IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing

Papadaki, Vasiliki; Erpapazoglou, Zoi; Kokkori, Maria; Rogalska, Malgorzata; Potiri, Myrto; Birladeanu, Andrada Maria; Tsakiri, Eleni N.; Ashktorab, Hassan; Smoot, Duane T.; Papanikolopoulou, Katerina; Samiotaki, Martina; Kafasla, Panagiota

IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing

Mostra el registre complet Registre parcial de l'ítem

dc.contributor.author Papadaki, Vasiliki
dc.contributor.author Erpapazoglou, Zoi
dc.contributor.author Kokkori, Maria
dc.contributor.author Rogalska, Malgorzata
dc.contributor.author Potiri, Myrto
dc.contributor.author Birladeanu, Andrada Maria
dc.contributor.author Tsakiri, Eleni N.
dc.contributor.author Ashktorab, Hassan
dc.contributor.author Smoot, Duane T.
dc.contributor.author Papanikolopoulou, Katerina
dc.contributor.author Samiotaki, Martina
dc.contributor.author Kafasla, Panagiota
dc.date.accessioned 2023-12-19T07:04:27Z
dc.date.available 2023-12-19T07:04:27Z
dc.date.issued 2023
dc.description.abstract Constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer cells, resulting in proliferative advantages, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein regulating AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1KO and parental cells show that IQGAP1KO alters an AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1KO cells, CI intermediates accumulate, resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer cells relying highly on mitochondrial respiration.
dc.description.sponsorship InfrafrontierGR/Phenotypos Infrastructure, co-funded by Greece and the European Union (European Regional Development Fund) [NSRF 2014–2020, MIS 5002135]; NETRF [Pilot Award 857222 to P.K.]; Hellenic Foundation for Research & Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT) [846 to Z.E.]; M.R. was supported by the European Research Council [ERC AdvG 670146].
dc.format.mimetype application/pdf
dc.identifier.citation Papadaki V, Erpapazoglou Z, Kokkori M, Rogalska ME, Potiri M, Birladeanu A, Tsakiri EN, Ashktorab H, Smoot DT, Papanikolopoulou K, Samiotaki M, Kafasla P. IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing. NAR Cancer. 2023 Aug 24;5(3):zcad046. DOI: 10.1093/narcan/zcad046
dc.identifier.doi http://dx.doi.org/10.1093/narcan/zcad046
dc.identifier.issn 2632-8674
dc.identifier.uri http://hdl.handle.net/10230/58590
dc.language.iso eng
dc.publisher Oxford University Press
dc.relation.ispartof NAR Cancer. 2023 Aug 24;5(3):zcad046
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/670146
dc.rights © The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
dc.subject.other Mitocondris
dc.subject.other Homeòstasi
dc.subject.other Evolució molecular
dc.title IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Center for Genomic Regulation (CRG))
Documents OpenAIRE (Open Access Infrastructure for Research in Europe)