Palmitate induces apoptosis via a direct effect on mitochondria

被引:69
作者
de Pablo, MA [1 ]
Susin, SA [1 ]
Jacotot, E [1 ]
Larochette, N [1 ]
Costantini, P [1 ]
Ravagnan, L [1 ]
Zamzami, N [1 ]
Kroemer, G [1 ]
机构
[1] CNRS, Unite Propre Rech 420, F-94801 Villejuif, France
关键词
Bcl-2; carnitine; fatty acids; mitochondrial megachannel; permeability transition pore;
D O I
10.1023/A:1009694124241
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The fatty acid palmitate can induce apoptosis. Here we show that the palmitate-induced dissipation of the mitochondrial transmembrane potential (Delta Psi(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 over-expressing cells are protected against the palmitate-stimulated release of such factors. These data suggest that palmitate causes apoptosis via a direct effect on mitochondria.
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页码:81 / 87
页数:7
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