AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation

Dietary restriction increases the longevity of many organisms, but the cell signaling and organellar mechanisms underlying this capability are unclear. 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. AMP-activated protein kinase (AMPK) activation triggered this pathway, which required 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. During acute glucose restriction, activated AMPK was stabilized from degradation and interacted with Atg14p. This prompted Atg14p redistribution from ER exit sites onto liquid-ordered vacuole membrane domains, initiating µ-lipophagy. 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.

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β-Oxidation and autophagy are critical energy providers during acute glucose depletion in Saccharomyces cerevisiae

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1913370117 ◽

2020 ◽

Vol 117 (22) ◽

pp. 12239-12248 ◽

Cited By ~ 1

Author(s):

Carmen A. Weber ◽

Karthik Sekar ◽

Jeffrey H. Tang ◽

Philipp Warmer ◽

Uwe Sauer ◽

...

Keyword(s):

Energy Production ◽

Metabolic Response ◽

Critical Energy ◽

Yeast Cells ◽

Glucose Starvation ◽

Energy Status ◽

Term Survival ◽

Glucose Depletion ◽

Living Organisms

The ability to tolerate and thrive in diverse environments is paramount to all living organisms, and many organisms spend a large part of their lifetime in starvation. Upon acute glucose starvation, yeast cells undergo drastic physiological and metabolic changes and reestablish a constant—although lower—level of energy production within minutes. The molecules that are rapidly metabolized to fuel energy production under these conditions are unknown. Here, we combine metabolomics and genetics to characterize the cells’ response to acute glucose depletion and identify pathways that ensure survival during starvation. We show that the ability to respire is essential for maintaining the energy status and to ensure viability during starvation. Measuring the cells’ immediate metabolic response, we find that central metabolites drastically deplete and that the intracellular AMP-to-ATP ratio strongly increases within 20 to 30 s. Furthermore, we detect changes in both amino acid and lipid metabolite levels. Consistent with this, both bulk autophagy, a process that frees amino acids, and lipid degradation via β-oxidation contribute in parallel to energy maintenance upon acute starvation. In addition, both these pathways ensure long-term survival during starvation. Thus, our results identify bulk autophagy and β-oxidation as important energy providers during acute glucose starvation.

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Decision letter: AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation

10.7554/elife.21690.028 ◽

2016 ◽

Keyword(s):

Energy Production ◽

Glucose Starvation ◽

Term Survival ◽

Long Term Survival

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Author response: AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation

10.7554/elife.21690.029 ◽

2017 ◽

Cited By ~ 2

Author(s):

Arnold Y Seo ◽

Pick-Wei Lau ◽

Daniel Feliciano ◽

Prabuddha Sengupta ◽

Mark A Le Gros ◽

...

Keyword(s):

Energy Production ◽

Author Response ◽

Glucose Starvation ◽

Term Survival ◽

Long Term Survival

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Lipid digestion and autophagy are critical energy providers during acute glucose depletion in Saccharomyces cerevisiae

10.1101/728667 ◽

2019 ◽

Author(s):

Carmen A. Weber ◽

Karthik Sekar ◽

Jeffrey H. Tang ◽

Philipp Warmer ◽

Uwe Sauer ◽

...

Keyword(s):

Energy Production ◽

Metabolic Response ◽

Critical Energy ◽

Yeast Cells ◽

Glucose Starvation ◽

Energy Status ◽

Lipid Digestion ◽

Term Survival ◽

Glucose Depletion ◽

Living Organisms

AbstractThe ability to tolerate and thrive in diverse environments is paramount to all living organisms, and many organisms spend a large part of their lifetime in starvation. Upon acute glucose starvation, yeast cells undergo drastic physiological and metabolic changes and reestablish a constant - though lower – level of energy production within minutes. The molecules that are rapidly metabolized to fuel energy production under these conditions are unknown. Here, we combine metabolomics and genetics, to characterize the cells’ response to acute glucose depletion and identify pathways that ensure survival during starvation. We show that the ability to respire is essential for maintaining the energy status and to ensure viability during starvation. Measuring the cells’ immediate metabolic response, we find that central metabolites drastically deplete and that the intracellular AMP to ATP ratio strongly increases within 20-30 seconds. Furthermore, we detect changes in both amino acid and lipid metabolite levels. Consistent with this, bulk autophagy, a process that frees amino acids, as well as lipid degradation via β-oxidation contribute in parallel to energy maintenance upon acute starvation. In addition, both these pathways ensure long-term survival during starvation. Thus, our results identify bulk autophagy and β-oxidation as important energy providers during acute glucose starvation.

Download Full-text