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

Abstract

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.

Authors:
ORCiD logo [1];  [2];  [1];  [1];  [3];  [4]; ORCiD logo [3]; ORCiD logo [1]
  1. Howard Hughes Medical Institute, Ashburn, VA (United States); National Institutes of Health, Bethesda, MD (United States)
  2. National Institutes of Health, Bethesda, MD (United States)
  3. Univ. of California, San Francisco, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  4. Univ. of California, San Francisco, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1351057
Alternate Identifier(s):
OSTI ID: 1351058; OSTI ID: 1379802
Grant/Contract Number:
AC02-05CH11231; AC02-5CH11231
Resource Type:
Journal Article: Published Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Seo, Arnold Y., Lau, Pick -Wei, Feliciano, Daniel, Sengupta, Prabuddha, Gros, Mark A. Le, Cinquin, Bertrand, Larabell, Carolyn A., and Lippincott-Schwartz, Jennifer. AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation. United States: N. p., 2017. Web. doi:10.7554/eLife.21690.
Seo, Arnold Y., Lau, Pick -Wei, Feliciano, Daniel, Sengupta, Prabuddha, Gros, Mark A. Le, Cinquin, Bertrand, Larabell, Carolyn A., & Lippincott-Schwartz, Jennifer. AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation. United States. doi:10.7554/eLife.21690.
Seo, Arnold Y., Lau, Pick -Wei, Feliciano, Daniel, Sengupta, Prabuddha, Gros, Mark A. Le, Cinquin, Bertrand, Larabell, Carolyn A., and Lippincott-Schwartz, Jennifer. Mon . "AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation". United States. doi:10.7554/eLife.21690.
@article{osti_1351057,
title = {AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation},
author = {Seo, Arnold Y. and Lau, Pick -Wei and Feliciano, Daniel and Sengupta, Prabuddha and Gros, Mark A. Le and Cinquin, Bertrand and Larabell, Carolyn A. and Lippincott-Schwartz, Jennifer},
abstractNote = {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.},
doi = {10.7554/eLife.21690},
journal = {eLife},
number = ,
volume = 6,
place = {United States},
year = {Mon Apr 10 00:00:00 EDT 2017},
month = {Mon Apr 10 00:00:00 EDT 2017}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.7554/eLife.21690

Citation Metrics:
Cited by: 4works
Citation information provided by
Web of Science

