title: Role of FAST Kinase Domains 3 (FASTKD3) in Post-transcriptional Regulation of Mitochondrial Gene Expression.
abstract: The Fas-activated serine/threonine kinase (FASTK) family of proteins has recently emerged as a central regulator of mitochondrial gene expression through the function of an unusual RNA-binding domain named RAP (for RNA-binding domain abundant in Apicomplexans), shared by all six members of the family. Here we describe the role of one of the less characterized members, FASTKD3, in mitochondrial RNA metabolism. First, we show that, in contrast to FASTK, FASTKD2, and FASTKD5, FASTKD3 does not localize in mitochondrial RNA granules, which are sites of processing and maturation of mtRNAs and ribosome biogenesis. Second, we generated FASTKD3 homozygous knock-out cell lines by homologous recombination and observed that the absence of FASTKD3 resulted in increased steady-state levels and half-lives of a subset of mature mitochondrial mRNAs: ND2, ND3, CYTB, COX2, and ATP8/6. No aberrant processing of RNA precursors was observed. Rescue experiments demonstrated that RAP domain is required for FASTKD3 function in mRNA stability. Besides, we describe that FASTKD3 is required for efficient COX1 mRNA translation without altering mRNA levels, which results in a decrease in the steady-state levels of COX1 protein. This finding is associated with reduced mitochondrial complex IV assembly and activity. Our observations suggest that the function of this family of proteins goes beyond RNA processing and ribosome assembly and includes RNA stability and translation regulation within mitochondria.
authors: From the Department of Cell Biology, University of Geneva, 1211 Genève 4, Switzerland.
authors: Erik
authors: E
authors: Boehm
authors: the Departamento de Biología, Histología y Farmacología, Universidad de Valladolid, Instituto de Biología y Genética Molecular, Valladolid 47003, Spain.
authors: María
authors: M
authors: Zornoza
authors: From the Department of Cell Biology, University of Geneva, 1211 Genève 4, Switzerland.
authors: Alexis A
authors: AA
authors: Jourdain
authors: Instituto de Investigación, Hospital Universitario 12 de Octubre (i+12), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, Madrid 28041, Spain.
authors: Aitor
authors: A
authors: Delmiro Magdalena
authors: Instituto de Investigación, Hospital Universitario 12 de Octubre (i+12), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, Madrid 28041, Spain.
authors: Inés
authors: I
authors: García-Consuegra
authors: the Departamento de Biología, Histología y Farmacología, Universidad de Valladolid, Instituto de Biología y Genética Molecular, Valladolid 47003, Spain.
authors: Rebeca
authors: R
authors: Torres Merino
authors: the Departamento de Microbiología, Facultad de Medicina, Edificio de Ciencias de la Salud, Valladolid 47005, Spain, and.
authors: Antonio
authors: A
authors: Orduña
authors: Instituto de Investigación, Hospital Universitario 12 de Octubre (i+12), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, Madrid 28041, Spain.
authors: Miguel A
authors: MA
authors: Martín
authors: From the Department of Cell Biology, University of Geneva, 1211 Genève 4, Switzerland.
authors: Jean-Claude
authors: JC
authors: Martinou
authors: the Departamento de Biología, Histología y Farmacología, Universidad de Valladolid, Instituto de Biología y Genética Molecular, Valladolid 47003, Spain.
authors: Miguel A
authors: MA
authors: De la Fuente
authors: the Departamento de Microbiología, Facultad de Medicina, Edificio de Ciencias de la Salud, Valladolid 47005, Spain, and maria.simarro.grande@uva.es.|the Departamento de Enfermería, Facultad de Enfermería, Edificio de Ciencias de la Salud, Avda Ramón y Cajal 7, Valladolid 47005, Spain.
authors: María
authors: M
authors: Simarro
mesh_terms: D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000096:biosynthesis / Q000235:genetics; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D000077278:RNA, Mitochondrial
chemical_list: D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D012313:RNA; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D003576:Electron Transport Complex IV; C553800:FASTKD3 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: FASTKD3; RNA; RNA metabolism; gene expression; mitochondria; post-transcriptional regulation; translation; translation control