![]() ![]() Using the budding yeast Saccharomyces cerevisiae as our model system, we demonstrate that to initiate and sustain bulk autophagy and lipid droplet (LD) breakdown pathways together, starved cells need to sense an acute reduction in glucose levels. In this study, we use imaging and functional analysis approaches to investigate the conditions, and signaling and organellar systems, that trigger bulk autophagy and lipid consumption pathways to permit long-term survival under starvation. These results raise the possibility that cells mount distinct survival responses depending on the starvation condition, with only some regimens activating both lipid catabolism and autophagy, which are necessary for long-term survival. For example, yeast cells starved by different nutrient regimes either die quickly or live long-term ( Goldberg et al., 2009) mice strains with differing sensitivities to different nutrients show variable responses to caloric restriction ( Liao et al., 2010) and non-human primates exhibit short or long lifespans on different starvation diets ( Colman et al., 2014). But not all caloric restriction programs have the same beneficial effects on organismal health and survival ( Greer and Brunet, 2009 Wu et al., 2013). ![]() Its answer is particularly relevant to aging research as caloric restriction and enhanced lifespan in various organisms are related ( Cantó and Auwerx, 2011). How bulk autophagy and lipid consumption pathways are coordinated to permit long-term survival in starved cells represents a fundamental and challenging question. Unless both responses are triggered, cell and organismal survival are jeopardized. The first is achieved through self-digestion involving bulk autophagy pathways ( Green et al., 2011 Yen and Klionsky, 2008), and the second requires a shift to metabolizing lipids for ATP production given the unavailability of glucose ( Hardie and Carling, 1997 Zechner et al., 2012). Nutrient-depleted cells can only persist long-term by initiating a two-pronged survival response: they need to be able to recycle cytoplasmic components and they need a source of energy available from within the cell. Our findings that activated AMPK and Atg14p are required to orchestrate µ-lipophagy for energy production in starved cells is relevant for studies on aging and evolutionary survival strategies of different organisms. This prompted Atg14p redistribution from ER exit sites onto liquid-ordered vacuole membrane domains, initiating µ-lipophagy. ![]() During acute glucose restriction, activated AMPK was stabilized from degradation and interacted with Atg14p. More gradual glucose starvation, amino acid deprivation or rapamycin did not trigger µ-lipophagy and failed to provide the needed substitute energy source for long-term survival. AMP-activated protein kinase (AMPK) activation triggered this pathway, which required Atg14p. We demonstrate that to permit long-term survival in response to sudden glucose depletion, yeast cells activate lipid-droplet (LD) consumption through micro-lipophagy (µ-lipophagy), in which fat is metabolized as an alternative energy source. Dietary restriction increases the longevity of many organisms, but the cell signaling and organellar mechanisms underlying this capability are unclear. ![]()
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