Palmitate induces apoptosis via a direct effect on mitochondria

The fatty acid palmitate can induce apoptosis. Here we show that the palmit ate-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 s ignaling. However, the mitochondrial and nuclear effects of palmitate are i nhibited by overexpression of anti-apoptotic proto-oncogene product Bcl-2 a nd exacerbated by 2-bromo-palmitate as well as by carnitine. The cytoprotec tive actions of Bcl-2, respectively, is not antagonized by etomoxir, an inh ibitor of carnitine palmitoyl transferase 1 (CPT1), suggesting that the rec ently described physical interaction between CPT1 and Bcl-2 is irrelevant t o Bcl-2-mediated inhibition of palmitate-induce apoptosis. When added to pu rified mitochondria, palmitate causes the release of soluble factors capabl e of stimulating the apoptosis of isolated nuclei in a cell-free system. Mi tochondria purified from Bcl-2 over-expressing cells are protected against the palmitate-stimulated release of such factors. These data suggest that p almitate causes apoptosis via a direct effect on mitochondria.