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Abstract
Autophagy is a major catabolic process that is involved in cellular degradation of unnecessary or dysfunctional cellular components via the lysosomal machinery. Autophagy is involved in a variety of biological processes such as programmed cell death, removal of damaged organelles and development of different tissue-specific functions. In recent experiments, the role of autophagy as an important mediator of the pathological response to redox signalling of cellular damage has been elucidated and expanded. Oxidative stresses to the cellular system induces autophagy as a means to selectively remove oxidatively modified macromolecules and organelles. Reactive oxygen species (ROS) are highly reactive oxygen free radicals that are produced as by-products of cellular metabolism, primarily by mitochondria and NADPH oxidases. ROS can be beneficial or harmful to cells and tissues by depending on their concentration and location. ROS function as redox messengers in intracellular signalling at physiologically low level, whereas excess ROS can induce oxidative modification of cellular macromolecules and eventually promote cell death. Thus, the interface of autophagy-related oxidative stress adaptation and cell death is important for understanding redox biology and pathogenesis. In this review, we describe the basic mechanism and function of autophagy in the context of response to oxidative stress and redox signalling in pathogenesis.
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Fig. 1
Schematic diagram of the steps of autophagy. Autophagy is initiated by the formation of the isolation membrane. The concerted action of the autophagy core machinery proteins at the phagophore assembly site (PAS) is thought to lead to the expansion of the isolation membrane into an autophagosome (vesicle elongation). Ubiquitinylated proteins may be directly targeted for degradation via the autophagic pathway. The p62 protein interacts with ubiquitinylated-damaged proteins in cells. The complex is then selectively tied to the autophagosome through the interaction between p62 and light chain 3-II (LC3-II). When the outer membrane of the autophagosome fuses with a lysosome, it forms an autophagolysosome. Finally, the sequestered material is degraded inside the autophagolyosome and recycled.
Fig. 2
Reactive oxygen species-induced autophagy. ROS production can induce protein aggregates, generated by the mitochondrial electron transport chain activities and by NADPH oxidase. These ROS, which include hydrogen superoxide (O2-), peroxide (H2O2), nitric oxide (NO), peroxynitrite (ONOO-), can damage proteins and celluar organelles to stimulate autophagy. Atg4 Cys81 thiol modification is involved in H2O2-induced autophagy. S-nitrosation of inhibitor of κB kinase β (IKKβ) and c-Jun N-terminal kinase1 (JNK1) are involved in NO-induced inhibition of autophagy. Hypoxia-induced ROS also activates autophagic pathway by hypoxia inducible factors (HIFs) and their adapt proteins. Moreover, autophagy can stimulate the ROS generation to enhance the autophagic signalling.
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