Heat-shock treatment lethal for mammalian cells deprived of glucose and glutamine: Protection by α-keto acids

Gomes, Maria Isabel Franchi Vasconcelos; Kim, Wan Joon; Lively, Mary K.; Amos, Harold

doi:10.1016/0006-291x(85)91340-3

Cited by 9 publications

(3 citation statements)

References 8 publications

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“…A recent report indicating a role for SGs in mediating ROS damage is therefore consistent with the idea that SGs downregulate FAO ( Takahashi et al., 2013 ). So, too, is the observation made many years ago that heat shock is lethal for mammalian cells deprived of their preferred nutrients ( Gomes et al., 1985 ). Heat shock triggers SG formation, thereby inhibiting FAO, which is the alternative for ATP generation in the absence of glucose and amino acids.…”

Section: Discussionmentioning

confidence: 99%

Stress granules inhibit fatty acid oxidation by modulating mitochondrial permeability

Amen

Kaganovich

2021

Cell Reports

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Summary The formation of stress granules (SGs) is an essential aspect of the cellular response to many kinds of stress, but its adaptive role is far from clear. SG dysfunction is implicated in aging-onset neurodegenerative diseases, prompting interest in their physiological function. Here, we report that during starvation stress, SGs interact with mitochondria and regulate metabolic remodeling. We show that SG formation leads to a downregulation of fatty acid β-oxidation (FAO) through the modulation of mitochondrial voltage-dependent anion channels (VDACs), which import fatty acids (FAs) into mitochondria. The subsequent decrease in FAO during long-term starvation reduces oxidative damage and rations FAs for longer use. Failure to form SGs, whether caused by the genetic deletion of SG components or an amyotrophic lateral sclerosis (ALS)-associated mutation, translates into an inability to downregulate FAO. Because metabolic dysfunction is a common pathological element of neurodegenerative diseases, including ALS, our findings provide a direction for studying the clinical relevance of SGs.

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Section: Discussionmentioning

confidence: 99%

Stress granules inhibit fatty acid oxidation by modulating mitochondrial permeability

Amen

Kaganovich

2021

Cell Reports

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“…We cannot, however, rule out the possibility that the amino acids exert their protective effects at the cell surface. Gomes et al (1985) have found that the nonmetabolizable alpha-keto acids, alpha-ketobutyrate and acetopyruvate, prevent the thermal sensitization of Nil hamster cells caused by the removal of both glucose and glutamine. They have postulated a mode of heat protection similar to that which we have presented, that these molecules prevent the thermal denaturation of some heat-sensitive protein(& We do not believe that the modulation of heat sensitivity by amino acids is related to the cellular energy status because: 1) the amino acid-deprived cells are maintained in medium with a high (16.7 mM) glucose concentration, 2) the plating efficiency of nonheated cells is not affected by amino acid starvation over the time periods tested, 3) the TCA cycle intermediates alpha-ketoglutarate and oxalacetate have no protective effect whatsoever when fed to amino acid-starved cells (data no shown), 4) the nonmetabolizable amino acid AIB is as effective as the class I11 amino acids at reversing the sensitization, 5) plateau-phase cells become instantly sensitized to heat when given amino acid-free medium (Fig.…”

Section: The Nonmetabolizable Amino Acid Aib Protects From Heat Killingmentioning

confidence: 99%

Modulation of cellular heat sensitivity by specific amino acids

Vidair

Dewey

1987

Journal Cellular Physiology

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When either plateau-phase or exponentially growing Chinese hamster ovary (CHO) cells are incubated in amino acid-free medium, the cells become sensitized to killing by heat. For cells deprived of amino acids for 12 h survival decreases from 1 X 10(-2) for controls to 1 X 10(-6) for the deprived cells, following heating at 45 degrees C for 38 min. The survival of these sensitized cells is rapidly increased by the addition of a single amino acid just prior to heating. Of the 21 amino acids which are added in purified form to make McCoy's 5a medium, 12 show no protective effect, four have a small protective effect, and either alanine, asparagine, glutamine, serine, or theronine raise survival to a level similar to that of the control cells. The nonmetabolizable alanine analogue, 2-aminoisobutyric acid (AIB), increases survival of amino acid-deprived cells as effectively as each member of the group of five listed above, suggesting that metabolic conversion of the amino acids is not required for their protective effect. The data suggest that an increase in the intracellular concentrations of specific amino acids, independent of any change in cellular ATP content or the rate of protein synthesis, enables these cells to become quickly more resistant to killing by heat. We also conclude that the amino acid concentrations in poorly vascularized regions of some tumors should be considered, along with the oxygen, glucose, and proton concentrations, as factors which determine cellular survival following hyperthermia.

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“…Moreover, metabolic flexibility and remodeling require communication between metabolic modules that otherwise function independently (Muoio, 2014). Fine-tuned metabolic flexibility is particularly essential during starvation stress, when parts of the metabolic infrastructure have to be uprooted and replaced in response to changing fuel sources, before ATP shortages prove fatal (Gomes et al, 1985;Leprivier et al, 2013). In order for cells to survive extreme fluctuations in fuel sources, they must solve the multidimensional problem of balancing energy production with the rationing of scarce resources and the damage caused by metabolic activity.…”

Section: Discussionmentioning

confidence: 99%

Protein aggregation in the cytoplasm

Triana¹

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The hypothesis motivating this thesis is that aggregation of proteins in the cytoplasm can have protective functions and can facilitate cell survival. Conversely, the disruption of functional aggregation can lead to cellular dysfunction and death. There is, therefore, a tremendous need to understand the mechanisms and precise sub-cellular architecture of functional aggregates. So far, the multitude of cellular aggregate structures or granules have been proposed to function as enzyme storage compartments, centers of memory retention, signaling hubs, mRNA triage compartments, degradation and protein refolding depots, structural elements, and transport granules. One of the unifying aspects of cytoplasmic granules appears to be stress dependent transient formation. In order to study cellular aggregation in live cells I chose to investigate factors that regulate the formation and clearance of cellular inclusions and their functions in cellular metabolism and signaling pathways. In this thesis I describe regulatory pathways that govern formation and function of granules with the focus on ribonucleoprotein granules, Stress Granules.

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Heat-shock treatment lethal for mammalian cells deprived of glucose and glutamine: Protection by α-keto acids

Cited by 9 publications

References 8 publications

Stress granules inhibit fatty acid oxidation by modulating mitochondrial permeability

Stress granules inhibit fatty acid oxidation by modulating mitochondrial permeability

Modulation of cellular heat sensitivity by specific amino acids

Protein aggregation in the cytoplasm

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