[Abstract unavailable

proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

Defective apoptosis renders immortalized epithelial cells highly tumorigenic, but how this is impacted by other common tumor mutations is not known. In apoptosis-defective cells, inhibition of autophagy by AKT activation or by allelic disruption of beclin1 confers sensitivity to metabolic stress by inhibiting an autophagy-dependent survival pathway. While autophagy acts to buffer metabolic stress, the combined impairment of apoptosis and autophagy promotes necrotic cell death in vitro and in vivo. Thus, inhibiting autophagy under conditions of nutrient limitation can restore cell death to apoptosis-refractory tumors, but this necrosis is associated with inflammation and accelerated tumor growth. Thus, autophagy may function in tumor suppression by mitigating metabolic stress and, in concert with apoptosis, by preventing death by necrosis.

Autophagy is a process of self-cannibalization. Cells capture their own cytoplasm and organelles and consume them in lysosomes. The resulting breakdown products are inputs to cellular metabolism, through which they are used to generate energy and to build new proteins and membranes. Autophagy preserves the health of cells and tissues by replacing outdated and damaged cellular components with fresh ones. In starvation, it provides an internal source of nutrients for energy generation and, thus, survival. A powerful promoter of metabolic homeostasis at both the cellular and whole-animal level, autophagy prevents degenerative diseases. It does have a downside, however-cancer cells exploit it to survive in nutrient-poor tumors.Living organisms from yeast to humans are capable of eating parts of themselves in order to survive. This involves the degradation of cellular components, either because they are deleterious (e.g., damaged organelles and microbial invaders) or because the resulting breakdown products are needed to support metabolism. This process was aptly termed autophagy from the Greek "auto" or oneself and "phagy" or to eat. It has gained attention recently as an essential contributor to human health and disease.There are several forms of autophagy, each of which involves delivering intracellular cargo to lysosomes for degradation. The predominant form, macroautophagy (autophagy hereafter), produces vesicles called autophagosomes that capture and deliver cytoplasmic material to lysosomes (1). The autophagy-related genes (the atg genes) are conserved from yeast to mammals and regulate the cannibalism of intracellular cytoplasm, proteins, and organelles.Autophagy is the only mechanism to degrade large structures such as organelles and protein aggregates. In the absence of stress, basal autophagy serves a housekeeping function. It provides a routine "garbage disposal" service to cells, eliminating damaged components that could otherwise become toxic. Such cellular refreshing is particularly important in quiescent and terminally differentiated cells, where damaged components are not diluted by cell replication. In starvation, autophagy provides a nutrient source, promoting survival. Autophagy is induced by a broad range of other stressors and can degrade protein aggregates, oxidized lipids, damaged organelles, and even intracellular pathogens. Although it is not always possible to resolve the metabolic and garbage disposal roles for autophagy, it is clear that autophagy prevents disease. Defects in autophagy are linked to liver disease, neurodegeneration, Crohn's disease, aging, cancer, and metabolic syndrome.