Two Distinct Pathways Leading to Nuclear Apoptosis

By S. Susin, E. Daugas, L. Ravagnan, K. Samejima, N. Zamzami, M. Loeffler, P. Costantini, K. Ferri, T. Irinopoulou, M. Prevost and 5 more. Journal of Experimental Medicine, 2000

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Apaf-1−/− or caspase-3−/− cells treated with a variety of apoptosis inducers manifest apoptosis-associated alterations including the translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, large scale DNA fragmentation, and initial chromatin condensation (stage I). However, when compared with normal control cells, Apaf-1−/− or caspase-3−/− cells fail to exhibit oligonucleosomal chromatin digestion and a more advanced pattern of chromatin condensation (stage II). Microinjection of such cells with recombinant AIF only causes peripheral chromatin condensation (stage I), whereas microinjection with activated caspase-3 or its downstream target caspase-activated DNAse (CAD) causes a more pronounced type of chromatin condensation (stage II). Similarly, when added to purified HeLa nuclei, AIF causes stage I chromatin condensation and large-scale DNA fragmentation, whereas CAD induces stage II chromatin condensation and oligonucleosomal DNA degradation. Furthermore, in a cell-free system, concomitant neutralization of AIF and CAD is required to suppress the nuclear DNA loss caused by cytoplasmic extracts from apoptotic wild-type cells. In contrast, AIF depletion alone suffices to suppress the nuclear DNA loss contained in extracts from apoptotic Apaf-1−/− or caspase-3−/− cells. As a result, at least two redundant parallel pathways may lead to chromatin processing during apoptosis. One of these pathways involves Apaf-1 and caspases, as well as CAD, and leads to oligonucleosomal DNA fragmentation and advanced chromatin condensation. The other pathway, which is caspase-independent, involves AIF and leads to large-scale DNA fragmentation and peripheral chromatin condensation.

Subfields: Molecular Biology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/75eaf9a6d9ecb7de58d39832e804b2abdaef4f58

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Citations in the corpus

Organelle-specific initiation of cell death pathways (2001, background): “For the purpose of the present discussion, therefore, we consider that the 'central executioner' indistinguishably involves both caspase activation and MMP, although caspase-independent, presumably MMP-dependent, apoptotic pathways also exis”
Cell death by mitotic catastrophe: a molecular definition (2004, background): “However, it is now well established that apoptosis may occur in a caspase-independent manner (Susin et al., 1999, 2000; Joza et al., 2001), meaning that failure to prevent cell death by caspase inhibitors cannot be used as an argument to define this type of cell death as nonapoptotic.”
Caspase-independent cell death (2005, background): “, from the aspect of classical apoptosis to the occurrence of 'apoptosis-like' cell deat”
Apoptosis: A Review of Programmed Cell Death (2007, background): “This later and more pronounced chromatin condensation is referred to as “stage II” condensation (Susin et al., 2000).”
Role of Bcl-2 family proteins and caspases in the regulation of apoptosis (2011, background): “The mechanism of AIF-induced large-scale chromatin condensation and DNA fragmentation is still not clear [128, 131, 134–136].”
Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome (2002, background): “Although Apaf-1-deficient embryonic stem cells and fibroblasts treated with cytotoxic agents were reported to die by a non-apoptotic mechanis”
The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet (2002, background): “AIF, which bears both mitochondrial and nuclear signal sequences, is normally confined to the mitochondrial intermembrane space but translocates to the nucleus in response to apoptogenic stimuli causing large-scale (*50 kb) DNA fragmentation and peripheral chromatin condensation, but not oligonucleo”
Titanium dioxide nanoparticles: a review of current toxicological data (2013, background): “Accumulation of ROS may be accompanied by the production of reactive nitrogen species [205], such as the highly reactive peroxynitrite anion, a strong oxidant formed by the reaction of O2 −•”