Intersection of Apoptosis and Autophagy Cell Death Pathways

Special Article - Cell Death and Autophagy

Austin J Mol & Cell Biol. 2015; 2(1): 1004.

Intersection of Apoptosis and Autophagy Cell Death Pathways

Masayuki Noguchi¹*, Noriyuki Hirata¹, Tatsuma Edamura¹, Satoko Ishigaki¹ and Futoshi Suizu¹

¹Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Japan

*Corresponding author: Masayuki Noguchi, Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, N15, W7, Kita-ku, Sapporo 060- 0815, Japan,

Received: April 24, 2015; Accepted: May 20, 2015; Published: May 22, 2015


The balance 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.

Keywords: Apoptosis; Autophagy; Autophagy-related genes (ATG); Cell Death


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 [1,2]. Defective autophagy underlies a wide variety of human disease and physiology including cancer, neurodegeneration, and infectious diseases [3-5]. 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 [6,7] 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.

There is accumulating evidence for cross-talk in the regulation of apoptosis and induction of autophagy [8-12]. The present review examines how these three types of cell death interact in mammalian cells.

Three types of cell death in mammalian cells

Three different mechanisms of cell death are known to exist in mammalian cells, namely apoptosis (type I), autophagy (type II), and necrosis (type III) [6,7,13] (Table 1). Apoptosis, a form of programmed cell death [14], was originally distinguished from traumatic or necrotic cell death based on cytological features by electron microscopy. Research over the past two decades has elucidated the major molecules in apoptotic signaling pathways from the plasma membrane to the nucleus; it is known to be triggered by ligands such as Tumor Necrosis Factor (TNF) and Tnf-Related Apoptosis-Inducing Ligand (TRAIL) that activate cell death receptors such as Fas-Associated Protein with Death Domain (FADD) [15].