Intersection of Apoptosis and Autophagy Cell Death Pathways

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Thebalance between cell survival and death is a critical parameter in the regulation of cell and tissue homeostasis. Autophagy is an evolutionarily conserved mechanism for the gross disposal and recycling of intracellular proteins in mammalian cells. Autophagy also kills cells under certain conditions, in a process called autophagic cell death; this involves pathways and mediators different from those of apoptosis. Therefore, three different mechanisms of cell death have been identified in mammalian cells; namely, apoptosis (type I), autophagic cell death (type II), and necrosis (type III). Whether and how these different processes of cell death interconnected each other has not been fully clarified. In this review we discuss the evidence supporting a mechanistic link especially focusing between apoptosis and autophagy associated cell death—including the possibility of cross–talk between the relevant signaling pathways—that could serve to maintain cellular homeostasis in mammals.

In recent decades, insight into the molecular regulation of autophagy in mammalian cells has come from the discovery and functional analysis of Autophagy-Related Gene (ATG). Autophagy is an evolutionally conserved homeostatic process for intracellular degradation by which intracellular proteins are sequestered in a double–membrane–bound autophagosome and delivered to the lysosome during stress conditions; this process facilitates both degradation and recycling of intracellular proteins in mammalian cells. The molecular machinery of autophagy co-ordinates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Defective autophagy underlies a wide variety of human disease and physiology including cancer, neurodegeneration, and infectious diseases. Mammalian orthologues of ATG family proteins have been identified and various functions of ATG proteins have been elucidated, including how these proteins control the formation of autophagosomes. Although autophagy was originally characterized as a cytoprotective process in yeast under starvation conditions, it is now thought to be a form of cell death along with the two classical mechanisms of apoptosis and necrosis in mammalian cells.

Three possible mechanisms for cell death have been known to exist in mammalian cells, namely apoptosis (type I cell death), autophagic cell death (type II cell death), and necrosis (type III cell death). Apoptotic cell death (type I cell death) is characterized by rounding up of the cell and reduction of cell volume, chromatin condensation, nuclear fragmentation, no modification of cytoplasmic organelle, and plasma membrane blebbing without involvement of gene activity. Since autophagy is thought to be a pro-survival pathway, whether or not autophagy indeed induce cell death is still under debate. However, under certain circumstances, autophagy can induce cell death (type II cell death) which is characterized by presence of massive autophagic vacuole in the cytoplasm. Necrosis (type III cell death) is most classical form of cell death with characteristic morphological feature of a gain of cell volume, swelling of organelles with plasma membrane rupture without blebbing.