The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis.
Mitochondrial fission ensures organelle inheritance during cell division and participates in apoptosis. The fission protein hFis1 triggers caspase-dependent cell death, by causing the release of cytochrome c from mitochondria. Here we show that mitochondrial fission induced by hFis1 is genetically distinct from apoptosis. In cells lacking the multidomain proapoptotic Bcl-2 family members Bax and Bak (DKO), hFis1 caused mitochondrial fragmentation but not organelle dysfunction and apoptosis. Similarly, a mutant in the intermembrane region of hFis1-induced fission but not cell death, further dissociating mitochondrial fragmentation from apoptosis induction. Selective correction of the endoplasmic reticulum (ER) defect of DKO cells restored killing by hFis1, indicating that death by hFis1 relies on the ER gateway of apoptosis. Consistently, hFis1 did not directly activate BAX and BAK, but induced Ca(2+)-dependent mitochondrial dysfunction. Thus, hFis1 is a bifunctional protein that independently regulates mitochondrial fragmentation and ER-mediated apoptosis.
Alirol
Emilie
E
Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, I-35129 Padova, Italy.
James
Dominic
D
Huber
Denise
D
Marchetto
Andrea
A
Vergani
Lodovica
L
Martinou
Jean-Claude
JC
Scorrano
Luca
L
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019069:Cell Respiration / Q000502:physiology; D004252:DNA Mutational Analysis; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000648:ultrastructure; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency; D051028:bcl-2-Associated X Protein / Q000172:deficiency
C476525:FIS1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D000251:Adenosine Triphosphatases