Smaug1 membrane-less organelles respond to AMPK and mTOR and affect mitochondrial function

Autor: María Gabriela Thomas, Agustín Andrés Corbat, Graciela L. Boccaccio, Hernán E. Grecco, Lara Boscaglia, Pablo E La Spina, Ana Julia Fernández-Alvarez, Anne Plessis, Malena Lucía Pascual, Jerónimo Pimentel, Marta Casado, Joao Pessoa, Maria Carmo-Fonseca, Martín Habif
Přispěvatelé: Repositório da Universidade de Lisboa, Agencia Nacional de Promoción Científica y Tecnológica (Argentina), Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina), Université Paris Diderot, Ministerio de Ciencia, Tecnología e Innovación Productiva (Argentina), Fondation ARC pour la Recherche sur le Cancer, Ministerio de Economía, Industria y Competitividad (España), Generalitat Valenciana
Jazyk: angličtina
Předmět:
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
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ISSN: 1477-9137
0021-9533
DOI: 10.1242/jcs.253591
Popis: 19 páginas, 8 figuras
Smaug is a conserved translational regulator that binds numerous mRNAs, including nuclear transcripts that encode mitochondrial enzymes. Smaug orthologs form cytosolic membrane-less organelles (MLOs) in several organisms and cell types. We have performed single-molecule fluorescence in situ hybridization (FISH) assays that revealed that SDHB and UQCRC1 mRNAs associate with Smaug1 bodies in U2OS cells. Loss of function of Smaug1 and Smaug2 (also known as SAMD4A and SAMD4B, respectively) affected both mitochondrial respiration and morphology of the mitochondrial network. Phenotype rescue by Smaug1 transfection depends on the presence of its RNA-binding domain. Moreover, we identified specific Smaug1 domains involved in MLO formation, and found that impaired Smaug1 MLO condensation correlates with mitochondrial defects. Mitochondrial complex I inhibition upon exposure to rotenone, but not strong mitochondrial uncoupling upon exposure to CCCP, rapidly induced the dissolution of Smaug1 MLOs. Metformin and rapamycin elicited similar effects, which were blocked by pharmacological inhibition of AMP-activated protein kinase (AMPK). Finally, we found that Smaug1 MLO dissolution weakens the interaction with target mRNAs, thus enabling their release. We propose that mitochondrial respiration and the AMPK-mTOR balance controls the condensation and dissolution of Smaug1 MLOs, thus regulating nuclear mRNAs that encode key mitochondrial proteins. This article has an associated First Person interview with the first authors of the paper.
This work was supported by the following grants: PICT 2013-3280 to G.L.B.; PICT 2014-3658 to G.L.B. and H.E.G.; PICT 2013-1301 to H.E.G.; PICT 2015-1302 to A.J.F.-A.; PICT 2012-2493 to M.G.T., PICT 2018-01790 to M.G.T. and A.J.F.-A., all from Agencia Nacional de Promoción Cientıfica y Tecnolo ́ ́gica (ANPCyT; Argentina); PIP2011-205 (Consejo Nacional de Investigaciones Cientıficas y ́ Técnicas, CONICET, Argentina) to M.G.T.; an Alicia Moreau Chair from Paris Diderot University (France) to G.L.B. and A14S03 to G.L.B. and A.P. (MINCYTECOS SUD, Ministerio de Ciencia, Tecnologıa e Innovacio ́ ́n Productiva); grant 1112 from the Fondation ARC pour la Recherche sur le Cancer to A.P., and SAF2016- 75004-R (Ministerio de Economıa, Industria y Competitividad, Gobierno de Espan ́ ̃ a; MINECO, Spain) and PROMETEO/2018/055 (Generalitat Valenciana, Spain) to M.C. M.C. participates in COST Action CA15203 MITOEAGLE. A.J.F.-A., M.G.T., H.G. and G.L.B. are investigators from CONICET, G.L.B. and H.E.G. are professors at the University of Buenos Aires, Argentina; M.L.P., M.H., P.E.L.S., J.P. and A.A.C. received fellowships from CONICET, J.P. visited Carmo Fonseca’s Lab supported by H2020-Marie Sklodowska-Curie Research and Innovation Staff Exchanges [734825-LysoMod], A.P. is a professor at the University Paris Diderot.
Databáze: OpenAIRE
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