Autophagy protects against hypoxic injury in C. elegans.
Macroautophagy has been implicated in a variety of pathological processes. Hypoxic/ischemic cellular injury is one such process in which autophagy has emerged as an important regulator. In general, autophagy is induced after a hypoxic/ischemic insult; however, whether the induction of autophagy promotes cell death or recovery is controversial and appears to be context dependent. We have developed C. elegans as a genetically tractable model for the study of hypoxic cell injury. Both necrosis and apoptosis are mechanisms of cell death following hypoxia in C. elegans. However, the role of autophagy in hypoxic injury in C. elegans has not been examined. Here, we found that RNAi knockdown of the C. elegans homologs of beclin 1/Atg6 (bec-1) and LC3/Atg8 (lgg-1, lgg-2), and mutation of Atg1 (unc-51) decreased animal survival after a severe hypoxic insult. Acute inhibition of autophagy by the type III phosphatidylinositol 3-kinase inhibitors, 3-methyladenine and Wortmannin, also sensitized animals to hypoxic death. Hypoxia-induced neuronal and myocyte injury as well as necrotic cellular morphology were increased by RNAi knockdown of BEC-1. Hypoxia increased the expression of a marker of autophagosomes in a bec-1-dependent manner. Finally, we found that the hypoxia hypersensitive phenotype of bec-1(RNAi) animals could be blocked by loss-of-function mutations in either the apoptosis or necrosis pathway. These results argue that inhibition of autophagy sensitizes C. elegans and its cells to hypoxic injury and that this sensitization is blocked or circumvented when either of the two major cell-death mechanisms is inhibited.
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110-1010, USA.
Victor
V
Samokhvalov
Barbara A
BA
Scott
C Michael
CM
Crowder
D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D015687:Cell Hypoxia / Q000187:drug effects; D055785:Gene Knockdown Techniques; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D023421:Models, Animal; D032342:Muscle Cells / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000473:pathology; D034622:RNA Interference; D033921:Vesicular Transport Proteins
D029742:Caenorhabditis elegans Proteins; D033921:Vesicular Transport Proteins; C477268:bec-1 protein, C elegans