Mitochondrial dysfunction in CD47-mediated caspase-independent cell death: ROS production in the absence of cytochrome c and AIF release.
Ligation of CD47 by its natural ligand thrombospondin (TSP), or cross-linking by CD47 antibodies, triggers caspase-independent cell death in normal and leukemic cells. This kind of cell death is characterised by the cytoplasmic events of apoptosis including externalisation of phosphatidylserines and mitochondria swelling. We report herein selective mitochondrial changes in CD47-dependent cell death of T cells. After T cell stimulation via CD47, a rapid mitochondrial transmembrane potential (deltapsi(m)) disruption is accompanied by the production of reactive oxygen species (ROS) and phosphatidylserine exposure. Surprisingly, mitochondrial dysfunction does not induce cytochrome c or AIF release. Moreover, the dying cells do not exhibit caspase-3 activation and display intact nuclei without any large-scale, or oligonucleosomal DNA fragmentation. We conclude that DeltaPsi(m) loss and ROS production are an early step in CD47-dependent killing and neither cytochrome c, nor AIF are implicated in this new cell death pathway.
Groupe apoptose et système immunitaire, CNRS-URA 1961, Institut Pasteur, 25, rue du Dr Roux, 75015 Paris, France.
Gaël
G
Roué
Natacha
N
Bitton
Victor J
VJ
Yuste
Thomas
T
Montange
Manuel
M
Rubio
Frédéric
F
Dessauge
Cécile
C
Delettre
Hélène
H
Merle-Béral
Marika
M
Sarfati
Santos A
SA
Susin
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D051033:Apoptosis Inducing Factor; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D015638:Cytochalasin D / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005420:Flavoproteins / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008564:Membrane Potentials / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism*
C494829:AIFM1 protein, human; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051033:Apoptosis Inducing Factor; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D005420:Flavoproteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D015638:Cytochalasin D; D045304:Cytochromes c; D020169:Caspases