--- OA_place: publisher OA_type: hybrid PlanS_conform: '1' _id: '21860' abstract: - lang: eng text: Glutamate excitotoxicity is a cell death mechanism triggered by accumulation of glutamate in the extracellular space. The α-ketoglutarate dehydrogenase complex (αKGDHC), an enzyme of the tricarboxylic acid cycle, represents a branching point controlling glutamate formation and its consumption as a fuel. Hence, modulation of the activity of αKGDHC might alter the amount of glutamate available for excitotoxic effects. To address this hypothesis, hippocampal neurons in primary co-culture with glial cells were exposed to zero-Mg2 buffer to elicit excitotoxicity through N-methyl-D-aspartic acid (NMDA) receptor disinhibition. Pretreatment of the cultures with succinyl phosphonate, to inhibit αKGDHC, enhanced excitotoxity, whereas promotion of αKGDHC activity by pretreatment with thiamine caused an opposite action. Moreover, NMDA receptor currents – but not those mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors – were potentiated in neurons with impaired αKGDHC activity and diminished in neurons with boosted αKGDHC activity. The sensitization of NMDA receptors involved mGluR1 activation and was accompanied by enhanced neuronal discharge activity, elevated basal cytosolic Ca2+ levels, and augmented Ca2+ responses evoked by glutamate application. These results suggest that mGluR1-mediated potentiation of NMDA receptors contributes to a mechanism by which inhibition of αKGDHC might exacerbate glutamate excitotoxicity. acknowledgement: The technical assistance by Tanja Wagner and Elena Lilliu is gratefully acknowledged. This research was funded in whole or in part by the Austrian Science Fund (FWF) (P36145 to H.K., PAT8605623 to M.H. and P33799 to A.V.K.]. Open Access funding provided by Medical University of Vienna and the Austrian Science Fund (FWF). Deposited in PMC for immediate release. article_number: jcs264420 article_processing_charge: Yes (via OA deal) article_type: original author: - first_name: Vanessa full_name: Goeschl, Vanessa last_name: Goeschl - first_name: Matej full_name: Hotka, Matej last_name: Hotka - first_name: Bernhard full_name: Hochreiter, Bernhard id: e6cab3de-17f6-11ed-9210-c1e42e045e9d last_name: Hochreiter - first_name: Karlheinz full_name: Hilber, Karlheinz last_name: Hilber - first_name: Stefan full_name: Boehm, Stefan last_name: Boehm - first_name: Andrey V. full_name: Kozlov, Andrey V. last_name: Kozlov - first_name: Helmut full_name: Kubista, Helmut last_name: Kubista citation: ama: Goeschl V, Hotka M, Hochreiter B, et al. α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary cultures. Journal of Cell Science. 2026;139(8). doi:10.1242/jcs.264420 apa: Goeschl, V., Hotka, M., Hochreiter, B., Hilber, K., Boehm, S., Kozlov, A. V., & Kubista, H. (2026). α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary cultures. Journal of Cell Science. The Company of Biologists. https://doi.org/10.1242/jcs.264420 chicago: Goeschl, Vanessa, Matej Hotka, Bernhard Hochreiter, Karlheinz Hilber, Stefan Boehm, Andrey V. Kozlov, and Helmut Kubista. “α-Ketoglutarate Dehydrogenase Complex Activity Modulates Glutamate Excitotoxicity via Metabotropic Regulation of NMDA Receptors in Primary Cultures.” Journal of Cell Science. The Company of Biologists, 2026. https://doi.org/10.1242/jcs.264420. ieee: V. Goeschl et al., “α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary cultures,” Journal of Cell Science, vol. 139, no. 8. The Company of Biologists, 2026. ista: Goeschl V, Hotka M, Hochreiter B, Hilber K, Boehm S, Kozlov AV, Kubista H. 2026. α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary cultures. Journal of Cell Science. 139(8), jcs264420. mla: Goeschl, Vanessa, et al. “α-Ketoglutarate Dehydrogenase Complex Activity Modulates Glutamate Excitotoxicity via Metabotropic Regulation of NMDA Receptors in Primary Cultures.” Journal of Cell Science, vol. 139, no. 8, jcs264420, The Company of Biologists, 2026, doi:10.1242/jcs.264420. short: V. Goeschl, M. Hotka, B. Hochreiter, K. Hilber, S. Boehm, A.V. Kozlov, H. Kubista, Journal of Cell Science 139 (2026). date_created: 2026-05-11T10:52:27Z date_published: 2026-04-27T00:00:00Z date_updated: 2026-05-12T06:40:18Z day: '27' ddc: - '570' department: - _id: Bio doi: 10.1242/jcs.264420 external_id: pmid: - '41834724' file: - access_level: open_access checksum: 8db35c97588c2f6ef88c7e8d5924cf8c content_type: application/pdf creator: dernst date_created: 2026-05-12T06:27:54Z date_updated: 2026-05-12T06:27:54Z file_id: '21861' file_name: 2026_JourCellScience_Goeschl.pdf file_size: 1957057 relation: main_file success: 1 file_date_updated: 2026-05-12T06:27:54Z fulldoi: https://doi.org/10.1242/jcs.264420 has_accepted_license: '1' intvolume: ' 139' issue: '8' language: - iso: eng month: '04' oa: 1 oa_version: Published Version pmid: 1 publication: Journal of Cell Science publication_identifier: eissn: - 1477-9137 issn: - 0021-9533 publication_status: published publisher: The Company of Biologists quality_controlled: '1' scopus_import: '1' status: public title: α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary cultures tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 139 year: '2026' ... --- DOAJ_listed: '1' OA_place: publisher OA_type: gold PlanS_conform: '1' _id: '23148' abstract: - lang: eng text: Presenilin-1 (PS1) is an endoplasmic reticulum protein, most known for its role in pathogenesis of familial Alzheimer’s Disease (AD). PS1 has been attributed roles in intracellular calcium homeostasis in the brain, as well as in the pancreatic beta cells, where it has been shown to be fundamental for the initial phase of glucose-induced insulin secretion. To gain mechanistic insight into beta cell autonomous function of PS1, we have examined various beta cell models and found that PS1 controls glycolytic flux of pancreatic beta cells by regulating sub-mitochondrial Ca2+ homeostasis. Transient knock down of PS1 yielded a glycolytic bottleneck at the step catalyzed by glyceraldehyde-3-phosphate dehydrogenase, resulting in defective glucose responsiveness. Moreover, we show that PS1 is needed for the preservation of beta cell identity, likely due to its role in glycolysis. Finally, we show that mouse islets from an in vivo model of AD mimic the defective glucose responsiveness seen in beta cells with transient PS1 knock down, while the identity loss and whole-body glucose homeostasis are not severely impacted, suggesting an adaptive response. Thus, the current work highlights beta cell autonomous role of PS1 and adds a layer of complexity in its impact on whole body metabolism. acknowledgement: We appreciate the technical assistance from Anna Schreilechner. We are grateful for support by all members of the animal facility team at IMB, University of Graz, as well as K. Zierler for assistance with animal licenses. F.M, T.E., T.M., T.P., and W.F.G. are grateful to the Austrian Science Fund (FWF) for the excellence cluster 10.55776/COE14 (MetAGE), which was additionally supported by Land Styria, Stadt Graz, University of Graz and Medical University of Graz. This research was further supported by the FWF via the DKplus program 10.55776/W1226 (DK-MCD) to F.M., T.M., R.B.G., and W.F.G., 10.55776/P28529, 10.55776/I3716 (to R.M.), 10.55776/P28854, 10.55776/I3792, 10.55776/DOC130 (to T.M.), and 10.55776/I4319 (to. M.S.R.); the Austrian Research Promotion Agency (FFG) grants 864690 and 870454; the Integrative Metabolism Research Center Graz; the Austrian Infrastructure Program 2016/2017 (to T.M.), and 10.55776/COE7, 10.55776/COE17, 10.55776/FG12 and 10.55776/F73 (to R.B.G.); the Styrian Government; the City of Graz; and BioTechMed-Graz (flagship project) (to T.M.); the MEFO Graz (to W.F.G.). F.E.O., J.G. and