NITRIC-OXIDE INDUCES APOPTOSIS VIA TRIGGERING MITOCHONDRIAL PERMEABILITY TRANSITION

Nitric oxide (NO) induces apoptosis in thymocytes, peripheral T cells, myeloid cells and neurons, Here we show that NO is highly efficient i n inducing mitochondrial permeability transition, thereby causing the liberation of apoptogenic factors from mitochondria which can induce n uclear apoptosis (DNA condensation and DNA fragmentation) in isolated nuclei in vitro. In intact thymocytes, NO triggers disruption of the m itochondrial transmembrane potential, followed by hypergeneration of r eactive oxygen species, exposure of phosphatidyl serine on the outer p lasma membrane leaflet, and nuclear apoptosis. Inhibitors of mitochond rial permeability transition such as bongkrekic acid and a cyclophilin D-binding cyclosporin A derivative, N-methyl-Val-4-cyclosporin A, pre vent the mitochondrial as well as all post-mitochondrial signs of apop tosis induced by NO including nuclear DNA fragmentation and exposure o f phosphatidylserine residues on the cell surface. These findings indi cate that NO can cause apoptosis via triggering of permeability transi tion. (C) 1997 Federation of European Biochemical Societies.