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  • 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 interactedmore » 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.« less
    Cited by 4
  • 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 interactedmore » 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.« less
  • Thirty-eight children aged two and under who received radiotherapy alone or post-operatively for primary intracranial tumors from 1957 to 1974 were retrospectively studied for survival rate, late radiation sequelae, and quality of survival. There were 24 deaths, all attributed to the primary disease or its complications. The five, ten, and fifteen year absolute survival rates were 50%, 39%, and 38%, respectively, with posterior fossa tumors faring best. The 14 survivors, aged 6 to 21 1/2 years, were evaluated for physical, neurologic, endocrinologic, and physchologic abnormalities. Eight were found to have minimal or no abnormal neurologic findings, 11 were within themore » educable range on formal intelligence testing, and 12 had Karnofsky performance scores of 70 or better. There was little clinical evidence of severe endocrinologic dysfunction except for short stature in three patients correlated with a dose of greater than 3600 rad to the hypothalamic-pituitary region. The patients were assigned to a proposed Composite Quality of Survival Scale (CQS) graded 1 to 5 based upon their overall quality of life evaluation. Eight of the patients were rated Grade 3 or better, with three patientss essentially normal in most respects. We conclude that the data justify the continued use of radiotherapy in the treatment of very young children with brain tumors. However, there is the obvious need for further optimization of radiotherapy factors (time, dose, volume) in order to minimize the potential late effects of radiation to the central nervous system.« less
  • BIOGEOCHEMICAL MODELING OF GROUNDWATER FLOW AND NUTRIENT FLUX IN SUBSURFACE ENVIRONMENTS INDICATES THAT INHABITANT MICROORGANISMS EXPERIENCE SEVERE NUTRIENT LIMITATION. USING LABORATORY AND FIELD METHODS, WE HAVE BEEN TESTING STARVATION SURVIVAL IN SUBSURFACE MICROORGANISMS. IN MICROCOSM EXPERIMENTS, WE HAVE SHOWN THAT STRAINS OF TWO COMMONLY ISOLATED SUBSURFACE GENERA, ARTHROBACTER AND PSEUDOMONAS, ARE ABLE TO MAINTAIN VIABILITY IN LOW-NUTRIENT, NATURAL SUBSURFACE SEDIMENTS FOR OVER ONE YEAR. THESE NON-SPORE-FORMING BACTERIA UNDERGO RAPID INITIAL MINIATURIZATION FOLLOWED BY A STABILIZATION OF CELL SIZE. MEMBRANE LIPID PHOSPHOLIPID FATTY ACID (PLFA) PROFILES OF THE PSEUDOMONAS ARE CONSISTENT WITH ADAPTATION TO NUTRIENT STRESS; ARTHROBACTER APPARENTLY RESPONDS TO NUTRIENTmore » DEPRIVATION WITHOUT ALTERING MEMBRANE PLFA. TO TEST SURVIVABILITY OF MICROORGANISMS OVER A GEOLOGIC TIME SCALE, WE CHARACTERIZED MICROBIAL COMMUNITIES IN A SEQUENCE OF UNSATURATED SEDIMENTS RANGING IN AGE FROM MODEM TO {gt}780,000 years. Sediments were relatively uniform silts in Eastern Washington State. Porewater ages at depth (measured by the chloride mass-balance approach) were as old as 3,600 years. Microbial abundance, biomass, and activities (measured by direct counts, culture counts, total PLFAs, and radiorespirometry) declined with sediment age. The pattern is consistent with laboratory microcosm studies of Microbial survival: rapid short-term change followed by long-term survival of a proportion of cells. Even the oldest sediments evinced a small but viable Microbial community. Microbial survival appeared to be a function of sediment age. Porewater age appeared to influence the markup of surviving communities, as indicated by PLFA profiles. Sites with different Porewater recharge rates and patterns of Pleistocene flooding had different communities.« less
  • In the present study we determined the uptake and disposition of glucose in serum-deprived rabbit coronary microvessel endothelial (RCME) cells. RCME cells exhibited stereospecific hexose uptake inhibited by cytochalasin B. Pretreatment of the RCME cells with potassium cyanide or 2,4-dinitrophenol inhibited 2-deoxyglucose uptake but not 3-O-methylglucose transport. A major proportion (30-60%) of the 2-deoxyglucose present in the RCME cells was not phosphorylated. These two observations suggested that the rate-limiting step in the uptake of 2-deoxyglucose was not transport but rather the phosphorylation of 2-deoxyglucose to 2-deoxyglucose 6-phosphate. When glucose-deprived cells were incubated 2 hr with (U-14C)glucose the disposition of themore » label was as follows: glycogen 60%, acid-soluble fraction 30%, and lipid less than 5%. In contrast glucose-fed cells exhibited lower overall glucose incorporation, and a slightly different disposition: glycogen 45%, acid-soluble fraction 50%, and lipid 5%. Glucose-deprived RCME cells also exhibited greater basal levels of 2-deoxyglucose uptake compared to glucose-fed cells. RCME cells incubated in the absence of glucose and serum for 16 hr exhibited dose-dependent insulin stimulation of hexose uptake and subsequent metabolism to macromolecules (i.e., glycogen and the acid-soluble fraction). Significant effects of insulin were observed with concentrations as low as 2 x 10(-10) M, well within the physiological range. In contrast, cells preincubated in serum-free culture medium containing 5.5 mM glucose did not exhibit insulin-enhanced hexose uptake or glucose metabolism (even at doses as high as 10(-7) M). These studies indicate that the effects of insulin on rabbit coronary microvascular endothelial cell glucose uptake and metabolism require both serum and glucose deprivation.« less