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Balancing Apoptosis and Autophagy

The role of macroautophagy, whereby cells envelop internal organelles for lysosomal degradation, is currently in debate; experimental studies have produced disparate results implicating macroautophagy in both promoting and protecting against programmed cell death. As these studies were conducted in different cell lines, the speculation is that the role of macroautophagy may be based on cell type.

Cells lacking macroautophagy (Atg-/-) produce higher levels of chaperone-mediated autophagy (blue) in response to menadione.

In this Paper of the Week, Yongjun Wang and colleagues reveal that cell-type specificity may not be the simple answer to the experimental discrepancies. Using mouse embryo fibroblasts with RNAi knockdown of the autophagic gene Atg5, they show that inhibiting macroautophagy can produce multiple end results in the same cell type, depending on the context. Atg5^-/- mouse embryonic fibroblasts (MEFs) had increased activation of caspase-dependent apoptosis in response to death receptor ligands Fas and TNF-, possibly due to the inability of the cell to envelop apoptotic mitochondria. In contrast, the loss of macroautophagy made MEFs more resistant to the intrinsic apoptosis pathway following menadione-generated oxidative stress or UV radiation; this intrinsic protection was due to an up-regulation of chaperone-mediated autophagy, which could sequester oxidized molecules. Overall, these results suggest that macroautophagy engages in a complex relationship with apoptosis, and the specific stimuli that trigger cell death may govern the cell's response.

FOOTNOTES

See referenced article, J. Biol. Chem. 2008, 283, 4766-4777

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