The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis.
In healthy cells, fusion and fission events participate in regulating mitochondrial morphology. Disintegration of the mitochondrial reticulum into multiple punctiform organelles during apoptosis led us to examine the role of Drp1, a dynamin-related protein that mediates outer mitochondrial membrane fission. Upon induction of apoptosis, Drp1 translocates from the cytosol to mitochondria, where it preferentially localizes to potential sites of organelle division. Inhibition of Drp1 by overexpression of a dominant-negative mutant counteracts the conversion to a punctiform mitochondrial phenotype, prevents the loss of the mitochondrial membrane potential and the release of cytochrome c, and reveals a reproducible swelling of the organelles. Remarkably, inhibition of Drp1 blocks cell death, implicating mitochondrial fission as an important step in apoptosis.
Frank
S
S
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Behesda, Maryland 20892, USA.
Gaume
B
B
Bergmann-Leitner
E S
ES
Leitner
W W
WW
Robert
E G
EG
Catez
F
F
Smith
C L
CL
Youle
R J
RJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D003574:Cytochrome c Group / Q000378:metabolism; D034281:Dynamins; D020558:GTP Phosphohydrolases; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism / Q000648:ultrastructure; D008564:Membrane Potentials / Q000502:physiology; D016253:Microscopy, Immunoelectron; D008869:Microtubule-Associated Proteins; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins; D008933:Mitochondrial Swelling / Q000502:physiology; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014162:Transfection; D051028:bcl-2-Associated X Protein
D003574:Cytochrome c Group; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins