Mitochondrial fission proteins regulate programmed cell death in yeast.
The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we found that the Saccharomyces cerevisiae homolog of human Drp1, Dnm1, promotes mitochondrial fragmentation/degradation and cell death following treatment with several death stimuli. Two Dnm1-interacting factors also regulate yeast cell death. The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission. In contrast to its fission function in healthy cells, Fis1 unexpectedly inhibits Dnm1-mediated mitochondrial fission and cysteine protease-dependent cell death in yeast. Furthermore, the ability of yeast Fis1 to inhibit mitochondrial fission and cell death can be functionally replaced by human Bcl-2 and Bcl-xL. Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function.
Fannjiang
Yihru
Y
Department of Pharmacology and Molecular Sciences, Johns Hopkins University Schools of Medicine, Baltimore, Maryland 21205, USA.
Cheng
Wen-Chih
WC
Lee
Sarah J
SJ
Qi
Bing
B
Pevsner
Jonathan
J
McCaffery
J Michael
JM
Hill
R Blake
RB
Basañez
Gorka
G
Hardwick
J Marie
JM
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008567:Membranes, Artificial; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D010743:Phospholipids / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein; D000098855:Collapsin Response Mediator Protein 1
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003546:Cysteine Endopeptidases; D020558:GTP Phosphohydrolases; D008567:Membranes, Artificial; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D019253:Proto-Oncogene Proteins c-bcl-2; D029701:Saccharomyces cerevisiae Proteins; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C102924:CRMP1 protein, human; D000098855:Collapsin Response Mediator Protein 1; C464859:FIS1 protein, S cerevisiae; C429283:MDV1 protein, S cerevisiae; C094774:DNM1 protein, S cerevisiae