title: Fast kinase domain-containing protein 3 is a mitochondrial protein essential for cellular respiration.
abstract: Fas-activated serine/threonine phosphoprotein (FAST) is the founding member of the FAST kinase domain-containing protein (FASTKD) family that includes FASTKD1-5. FAST is a sensor of mitochondrial stress that modulates protein translation to promote the survival of cells exposed to adverse conditions. Mutations in FASTKD2 have been linked to a mitochondrial encephalomyopathy that is associated with reduced cytochrome c oxidase activity, an essential component of the mitochondrial electron transport chain. We have confirmed the mitochondrial localization of FASTKD2 and shown that all FASTKD family members are found in mitochondria. Although human and mouse FASTKD1-5 genes are expressed ubiquitously, some of them are most abundantly expressed in mitochondria-enriched tissues. We have found that RNA interference-mediated knockdown of FASTKD3 severely blunts basal and stress-induced mitochondrial oxygen consumption without disrupting the assembly of respiratory chain complexes. Tandem affinity purification reveals that FASTKD3 interacts with components of mitochondrial respiratory and translation machineries. Our results introduce FASTKD3 as an essential component of mitochondrial respiration that may modulate energy balance in cells exposed to adverse conditions by functionally coupling mitochondrial protein synthesis to respiration.
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Simarro
authors.forename: Alfredo
authors.initials: A
authors.lastname: Gimenez-Cassina
authors.forename: Nancy
authors.initials: N
authors.lastname: Kedersha
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Lazaro
authors.forename: Guillaume O
authors.initials: GO
authors.lastname: Adelmant
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.forename: Kirsten
authors.initials: K
authors.lastname: Rhee
authors.forename: Sarah
authors.initials: S
authors.lastname: Tisdale
authors.forename: Nika
authors.initials: N
authors.lastname: Danial
authors.forename: Charaf
authors.initials: C
authors.lastname: Benarafa
authors.forename: Anonio
authors.initials: A
authors.lastname: Orduña
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
mesh_terms: D000818:Animals; D019069:Cell Respiration; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D024101:Mitochondrial Proteins; C553800:FASTKD3 protein, human; C553838:FASTKD3 protein, mouse; D017346:Protein Serine-Threonine Kinases