Glutamate dehydrogenase contributes to leucine sensing in the regulation of autophagy

Lorin, Séverine; Tol, Marc J.; Bauvy, Chantal; Strijland, Anneke; Poüs, Christian; Verhoeven, Arthur J.; Codogno, Patrice; Meijer, Alfred J.

doi:10.4161/auto.24083

Cited by 63 publications

(58 citation statements)

References 52 publications

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“…105,106 Similarly, a decrease in levels of GLUD1 augments the levels of ROS, probably due to a decrease in the production of NADPH and aKG. 36,87 Hence, glutaminolysis counteracts the constant oxidative stress to which cancer cells are exposed. 107 This, together with the advantages provided by glutaminolysis to cancer cell growth (including MTORC1 activation), renders this enzymatic process an interesting therapeutic target.…”

Section: Regulation and Role Of Autophagy In Cancer Cellsmentioning

confidence: 99%

“…19,84 Although the mechanism by which MTORC1 senses amino acids is complex and not completely understood, 18,19 MTORC1 can detect the presence of glutamine and leucine through glutaminolysis. 12,40,87 Thus, the production of aKG through glutaminolysis activates MTORC1 and hence, inhibits autophagy. The activation of MTORC1 exerted by aKG occurs via an increase in the GTP loading of RRAGB (a member of the RRAG family), which permits the translocation of MTORC1 to the lysosome surface, and its subsequent activation.…”

Section: Regulation and Role Of Autophagy In Cancer Cellsmentioning

confidence: 99%

“…The link between ROS and glutaminolysis is supported by the observation that the inhibition of either GLUD1 or GLS2 leads to an increase in ROS levels. 87,105 As glutamate produced by GLS sustains the synthesis of GSH, the inhibition of GLS decreases the levels of GSH and the ability of cells to counteract ROS. 105,106 Similarly, a decrease in levels of GLUD1 augments the levels of ROS, probably due to a decrease in the production of NADPH and aKG.…”

Section: Regulation and Role Of Autophagy In Cancer Cellsmentioning

confidence: 99%

“…11 The link established between glutaminolysis and MTORC1 partially accounts for glutamine addiction in cancer cells. 12,42,87,117 Therefore, targeting glutaminolysis, which is a process that both activates MTORC1 and provides substrates for the anabolic machinery led by MTORC1, is a rational therapeutic approach to target simultaneously metabolism and cell signaling in tumors. A logical conclusion from this connection is that the inhibition of MTORC1 can be addressed by inhibiting either the enzymes of glutaminolysis (GLS and GLUD1), or the intermediates between glutaminolysis and MTORC1, such as the EGLNs.…”

Section: Targeting Glutaminolysis and Autophagy As An Anticancer Therapymentioning

confidence: 99%

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Glutaminolysis and autophagy in cancer

et al. 2015

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Section: Regulation and Role Of Autophagy In Cancer Cellsmentioning

confidence: 99%

Section: Regulation and Role Of Autophagy In Cancer Cellsmentioning

confidence: 99%

Section: Regulation and Role Of Autophagy In Cancer Cellsmentioning

confidence: 99%

Section: Targeting Glutaminolysis and Autophagy As An Anticancer Therapymentioning

confidence: 99%

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Glutaminolysis and autophagy in cancer

et al. 2015

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“…A key enzyme in the glutaminolysis, glutamate dehydrogenase (GLUD1) involved in converting glutamine to glutamate, shows a critical role in autophagy regulation, which works as a leucine sensor. Intracellular leucine levels and ROS levels activate mTORC1, respectively, to influence autophagy activity [53]. As a consequence of rewired glutamine metabolism, ammonia at physiological concentration is produced from the amino acid catabolism or glutaminolysis and eventually increases autophagy.…”

Section: Autophagy In Glutamine Metabolismmentioning

confidence: 99%

Role of Autophagy in Cancer Metabolism

Cheong¹

2016

Autophagy in Current Trends in Cellular Physiology and Pathology

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Cancer cells undergo a wide range of metabolic reprogramming to take advantage for supporting rapid growth and survival. Autophagy plays a critical role in directly regulating cellular metabolism as a main catabolic process mediated by lysosomal degradation in response to the metabolic stress. During cancer development, autophagy plays opposite functions in suppressing or promoting tumors dependent of distinct stage. Autophagy maintains cellular homeostasis by degrading unnecessary cellular molecules and oncogenic products, thereby suppressing tumorigenesis. By contrast, autophagy enables to promote cancer growth in advanced tumor by supplying nutrients and relieving metabolic stress.In this book chapter, recent progress indicates how autophagy is integrated with cellular metabolic alteration during cancer development, particularly focusing on distinct metabolic substrates including glucose or glutamine. Multiple mechanisms would be suggested to explain the functions of autophagy at distinct stage of tumor progression. Cancer metabolic alterations associated with autophagy can be determined by certain oncogenic activators and/or tumor suppressors. Understanding the molecular mechanism of autophagy and metabolic alteration during cancer development may suggest potential targets for therapeutic intervention.

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The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

Borkum

2023

Advanced Biology

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Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high‐capacity sink for amine groups, facilitating autophagy, and prevent buildup of alpha‐ketoglutarate, supporting stem cell maintenance. Metabolic interventions also prevent the accumulation of succinate, thereby slowing DNA hypermethylation, facilitating the repair of DNA double‐strand breaks, reducing inflammatory and hypoxic signaling, and lowering reliance on glycolysis. In part through these mechanisms, metabolic interventions may decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, these processes function in reverse, accelerating aging and impairing longevity. Progressive damage to aconitase, inhibition of succinate dehydrogenase, and downregulation of hypoxia‐inducible factor‐1α, and phosphoenolpyruvate carboxykinase (PEPCK) emerge as potentially modifiable reasons for the loss of effectiveness of metabolic interventions.

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Glutamate dehydrogenase contributes to leucine sensing in the regulation of autophagy

Cited by 63 publications

References 52 publications

Glutaminolysis and autophagy in cancer

Glutaminolysis and autophagy in cancer

Role of Autophagy in Cancer Metabolism

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

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