Trends in Cell Biology
OpinionROS, mitochondria and the regulation of autophagy
Section snippets
Autophagy has a dual role in the cellular response to oxidative stress
High levels of ROS (Box 1) can oxidize cell constituents, such as lipids, proteins and DNA, and thus pose a threat to cell integrity (Box 2). Various defense mechanisms have been developed to protect cells against oxidative stress, such as up-regulation of antioxidants, removal of specific proteins by the ubiquitin–proteasome system [1] and removal of damaged proteins and organelles by autophagy [2]. Autophagy is a major pathway for delivery of proteins and organelles to lysosomes in mammals or
A signaling role for ROS in autophagic cell death
The main characteristic of ROS and the basis of their destructive nature is their high reactivity. This characteristic also makes ROS excellent signaling molecules when controlled tightly. Indeed, ROS act as signaling molecules in a variety of intracellular processes, leading to proliferation, apoptosis, immunity and defense against microorganisms 24, 25. That ROS might have such a signaling role in autophagy (Figure 2) was first suggested in the pathway leading to neuronal autophagic cell
ROS as signaling molecules in survival-prone autophagy
In addition to the harmful activities of ROS, both in oxidative damage (Figure 1) and as signaling molecules in death-related autophagy (Figure 2), recent findings show that ROS also regulate starvation-induced autophagy, which is clearly a survival pathway [36]. Nutrient starvation was reported to lead, partially through class III phosphoinositide 3-kinase, to accumulation of H2O2 in the mitochondria, which was essential for the induction of autophagy. The oxidative signal in this experimental
Mitochondria as a source of ROS to regulate autophagy
Where does the redox signal originate? Several sources of ROS exist in cells, the most prominent being NADPH oxidase (NOX), dual oxidase (DUOX) 38, 39, 40, 41 and the mitochondria [42] (Box 1). Mitochondrial ROS are normally detoxified by superoxide dismutase (SOD), NADH and glutathione, and also by catalase in the cytosol 43, 44, 45. Disruption, however, of the delicate balance between ROS production and elimination might lead to accumulation of ROS in the mitochondria. Several studies
A role for mitochondria in autophagosome biogenesis
Is the role of mitochondria in the regulation of autophagy limited to ROS production? Atg9 is one of only two integral-membrane autophagy-related proteins identified to date, which was reported, in yeast, to cycle between peripheral sites in the cell and the pre-autophagosomal structure (PAS; see Box 3 for further explanation). These two characteristics make it a favorable candidate for membrane recruitment for autophagosome biogenesis [47]. Interestingly, some of the peripheral Atg9-positive
Concluding remarks
Autophagy was first discovered as a nonselective pathway for the degradation of cell constituents, activated in response to starvation. It is now clear that selective autophagy of specific organelles and proteins occurs in response to diverse stimuli, varying from survival-promoting removal of pathogens, through housekeeping degradation of damaged organelles and proteins, to programmed cell-death. Nevertheless, the basic machinery of autophagosome formation and degradation, as it is known
Acknowledgements
This work was supported in part by grants from the Israel Science Foundation and Binational Science Foundation.
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