Z.K. were doctoral fellows in the doctoral program Metabolic and Cardiovascular Disease (MCD) (FWF, 10.55776/W 1226) at the Medical University of Graz. S.v.A. and A.S. are thesis students in the excellence cluster 10.55776/COE14 (MetAGE, W.F.G.). M.H. was a fellow of the Molecular Medicine (MolMed) doctoral program at the Medical University of Graz supported by MEFO Graz. The SIM equipment is part of the Nikon Center of Excellence, Graz, and is supported by the Austrian infrastructure program 2013/ 2014, Nikon Austria Inc., and BioTechMed (to W.F.G.). Our thanks go to Shimadzu Austria for supporting this research through instrument access given in the Metabolomics and Bioprocess Analytics laboratory (TU Wien) (R.B.G.). For open access purposes, the authors have applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission.” We thank the Medical University of Graz for financial support. article_number: '1315' article_processing_charge: Yes article_type: original author: - first_name: Zhanat full_name: Koshenov, Zhanat last_name: Koshenov - first_name: Sandra full_name: Postic, Sandra last_name: Postic - first_name: Gabriela full_name: Schoiswohl, Gabriela last_name: Schoiswohl - first_name: Savina full_name: Van Amsterdam, Savina last_name: Van Amsterdam - first_name: Victoria full_name: Hois-Zelinka, Victoria last_name: Hois-Zelinka - first_name: Furkan E. full_name: Oflaz, Furkan E. last_name: Oflaz - first_name: Rene full_name: Rost, Rene last_name: Rost - first_name: Oleksandra full_name: Tiapko, Oleksandra last_name: Tiapko - first_name: Benjamin full_name: Gottschalk, Benjamin last_name: Gottschalk - first_name: Martin full_name: Hirtl, Martin last_name: Hirtl - first_name: Olaf G. full_name: Bachkoenig, Olaf G. last_name: Bachkoenig - first_name: Aigerim full_name: Koshenova, Aigerim last_name: Koshenova - first_name: Yusuf C. full_name: Erdogan, Yusuf C. last_name: Erdogan - first_name: Adlet full_name: Sagintayev, Adlet last_name: Sagintayev - first_name: Anita full_name: Krnjic, Anita last_name: Krnjic - first_name: Johannes U. full_name: Pfabe, Johannes U. last_name: Pfabe - first_name: Srdjan full_name: Sarikas, Srdjan id: 35F0286E-F248-11E8-B48F-1D18A9856A87 last_name: Sarikas - first_name: Bernhard full_name: Hochreiter, Bernhard id: e6cab3de-17f6-11ed-9210-c1e42e045e9d last_name: Hochreiter - first_name: Juergen full_name: Gindlhuber, Juergen last_name: Gindlhuber - first_name: Matthias full_name: Schittmayer, Matthias last_name: Schittmayer - first_name: Jelena full_name: Tadic, Jelena last_name: Tadic - first_name: Barbara full_name: Ehall, Barbara last_name: Ehall - first_name: Frank full_name: Madeo, Frank last_name: Madeo - first_name: Tobias full_name: Madl, Tobias last_name: Madl - first_name: Roland full_name: Malli, Roland last_name: Malli - first_name: Ruth full_name: Birner-Gruenberger, Ruth last_name: Birner-Gruenberger - first_name: Thomas full_name: Pieber, Thomas last_name: Pieber - first_name: Tobias full_name: Eisenberg, Tobias last_name: Eisenberg - first_name: Marjan full_name: Slak Rupnik, Marjan last_name: Slak Rupnik - first_name: Wolfgang F. full_name: Graier, Wolfgang F. last_name: Graier citation: ama: Koshenov Z, Postic S, Schoiswohl G, et al. Presenilin-1 controls glycolysis and identity of pancreatic beta cells. Communications Biology. 