Trends in Cell Biology
Volume 17, Issue 9, September 2007, Pages 422-427
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Opinion
ROS, mitochondria and the regulation of autophagy

https://doi.org/10.1016/j.tcb.2007.07.009Get rights and content

Accumulation of reactive oxygen species (ROS) is an oxidative stress to which cells respond by activating various defense mechanisms or, finally, by dying. At low levels, however, ROS act as signaling molecules in various intracellular processes. Autophagy, a process by which eukaryotic cells degrade and recycle macromolecules and organelles, has an important role in the cellular response to oxidative stress. Here, we review recent reports suggesting a regulatory role for ROS of mitochondrial origin as signaling molecules in autophagy, leading, under different circumstances, to either survival or cell death. We then discuss the relationship between mitochondria and autophagosomes and propose that mitochondria have an essential role in autophagosome biogenesis.

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.

References (60)

  • R.A. Kirkland

    Loss of cardiolipin and mitochondria during programmed neuronal death: evidence of a role for lipid peroxidation and autophagy

    Neuroscience

    (2002)
  • L. Xue

    Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution

    Mol. Cell. Neurosci.

    (1999)
  • M. Djavaheri-Mergny

    NF-κB activation represses tumor necrosis factor-α-induced autophagy

    J. Biol. Chem.

    (2006)
  • Y. Xu

    Autophagy contributes to caspase-independent macrophage cell death

    J. Biol. Chem.

    (2006)
  • I. Kissova

    Lipid oxidation and autophagy in yeast

    Free Radic. Biol. Med.

    (2006)
  • S. Reef

    A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death

    Mol. Cell

    (2006)
  • V. Adam-Vizi et al.

    Bioenergetics and the formation of mitochondrial reactive oxygen species

    Trends Pharmacol. Sci.

    (2006)
  • J. Dorval et al.

    Role of glutathione redox cycle and catalase in defense against oxidative stress induced by endosulfan in adrenocortical cells of rainbow trout (Oncorhynchus mykiss)

    Toxicol. Appl. Pharmacol.

    (2003)
  • C. Fleury

    Mitochondrial reactive oxygen species in cell death signaling

    Biochimie

    (2002)
  • J.R. Lancaster

    Inhibition of target cell mitochondrial electron transfer by tumor necrosis factor

    FEBS Lett.

    (1989)
  • T. Yamada

    Endothelial nitric-oxide synthase antisense (NOS3AS) gene encodes an autophagy-related protein (APG9-like2) highly expressed in trophoblast

    J. Biol. Chem.

    (2005)
  • I. Kissova

    Uth1p is involved in the autophagic degradation of mitochondria

    J. Biol. Chem.

    (2004)
  • J.J. Lemasters

    The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy

    Biochim. Biophys. Acta

    (1998)
  • R. Tal

    Aup1p, a yeast mitochondrial protein phosphatase homolog, is required for efficient stationary phase mitophagy and cell survival

    J. Biol. Chem.

    (2007)
  • S. Bjelland et al.

    Mutagenicity, toxicity and repair of DNA base damage induced by oxidation

    Mutat. Res.

    (2003)
  • R. Kiffin

    Oxidative stress and autophagy

    Antioxid. Redox Signal.

    (2006)
  • A. Terman et al.

    Lipofuscin: mechanisms of formation and increase with age

    APMIS

    (1998)
  • A. Donati

    Age-related changes in the autophagic proteolysis of rat isolated liver cells: effects of antiaging dietary restrictions

    J. Gerontol. A Biol. Sci. Med. Sci.

    (2001)
  • D.C. Rubinsztein

    The roles of intracellular protein-degradation pathways in neurodegeneration

    Nature

    (2006)
  • A.M. Cataldo

    Properties of the endosomal–lysosomal system in the human central nervous system: disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease

    J. Neurosci.

    (1996)
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