Hypoxia-induced autophagy: cell death or cell survival?

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Hypoxia (∼3–0.1% oxygen) is capable of rapidly inducing, via the hypoxia-inducible factor (HIF-1), a cell survival response engaging autophagy. This process is mediated by the atypical BH3-only proteins the Bcl-2/E1B 19 kDa-interacting protein 3 (BNIP3/BNIP3L (NIX)) that are induced by HIF-1. These mitochondrial associated BNIP proteins also mediate mitophagy, a metabolic adaptation for survival that is able to control reactive oxygen species (ROS) production and DNA damage. In contrast, severe hypoxic conditions or anoxia (<0.1% oxygen), where the latter is often confused with physiological hypoxia, are capable of inducing a HIF-independent autophagic response, generated via an extreme nutritional stress response implicating the AMPK-mTOR and unfolded protein response (UPR) pathways. The autophagic cell death that is often observed in these extreme stress conditions should be seen as the outcome of failed adaptation.

Introduction

Autophagy plays key physiological cellular functions such as degradation of long-lived proteins, organelle turnover, adaptation to nutrient depletion, extension of lifespan, cellular development, differentiation, and antiaging. However, autophagy also plays pathophysiological roles. Too much or too little autophagy is linked to: first, pathogen infection, by supplying nutrients to pathogens; second, neurodegeneration, allowing accumulation of aggregated proteins; third, muscular disorders, caused by the accumulation of autophagosomes that impair cellular functions; fourth, liver disease, as a result of excessive mitophagy; and finally, cancer, in which it acts as a protector against some cancer treatments and most importantly, prevents cell death in a hostile microenvironment [1]. Here we will outline the different mechanisms that trigger autophagy in cells cultured in a rich medium, in which oxygen is the only limiting factor, as well as in cells more severely restricted in oxygen and nutrients.

Section snippets

Autophagy, hypoxia, HIF, and BNIP3/BNIP3L

HIF is a key transcription factor that allows rapid adaptation to and survival in a large range of reduced oxygen concentrations. By controlling the transcription of hundreds of genes HIF drives, or strongly influences, many cellular process such as erythropoiesis, angiogenesis, energy metabolism, pH regulation, cell migration, and tumor invasion. HIF is a heterodimer of an α subunit that is unstable in the presence of relatively high levels of oxygen (above 5%), and a β subunit (or ARNT) that

Autophagy, HIF, and the others

BNIP3 and BNIP3L are not the only proteins involved in hypoxia-induced autophagy. In physiological conditions, a protein named sequestosome 1 (SQSTM1/p62) plays the role of a ‘garbage man’ of the cell driving the damaged or unfolded proteins to the autophagic pathway and degradation. Mathew et al. have shown that in autophagy-defective tumor cells, p62 accumulated thereby triggering a DNA damage response and tumorigenesis [19•]. It ensues that p62 emerged recently in the hypoxic picture as the

Autophagy, hypoxia but not HIF

Finally, HIF-1 is not always at the center of hypoxia-induced autophagic picture. Severe hypoxic conditions, often accompanied by drastic glucose and amino-acid restriction, will inhibit via HIF-independent mechanisms effecting the mTOR pathway, a central check point for autophagy. Parallel to HIF, an important player in this action is the energy sensor AMP-activated protein kinase (AMPK), which is switched on by metabolic stresses [23]. Another pathway that plays a key role in autophagic

Conclusions

The above brief description of ‘Autophagy and HIF’ points out that different types of cells do not respond identically to hypoxia. In fact some investigators have reported hypoxia-induced autophagy cell death whereas others reported, for the same cell types, hypoxia-induced cell survival. These discrepancies were particularly obvious when assigning the role of BNIP3s as prodeath or prosurvival proteins. These contradictory conclusions reflect the differences in defining ‘hypoxia’ (Figure 1).

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank MC Brahimi-Horn for critical reading. The laboratory is funded by grants from the Ligue Nationale Contre le Cancer (Equipe labellisée LNCC), the Association pour la Recherche contre le Cancer (ARC), the Agence Nationale pour la Recherche (ANR), the National Cancer Institute (INCa), and METOXIA (FP7-EU program), the Centre A. Lacassagne, the University of Nice, the CNRS and INSERM.

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