et al. “Dopamine Transporter Trafficking and Rit2 GTPase: Mechanism of Action and in Vivo Impact.” <i>Journal of Biological Chemistry</i>, vol. 295, no. 16, ASBMB Publications, 2020, pp. 5229–44, doi:<a href=\"https://doi.org/10.1074/jbc.RA120.012628\">10.1074/jbc.RA120.012628</a>.","apa":"Fagan, R. R., Kearney, P. J., Sweeney, C. G., Luethi, D., Schoot Uiterkamp, F. E., Schicker, K., … Melikian, H. E. (2020). Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact. <i>Journal of Biological Chemistry</i>. ASBMB Publications. <a href=\"https://doi.org/10.1074/jbc.RA120.012628\">https://doi.org/10.1074/jbc.RA120.012628</a>","chicago":"Fagan, Rita R., Patrick J. Kearney, Carolyn G. Sweeney, Dino Luethi, Florianne E Schoot Uiterkamp, Klaus Schicker, Brian S. Alejandro, Lauren C. O’Connor, Harald H. Sitte, and Haley E. Melikian. “Dopamine Transporter Trafficking and Rit2 GTPase: Mechanism of Action and in Vivo Impact.” <i>Journal of Biological Chemistry</i>. ASBMB Publications, 2020. <a href=\"https://doi.org/10.1074/jbc.RA120.012628\">https://doi.org/10.1074/jbc.RA120.012628</a>.","ista":"Fagan RR, Kearney PJ, Sweeney CG, Luethi D, Schoot Uiterkamp FE, Schicker K, Alejandro BS, O’Connor LC, Sitte HH, Melikian HE. 2020. Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact. Journal of Biological Chemistry. 295(16), 5229–5244.","short":"R.R. Fagan, P.J. Kearney, C.G. Sweeney, D. Luethi, F.E. Schoot Uiterkamp, K. Schicker, B.S. Alejandro, L.C. O’Connor, H.H. Sitte, H.E. Melikian, Journal of Biological Chemistry 295 (2020) 5229–5244.","ieee":"R. R. Fagan <i>et al.</i>, “Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact,” <i>Journal of Biological Chemistry</i>, vol. 295, no. 16. ASBMB Publications, pp. 5229–5244, 2020.","ama":"Fagan RR, Kearney PJ, Sweeney CG, et al. Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact. <i>Journal of Biological Chemistry</i>. 2020;295(16):5229-5244. doi:<a href=\"https://doi.org/10.1074/jbc.RA120.012628\">10.1074/jbc.RA120.012628</a>"},"language":[{"iso":"eng"}],"oa":1,"department":[{"_id":"SaSi"}],"month":"04","quality_controlled":"1","main_file_link":[{"open_access":"1","url":"https://escholarship.umassmed.edu/oapubs/4187"}],"page":"5229-5244","type":"journal_article","date_updated":"2023-08-21T06:26:22Z","_id":"7880","publisher":"ASBMB Publications","doi":"10.1074/jbc.RA120.012628","article_processing_charge":"No","date_published":"2020-04-17T00:00:00Z","pmid":1,"status":"public","publication":"Journal of Biological Chemistry","external_id":{"isi":["000530288000006"],"pmid":["32132171"]},"isi":1,"year":"2020"}]