title: A yeast BH3-only protein mediates the mitochondrial pathway of apoptosis.
abstract: Mitochondrial outer membrane permeabilization is a watershed event in the process of apoptosis, which is tightly regulated by a series of pro- and anti-apoptotic proteins belonging to the BCL-2 family, each characteristically possessing a BCL-2 homology domain 3 (BH3). Here, we identify a yeast protein (Ybh3p) that interacts with BCL-X(L) and harbours a functional BH3 domain. Upon lethal insult, Ybh3p translocates to mitochondria and triggers BH3 domain-dependent apoptosis. Ybh3p induces cell death and disruption of the mitochondrial transmembrane potential via the mitochondrial phosphate carrier Mir1p. Deletion of Mir1p and depletion of its human orthologue (SLC25A3/PHC) abolish stress-induced mitochondrial targeting of Ybh3p in yeast and that of BAX in human cells, respectively. Yeast cells lacking YBH3 display prolonged chronological and replicative lifespans and resistance to apoptosis induction. Thus, the yeast genome encodes a functional BH3 domain that induces cell death through phylogenetically conserved mechanisms.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Büttner
authors.forename: Doris
authors.initials: D
authors.lastname: Ruli
authors.forename: F-Nora
authors.initials: FN
authors.lastname: Vögtle
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Barbara
authors.initials: B
authors.lastname: Moitzi
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberg
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.forename: Lukas
authors.initials: L
authors.lastname: Habernig
authors.forename: Didac
authors.initials: D
authors.lastname: Carmona-Gutierrez
authors.forename: Patrick
authors.initials: P
authors.lastname: Rockenfeller
authors.forename: Peter
authors.initials: P
authors.lastname: Laun
authors.forename: Michael
authors.initials: M
authors.lastname: Breitenbach
authors.forename: Chamel
authors.initials: C
authors.lastname: Khoury
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Fröhlich
authors.forename: Gerald
authors.initials: G
authors.lastname: Rechberger
authors.forename: Chris
authors.initials: C
authors.lastname: Meisinger
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D028061:Phosphate Transport Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C474007:Bax protein (53-86); C435723:MIR1 protein, S cerevisiae; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D028061:Phosphate Transport Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D029701:Saccharomyces cerevisiae Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein