Interactions between reactive oxygen species and autophagy: Special issue: Death mechanisms in cellular homeostasis.

Oxidative stress is defined as "a serious imbalance between the generation of reactive oxygen species (ROS) and antioxidant defences in favour of ROS, causing excessive oxidative damage to biomolecules". Different stressors that induce autophagy, such as starvation and hypoxia, can increase production of ROS such as superoxide and hydrogen peroxide. This review provides brief summaries about oxidative stress and macroautophagy, and then considers current knowledge about the complex interactions between ROS and autophagy. ROS-induced autophagy could be a cellular protective mechanism that alleviates oxidative stress, or a destructive process. Increased ROS levels can regulate autophagy through several different pathways, such as activation of the AMPK signalling cascade and ULK1 complex, Atg4 oxidation, disruption of the Bcl-2/Beclin-1 interaction, and alteration of mitochondrial homeostasis leading to mitophagy. Autophagic degradation of Keap1 activates the antioxidant transcription factor Nrf2 and protects cells against ROS. Autophagy activation can, in turn, regulate oxidative stress by recycling damaged ROS-producing mitochondria. Macroautophagy plays an important role in degradation of large aggregates of oxidatively damaged/unfolded proteins, which are removed by the autophagy-lysosomal system. ROS can regulate autophagy, and in turn, autophagy can regulate oxidative stress. Future studies are necessary to improve understanding of the complex interactions between autophagy and oxidative stress.

Inhibition of autophagy sensitises cells to hydrogen peroxide-induced apoptosis: Protective effect of mild thermotolerance acquired at 40°C.

Various toxic compounds produce reactive oxygen species, resulting in oxidative stress that threatens cellular homeostasis. Yet, lower doses of stress can stimulate defence systems allowing cell survival, whereas intense stress activates cell death pathways such as apoptosis. Mild thermal stress (40°C, 3h) induces thermotolerance, an adaptive survival response that renders cells less sensitive to subsequent toxic stress, by activating defence systems like heat shock proteins, antioxidants, anti-apoptotic and ER-stress factors. This study aims to understand how autophagy and apoptosis are regulated in response to different doses of H2O2, and whether mild thermotolerance can protect cervical carcinoma cells against apoptosis by stimulating autophagy. Autophagy was monitored through Beclin-1 and LC3 expression and acid compartment activity, whereas apoptosis was tracked by caspase activity and chromatin condensation. Exposure of HeLa and C33 A cells to H2O2 for shorter times (15-30min) transiently induced autophagy; apoptosis was activated after longer times (1-3h). Mild thermotolerance at 40°C enhanced activation of autophagy by H2O2. Disruption of autophagy using bafilomycin A1 and 3-methyladenine sensitised cells to apoptosis induced by H2O2, in non-thermotolerant cells and, to a lesser extent, in thermotolerant cells. Inhibition of autophagy enhanced apoptosis through the mitochondrial, death receptor and endoplasmic reticulum pathways. Autophagy was activated by lower doses of stress and protects cells against apoptosis induced by higher doses of H2O2. This work improves understanding of mechanisms that might be involved in toxicity of various compounds and could eventually lead to protective strategies against deleterious effects of toxic compounds.

Activation of apoptosis signalling pathways by reactive oxygen species.

Reactive oxygen species (ROS) are short-lived and highly reactive molecules. The generation of ROS in cells exists in equilibrium with a variety of antioxidant defences. At low to modest doses, ROS are considered to be essential for regulation of normal physiological functions involved in development such as cell cycle progression and proliferation, differentiation, migration and cell death. ROS also play an important role in the immune system, maintenance of the redox balance and have been implicated in activation of various cellular signalling pathways. Excess cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes and organelles, which can lead to activation of cell death processes such as apoptosis. Apoptosis is a highly regulated process that is essential for the development and survival of multicellular organisms. These organisms often need to discard cells that are superfluous or potentially harmful, having accumulated mutations or become infected by pathogens. Apoptosis features a characteristic set of morphological and biochemical features whereby cells undergo a cascade of self-destruction. Thus, proper regulation of apoptosis is essential for maintaining normal cellular homeostasis. ROS play a central role in cell signalling as well as in regulation of the main pathways of apoptosis mediated by mitochondria, death receptors and the endoplasmic reticulum (ER). This review focuses on current understanding of the role of ROS in each of these three main pathways of apoptosis. The role of ROS in the complex interplay and crosstalk between these different signalling pathways remains to be further unravelled during the coming years.