2026;9. doi:10.1038/s42003-026-10581-6 apa: Koshenov, Z., Postic, S., Schoiswohl, G., Van Amsterdam, S., Hois-Zelinka, V., Oflaz, F. E., … Graier, W. F. (2026). Presenilin-1 controls glycolysis and identity of pancreatic beta cells. Communications Biology. Springer Nature. https://doi.org/10.1038/s42003-026-10581-6 chicago: Koshenov, Zhanat, Sandra Postic, Gabriela Schoiswohl, Savina Van Amsterdam, Victoria Hois-Zelinka, Furkan E. Oflaz, Rene Rost, et al. “Presenilin-1 Controls Glycolysis and Identity of Pancreatic Beta Cells.” Communications Biology. Springer Nature, 2026. https://doi.org/10.1038/s42003-026-10581-6. ieee: Z. Koshenov et al., “Presenilin-1 controls glycolysis and identity of pancreatic beta cells,” Communications Biology, vol. 9. Springer Nature, 2026. ista: Koshenov Z, Postic S, Schoiswohl G, Van Amsterdam S, Hois-Zelinka V, Oflaz FE, Rost R, Tiapko O, Gottschalk B, Hirtl M, Bachkoenig OG, Koshenova A, Erdogan YC, Sagintayev A, Krnjic A, Pfabe JU, Sarikas S, Hochreiter B, Gindlhuber J, Schittmayer M, Tadic J, Ehall B, Madeo F, Madl T, Malli R, Birner-Gruenberger R, Pieber T, Eisenberg T, Slak Rupnik M, Graier WF. 2026. Presenilin-1 controls glycolysis and identity of pancreatic beta cells. Communications Biology. 9, 1315. mla: Koshenov, Zhanat, et al. “Presenilin-1 Controls Glycolysis and Identity of Pancreatic Beta Cells.” Communications Biology, vol. 9, 1315, Springer Nature, 2026, doi:10.1038/s42003-026-10581-6. short: Z. Koshenov, S. Postic, G. Schoiswohl, S. Van Amsterdam, V. Hois-Zelinka, F.E. Oflaz, R. Rost, O. Tiapko, B. Gottschalk, M. Hirtl, O.G. Bachkoenig, A. Koshenova, Y.C. Erdogan, A. Sagintayev, A. Krnjic, J.U. Pfabe, S. Sarikas, B. Hochreiter, J. Gindlhuber, M. Schittmayer, J. Tadic, B. Ehall, F. Madeo, T. Madl, R. Malli, R. Birner-Gruenberger, T. Pieber, T. Eisenberg, M. Slak Rupnik, W.F. Graier, Communications Biology 9 (2026). das_tickbox: '1' dataavailabilitystatement: The data supporting the findings of this research can be obtained from the authors upon a reasonable request; please refer to the author’s contributions for details regarding specific datasets. Numerical source data underlying graphs in this article can be found in Supplementary data file. Supplementary Figs. and figure legends are included in the Supplementary file. The code used in this study is available from the authors on reasonable request. date_created: 2026-10-18T22:01:50Z date_published: 2026-10-08T00:00:00Z date_updated: 2026-10-19T06:23:26Z day: '08' ddc: - '570' department: - _id: FISS doi: 10.1038/s42003-026-10581-6 external_id: pmid: - '42387039' file: - access_level: open_access checksum: b90e60a625fcac8ef5d9ff968792d675 content_type: application/pdf creator: dernst date_created: 2026-10-19T06:19:39Z date_updated: 2026-10-19T06:19:39Z file_id: '23161' file_name: 2026_CommunicationsBiology_Koshenov.pdf file_size: 1819866 relation: main_file success: 1 file_date_updated: 2026-10-19T06:19:39Z fulldoi: https://doi.org/10.1038/s42003-026-10581-6 has_accepted_license: '1' intvolume: ' 9' language: - iso: eng month: '10' oa: 1 oa_version: Published Version pmid: 1 publication: Communications Biology publication_identifier: eissn: - 2399-3642 publication_status: published publisher: Springer Nature quality_controlled: '1' researchdata_availability: upon request scopus_import: '1' status: public supplementarymaterial: yes title: Presenilin-1 controls glycolysis and identity of pancreatic beta cells tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 9 year: '2026' ... --- OA_type: closed access _id: '20870' abstract: - lang: eng text: RNA sequencing (RNA-seq) methodologies have evolved rapidly, offering powerful tools to study gene expression, transcriptome dynamics, and molecular mechanisms in various biological contexts. However, the complexity of these approaches poses challenges in data interpretation, sensitivity, and applicability. This chapter provides a comprehensive overview of RNA-seq methodologies, highlighting their advantages, limitations, and applications, particularly in cardiovascular research. Bulk RNA sequencing enables high-throughput gene expression profiling but lacks the resolution to capture cellular heterogeneity and spatial context. Direct RNA sequencing preserves native RNA modifications, offering insights into post-transcriptional regulation, though it remains technically challenging. