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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Apoptosis*
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Blotting, Western
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Bone Neoplasms / genetics
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Bone Neoplasms / metabolism
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Cell Cycle
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Flow Cytometry
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Humans
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Immunoprecipitation
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Membrane Potential, Mitochondrial
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Mice
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Mitochondria / genetics
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Mitochondria / metabolism*
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Molecular Sequence Data
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Peptide Fragments / pharmacology*
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Phosphate Transport Proteins / genetics
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Phosphate Transport Proteins / metabolism
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Proto-Oncogene Proteins / pharmacology*
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism*
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Saccharomyces cerevisiae Proteins / antagonists & inhibitors
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism*
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Sequence Homology, Amino Acid
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Signal Transduction*
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Tumor Cells, Cultured
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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Bax protein (53-86)
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MIR1 protein, S cerevisiae
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Mitochondrial Proteins
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Peptide Fragments
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Phosphate Transport Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Small Interfering
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Saccharomyces cerevisiae Proteins
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bcl-2-Associated X Protein
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bcl-X Protein