Recent studies suggest that mitochondrial dynamics (fission and fusion) has a major impact on the regulation of mitochondrial outer membrane permeabilization, which in turn determines the point-of-no-return of apoptotic and necrotic cell death. Thus, programmed cell death, as it occurs in Caenorhabditis elegans development, is accompanied by mitochondrial fragmentation. Overexpression of a dominant-negative (DN) mutant of dynamin-related protein-1 (DRP-1), which inhibits mitochondrial fission, can reduce the incidence of cell death induced by a BH3-only protein in vivo, in C. elegans. These data confirm prior observations obtained in vitro, in mammalian cell culture systems, in which a DN point mutant of human DRP-1 (DRP-1K38A) was found to inhibit mitochondrial fragmentation and cell death induced by different apoptosis inducers. Conversely, the overexpression of wild-type DRP-1, which causes extensive mitochondrial fragmentation without cell death, can inhibit apoptosis induction by ceramide in tumor cells, presumably by reducing the transmission of calcium waves through the cytoplasm. Mitochondrial fragmentation has been previously reported to affect the organs of HIV-1 carriers subjected to highly active antiretroviral therapy (HAART) and in particular to treatment with HIV-specific protease inhibitors. Since some HIV-1- specific protease inhibitors such as ritonavir (Rtv) and nelfinavir (Nfv) can modulate apoptosis in vitro and in vivo, in mouse models of fulminant hepatitis, septic shock and temporary carotid occlusion, we investigated whether such protease inhibitors would regulate cell death via an effect on mitochondrial dynamics.
HIV-1 protease inhibitors and cytomegalovirus vMIA induce mitochondrial fragmentation without triggering apoptosis
SZABADKAI, Gyorgy;SIMONI, Anna Maria;RIZZUTO, Rosario;
2006
Abstract
Recent studies suggest that mitochondrial dynamics (fission and fusion) has a major impact on the regulation of mitochondrial outer membrane permeabilization, which in turn determines the point-of-no-return of apoptotic and necrotic cell death. Thus, programmed cell death, as it occurs in Caenorhabditis elegans development, is accompanied by mitochondrial fragmentation. Overexpression of a dominant-negative (DN) mutant of dynamin-related protein-1 (DRP-1), which inhibits mitochondrial fission, can reduce the incidence of cell death induced by a BH3-only protein in vivo, in C. elegans. These data confirm prior observations obtained in vitro, in mammalian cell culture systems, in which a DN point mutant of human DRP-1 (DRP-1K38A) was found to inhibit mitochondrial fragmentation and cell death induced by different apoptosis inducers. Conversely, the overexpression of wild-type DRP-1, which causes extensive mitochondrial fragmentation without cell death, can inhibit apoptosis induction by ceramide in tumor cells, presumably by reducing the transmission of calcium waves through the cytoplasm. Mitochondrial fragmentation has been previously reported to affect the organs of HIV-1 carriers subjected to highly active antiretroviral therapy (HAART) and in particular to treatment with HIV-specific protease inhibitors. Since some HIV-1- specific protease inhibitors such as ritonavir (Rtv) and nelfinavir (Nfv) can modulate apoptosis in vitro and in vivo, in mouse models of fulminant hepatitis, septic shock and temporary carotid occlusion, we investigated whether such protease inhibitors would regulate cell death via an effect on mitochondrial dynamics.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
