A lifespan-extending form of autophagy employs the vacuole-vacuole fusion machinery

Abstract

While autophagy is believed to be beneficial for life-span extension, it is controversial which forms or aspects of autophagy are responsible for this effect. We addressed this topic by analyzing the life span of yeast autophagy mutants under caloric restriction, a longevity manipulation. Surprisingly, we discovered that the majority of proteins involved in macroautophagy and several forms of microautophagy were dispensable for life-span extension. The only autophagy protein that is critical for life-span extension was Atg15, a lipase that is located in the endoplasmic reticulum (ER) and transported to vacuoles for disintegrating membranes of autophagic bodies. We further found that vacuole-vacuole fusion was required for life-span extension, which was indicated by the shortened life span of mutants missing proteins (ypt7Delta, nyv1Delta, vac8Delta) or lipids (erg6Delta) involved in fusion. Since a known function of vacuole-vacuole fusion is the maintenance of the vacuole membrane integrity, we analyzed aged vacuoles and discovered that aged cells had altered vacuolar morphology and accumulated autophagic bodies, suggesting that certain forms of autophagy do contribute to longevity. Like aged cells, erg6Delta accumulated autophagic bodies, which is likely caused by a defect in lipase instead of proteases due to the existence of multiple vacuolar proteases. Since macroautophagy is not blocked by erg6Delta, we propose that a new form of autophagy transports Atg15 via the fusion of vacuoles with vesicles derived from ER, and we designate this putative form of autophagy as secretophagy. Pending future biochemical studies, the concept of secretophagy may provide a mechanism for autophagy in life-span extension.

Linkage of autophagy to fungal development, lipid storage and virulence inMetarhizium robertsii

“…It is interesting to note that Atg15 extends yeast life span by mediating intravacuolar membrane disintegration. 35 The role of MrAtg15 in M. robertsii remains to be determined.…”

Autophagy-Is it a preferred route for lifespan extension?

“…Moreover, it has been reported that autophagy is both independent and dependent on S6K, which is a critical downstream substrate and effector of the TOR pathway. In Drosophila, Scott et al demonstrated that TOR-mediated suppression of autophagy occurs independently of S6K (56). Conversely, it was found that phosphorylation of ribosomal protein S6 inhibits autophagy in rat hepatocytes (45).…”

“…Micro-organisms: Recently, Tang et al (56) demonstrated that vacuole-vacuole fusion was required for extension of the lifespan of yeast in response to caloric restriction. Furthermore, it has been shown that the autophagy protein, Atg15p, is a lipase located in the ER that is essential for lifespan extension.…”

Autophagy proteins play cytoprotective and cytocidal roles in leucine starvation-induced cell death inSaccharomyces cerevisiae

“…13 Moreover, while Atg11 operated in processes that protected cells during zinc treatment and leucine starvation, it appeared to interfere or compete with life-extending processes during nitrogen starvation. More subtly, the loss of Atg15, a vacuolar lipase that extends the life span of cells during caloric restriction, 36 switched the primary pathway of death during nitrogen starvation from necrosis to apoptosis. It is possible that cells that are unable to breakdown their autophagosomes in the vacuole, and thus unable to recycle the autophagosome contents, are dying like cells starved for leucine.…”