TY - JOUR
T1 - Palmitate induces apoptosis via a direct effect on mitochondria
AU - De Pablo, M. A.
AU - Susin, S. A.
AU - Jacotot, E.
AU - Larochette, N.
AU - Costantini, P.
AU - Ravagnan, L.
AU - Zamzami, N.
AU - Kroemer, G.
N1 - Funding Information:
Supported by ANRS, ARC, CNRS, FRM, LNC, INSERM, and a grant from Sigma Tau. Manuel A. de Pablo was on leave of absence of the University of Jaén, Spain. Santos A. Susin, Etienne Jacotot and Paola Costantini received fellowships from the European Commission, Sidaction, and ARC, respectively.
PY - 1999/1/1
Y1 - 1999/1/1
N2 - The fatty acid palmitate can induce apoptosis. Here we show that the palmitate-induced dissipation of the mitochondrial transmembrane potential (ΔΨ(m)), which precedes nuclear apoptosis, is not prevented by inhibitors of mRNA synthesis, protein synthesis, caspases, or pro-apoptotic ceramide signaling. However, the mitochondrial and nuclear effects of palmitate are inhibited by overexpression of anti-apoptotic proto-oncogene product Bcl-2 and exacerbated by 2-bromo-palmitate as well as by carnitine. The cytoprotective actions of Bcl-2, respectively, is not antagonized by etomoxir, an inhibitor of carnitine palmitoyl transferase 1 (CPT1), suggesting that the recently described physical interaction between CPT1 and Bcl-2 is irrelevant to Bcl-2-mediated inhibition of palmitate-induce apoptosis. When added to purified mitochondria, palmitate causes the release of soluble factors capable of stimulating the apoptosis of isolated nuclei in a cell-free system. Mitochondria purified from Bcl-2 overexpressing cells are protected against the palmitate-stimulated release of such factors. These data suggest that palmitate causes apoptosis via a direct effect on mitochondria.
AB - The fatty acid palmitate can induce apoptosis. Here we show that the palmitate-induced dissipation of the mitochondrial transmembrane potential (ΔΨ(m)), which precedes nuclear apoptosis, is not prevented by inhibitors of mRNA synthesis, protein synthesis, caspases, or pro-apoptotic ceramide signaling. However, the mitochondrial and nuclear effects of palmitate are inhibited by overexpression of anti-apoptotic proto-oncogene product Bcl-2 and exacerbated by 2-bromo-palmitate as well as by carnitine. The cytoprotective actions of Bcl-2, respectively, is not antagonized by etomoxir, an inhibitor of carnitine palmitoyl transferase 1 (CPT1), suggesting that the recently described physical interaction between CPT1 and Bcl-2 is irrelevant to Bcl-2-mediated inhibition of palmitate-induce apoptosis. When added to purified mitochondria, palmitate causes the release of soluble factors capable of stimulating the apoptosis of isolated nuclei in a cell-free system. Mitochondria purified from Bcl-2 overexpressing cells are protected against the palmitate-stimulated release of such factors. These data suggest that palmitate causes apoptosis via a direct effect on mitochondria.
KW - Bcl-2
KW - Carnitine
KW - Fatty acids
KW - Mitochondrial mega-channel
KW - Permeability transition pore
UR - http://www.scopus.com/inward/record.url?scp=0032803798&partnerID=8YFLogxK
U2 - 10.1023/A:1009694124241
DO - 10.1023/A:1009694124241
M3 - Article
AN - SCOPUS:0032803798
SN - 1360-8185
VL - 4
SP - 81
EP - 87
JO - Apoptosis
JF - Apoptosis
IS - 2
ER -