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) bridge these gaps by resolving transcriptomic complexity at the cellular level and within tissue architecture, providing crucial insights into disease mechanisms such as atherosclerosis. By summarizing the strengths and limitations of these methodologies, this chapter aims to guide researchers in selecting the most suitable transcriptomic approach for their studies, ultimately advancing precision medicine and biomarker discovery in cardiovascular disease. article_processing_charge: No author: - first_name: Victoria full_name: Stopa, Victoria last_name: Stopa - first_name: Miron full_name: Sopić, Miron last_name: Sopić - first_name: Guanliang full_name: Li, Guanliang last_name: Li - first_name: Judith full_name: Sluimer, Judith last_name: Sluimer - first_name: José full_name: Basílio, José last_name: Basílio - first_name: Sander W. full_name: van der Laan, Sander W. last_name: van der Laan - first_name: David P. full_name: Kreil, David P. last_name: Kreil - first_name: Yvan full_name: Devaux, Yvan last_name: Devaux - first_name: Bernhard full_name: Hochreiter, Bernhard id: e6cab3de-17f6-11ed-9210-c1e42e045e9d last_name: Hochreiter citation: ama: 'Stopa V, Sopić M, Li G, et al. Essentials of transcriptomic methods: Navigating through RNA sequencing and beyond. In: Devaux Y, Sopic M, eds. Transcriptomics in Atherosclerosis. Elsevier; 2025:131-172. doi:10.1016/b978-0-443-33064-3.00016-5' apa: 'Stopa, V., Sopić, M., Li, G., Sluimer, J., Basílio, J., van der Laan, S. W., … Hochreiter, B. (2025). Essentials of transcriptomic methods: Navigating through RNA sequencing and beyond. In Y. Devaux & M. Sopic (Eds.), Transcriptomics in Atherosclerosis (pp. 131–172). Elsevier. https://doi.org/10.1016/b978-0-443-33064-3.00016-5' chicago: 'Stopa, Victoria, Miron Sopić, Guanliang Li, Judith Sluimer, José Basílio, Sander W. van der Laan, David P. Kreil, Yvan Devaux, and Bernhard Hochreiter. “Essentials of Transcriptomic Methods: Navigating through RNA Sequencing and Beyond.” In Transcriptomics in Atherosclerosis, edited by Yvan Devaux and Miron Sopic, 131–72. Elsevier, 2025. https://doi.org/10.1016/b978-0-443-33064-3.00016-5.' ieee: 'V. Stopa et al., “Essentials of transcriptomic methods: Navigating through RNA sequencing and beyond,” in Transcriptomics in Atherosclerosis, Y. Devaux and M. Sopic, Eds. Elsevier, 2025, pp. 131–172.' ista: 'Stopa V, Sopić M, Li G, Sluimer J, Basílio J, van der Laan SW, Kreil DP, Devaux Y, Hochreiter B. 2025.Essentials of transcriptomic methods: Navigating through RNA sequencing and beyond. In: Transcriptomics in Atherosclerosis. , 131–172.' mla: 'Stopa, Victoria, et al. “Essentials of Transcriptomic Methods: Navigating through RNA Sequencing and Beyond.” Transcriptomics in Atherosclerosis, edited by Yvan Devaux and Miron Sopic, Elsevier, 2025, pp. 131–72, doi:10.1016/b978-0-443-33064-3.00016-5.' short: V. Stopa, M. Sopić, G. Li, J. Sluimer, J. Basílio, S.W. van der Laan, D.P. Kreil, Y. Devaux, B. Hochreiter, in:, Y. Devaux, M. Sopic (Eds.), Transcriptomics in Atherosclerosis, Elsevier, 2025, pp. 131–172. date_created: 2025-12-29T12:16:22Z date_published: 2025-10-24T00:00:00Z date_updated: 2026-01-05T11:49:54Z day: '24' department: - _id: Bio doi: 10.1016/b978-0-443-33064-3.00016-5 editor: - first_name: Yvan full_name: Devaux, Yvan last_name: Devaux - first_name: Miron full_name: Sopic, Miron last_name: Sopic fulldoi: https://doi.org/10.1016/b978-0-443-33064-3.00016-5 language: - iso: eng month: '10' oa_version: None page: 131-172 publication: Transcriptomics in Atherosclerosis publication_identifier: isbn: - '9780443330643' publication_status: published publisher: Elsevier quality_controlled: '1' scopus_import: '1' status: public title: 'Essentials of transcriptomic methods: Navigating through RNA sequencing and beyond' type: book_chapter user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2025' ...