Dual roles of autophagy in the survival of Caenorhabditis elegans during starvation

Abstract

Autophagy is a major pathway used to degrade long-lived proteins and organelles. Autophagy is thought to promote both cell and organism survival by providing fundamental building blocks to maintain energy homeostasis during starvation. Under different conditions, however, autophagy may instead act to promote cell death through an autophagic cell death pathway distinct from apoptosis. Although several recent papers suggest that autophagy plays a role in cell death, it is not known whether autophagy can cause the death of an organism. Furthermore, why autophagy acts in some instances to promote survival but in others to promote death is poorly understood. Here we show that physiological levels of autophagy act to promote survival in Caenorhabditis elegans during starvation, whereas insufficient or excessive levels of autophagy contribute to death. We found that inhibition of autophagy decreases survival of wild-type worms during starvation, and that muscarinic signaling regulates starvation-induced autophagy, at least in part, through the death-associated protein kinase signaling pathway. Furthermore, we found that in gpb-2 mutants, in which muscarinic signaling cannot be down-regulated, starvation induces excessive autophagy in pharyngeal muscles, which in turn, causes damage that may contribute to death. Taken together, our results demonstrate that autophagy can have either prosurvival or prodeath functions in an organism, depending on its level of activation.[Keywords: Autophagy; muscarinic acetylcholine receptor signaling; starvation] Supplemental material is available at http://www.genesdev.org.

Autophagy and ageing: Insights from invertebrate model organisms

“…Indicatively, following DR, autophagy is stimulated in fat body, muscles and ovaries of Drosophila (Barth et al, 2011) and pharyngeal muscles of C. elegans (Kang et al, 2007). DR is the only environmental manipulation with a positive impact on the lifespan of all species tested so far.…”

“…Under complete starvation, pcm-1 mutant L2d larvae approaching the dauer molt, show reduced autophagy, and this likely underlies their inability to cope with starvation via dauer formation (Gomez et al, 2007). Importantly, unrestrained, excessive autophagy induced by over-activation of muscarinic acetylocholine receptor signalling in gpb-2 mutants reverses the protective effect of moderate autophagy and decreases survival upon starvation (Kang and Avery, 2008;Kang et al, 2007). In adult flies, conditional inactivation of autophagy genes does not have an effect on lifespan extension by DR (Ren et al, 2009).…”

Life and death partners: apoptosis, autophagy and the cross-talk between them

“…69 Furthermore, DAPk activity is also required for autophagic cell death, such as that induced by IFNg in HeLa cells, 72 and mutation or knock down of the Caenorhabditis elegans DAPk ortholog attenuated starvation-induced autophagy in the pharyngeal muscle. 73 Interestingly, tunicamycin-induced ER stress resulted in both apoptosis and autophagy in MEFs, both of which were reduced in DAPkÀ/À cells. 9 Thus, in this system, DAPk regulates both death processes simultaneously, suggesting a critical role for DAPk as an integrator of apoptotic/autophagic cross-talk.…”

Autophagy and cell death in model organisms

“…21 Physiological levels of autophagy promote optimal survival of C. elegans during starvation, whereas insufficient or excessive levels of autophagy render animals hypersensitive to starvation. 22 Autophagy is also upregulated during developmental transitions. In C. elegans the dauer larval stage is a quiescent, long-term survival diapause phase induced by nutrient deprivation, increased temperature and low insulin signalling.…”