title: The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.
abstract: Mitochondrial dysfunction is pervasive in human pathologies such as neurodegeneration, diabetes, cancer, and pathogen infections as well as during normal aging. Cells sense and respond to mitochondrial dysfunction by activating a protective transcriptional program known as the mitochondrial unfolded protein response (UPR(mt)), which includes genes that promote mitochondrial protein homeostasis and the recovery of defective organelles [1, 2]. Work in Caenorhabditis elegans has shown that the UPR(mt) is regulated by the transcription factor ATFS-1, which is regulated by organelle partitioning. Normally, ATFS-1 accumulates within mitochondria, but during respiratory chain dysfunction, high levels of reactive oxygen species (ROS), or mitochondrial protein folding stress, a percentage of ATFS-1 accumulates in the cytosol and traffics to the nucleus where it activates the UPR(mt) [2]. While similar transcriptional responses have been described in mammals [3, 4], how the UPR(mt) is regulated remains unclear. Here, we describe a mammalian transcription factor, ATF5, which is regulated similarly to ATFS-1 and induces a similar transcriptional response. ATF5 expression can rescue UPR(mt) signaling in atfs-1-deficient worms requiring the same UPR(mt) promoter element identified in C. elegans. Furthermore, mammalian cells require ATF5 to maintain mitochondrial activity during mitochondrial stress and promote organelle recovery. Combined, these data suggest that regulation of the UPR(mt) is conserved from worms to mammals.
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; BCMB Allied Program, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fiorese
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Schulz
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Rosin
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Pellegrino
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; BCMB Allied Program, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Lazare Medical Research Building, Worcester, MA 01605, USA. Electronic address: cole.haynes@umassmed.edu.
authors.forename: Cole M
authors.initials: CM
authors.lastname: Haynes
mesh_terms: D051696:Activating Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: C507532:ATF5 protein, human; C548052:ATFS-1 protein, C elegans; D051696:Activating Transcription Factors; D029742:Caenorhabditis elegans Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors