Nutrient sensing and metabolic decisions

Lindsley, Janet E.; Rutter, Jared

doi:10.1016/j.cbpc.2004.06.014

Cited by 131 publications

(109 citation statements)

References 192 publications

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“…As depletion of steady-state concentrations of amino acids is known to induce autophagy [51,52], the induction of ATG12 could relate to the significant decreases in several amino acids that we observed in the mutant cells. To determine whether the induction of ATG12 was a specific consequence of mtDNA deletions, we quantified ATG12 transcript levels in 143B osteosarcoma cybrid fusion controls (i.e.…”

Section: Amino Acid Concentration Is Deficient In Mutant Lymphoblastsmentioning

confidence: 85%

“…Increased protein oxidative damage has been demonstrated to inhibit ubiquitin-proteasomal activity, which is expected to decrease the rate of salvage of amino acids, and result in decreased amino acid concentration in cells, which has previously been demonstrated to decrease the activity of mTOR, which then represses protein synthesis and activates autophagy. Deletions were shown to result in decreased expression of nuclearencoded OXPHOS complex (of both the electron transport chain and ATP synthase), which must also inhibit ATP synthesis (which has been demonstrated at the biochemical level by others), and stimulate the activity of AMP kinase, which then should inhibit mTOR, which should result in the inhibition of protein synthesis and the activation of autophagy [52]. Cell lines and tissues used in the study, with size and percent of deletion and disease status.…”

Section: Implications Of the Proposed Mechanism For Kss Patientsmentioning

confidence: 94%

“…Amino acid deprivation is known to induce autophagy via inhibition of the mTOR pathway [51,52]. Amino acid deprivation is also known to signal GCN2 and stimulate eIF2-alpha phosphorylation [76][77][78], resulting in increased expression of unfolded protein response (UPR) genes and endoplasmic reticulum (ER) stress-related genes, many of which are induced in mutant cells.…”

Section: Amino Acid Deprivation Induces Autophagymentioning

confidence: 99%

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Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Alemi

Prigione

Wong

et al. 2007

Free Radical Biology and Medicine

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Deletions within the mitochondrial DNA (mtDNA) cause Kearns Sayre Syndrome (KSS) and Chronic Progressive External Opthalmoplegia (CPEO). The clinical signs of KSS include muscle weakness, heart block, pigmentary retinopathy, ataxia, deafness, short stature, and dementia. The identical deletions occur and rise exponentially as humans age, particularly in substantia nigra. Deletions at >30% concentration cause deficits in basic bioenergetic parameters, including membrane potential and ATP synthesis, but it is poorly understood how these alterations cause the pathologies observed in patients. To better understand the consequences of mtDNA deletions, we microarrayed 6 cell types containing mtDNA deletions from KSS and CPEO patients. There was a prominent inhibition of transcripts encoding ubiquitin-mediated proteasome activity, and a prominent induction of transcripts involved in the AMP kinase pathway, macroautophagy, and amino acid degradation. In mutant cells, we confirmed a decrease in proteasome biochemical activity, significantly lower concentration of several amino acids, and induction of an autophagic transcript. An interpretation consistent with the data is that mtDNA deletions increase protein damage, inhibit the ubiquitin-proteasome system, decrease amino acid salvage, and activate autophagy. This provides a novel pathophysiological mechanism for these diseases, and suggests potential therapeutic strategies.

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Section: Amino Acid Concentration Is Deficient In Mutant Lymphoblastsmentioning

confidence: 85%

Section: Implications Of the Proposed Mechanism For Kss Patientsmentioning

confidence: 94%

Section: Amino Acid Deprivation Induces Autophagymentioning

confidence: 99%

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Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Alemi

Prigione

Wong

et al. 2007

Free Radical Biology and Medicine

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“…23,24 This pathway integrates nutrient-and growth factor-derived signals to set overall growth rates and interfaces with the cell cycle machinery to coordinate cell growth and division. [25][26][27] mTOR is a serine/threonine kinase involved in gene regulation in response to signals from the environment that control translation of specific transcripts by regulating key translational mechanisms and is activated downstream of the PI 3-kinase pathway.…”

Section: Leptin Activates the Mtor Pathwaymentioning

confidence: 99%

“…Insulin and other growth factors can activate mTOR by activation of AKT downstream of PI3K with subsequent phosphorylation and inhibition of TSC1 and TSC2 (tuberous sclerosis complex 1 and 2), which is a physiologic inhibitor of mTOR. 23 mTOR's major functions include activation by phosphorylation of S6Kinase and activation of eIF4E by inhibition of 4E-BP1 (4E binding protein). These activations result in the initiation of translation and cell proliferation.…”

Section: Leptin Activates the Mtor Pathwaymentioning

confidence: 99%

Leptin and mTOR: Partners in metabolism and inflammation

Maya‐Monteiro¹,

Bozza²

2008

Cell Cycle

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Role of Short Chain Fatty Acid Receptors in Intestinal Physiology and Pathophysiology

Priyadarshini

Kotlo

Dudeja

et al. 2018

Comprehensive Physiology

155

115

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Nutrient sensing is a mechanism for organisms to sense their environment. In larger animals, including humans, the intestinal tract is a major site of nutrient sensing for the body, not surprisingly, as this is the central location where nutrients are absorbed. In the gut, bacterial fermentation results in generation of short chain fatty acids (SCFAs), a class of nutrients, which are sensed by specific membrane bound receptors, FFA2, FFA3, GPR109a, and Olfr78. These receptors are expressed uniquely throughout the gut and signal through distinct mechanisms. To date, the emerging data suggests a role of these receptors in normal and pathological conditions. The overall function of these receptors is to regulate aspects of intestinal motility, hormone secretion, maintenance of the epithelial barrier, and immune cell function. Besides in intestinal health, a prominent role of these receptors has emerged in modulation of inflammatory and immune responses during pathological conditions. Moreover, these receptors are being revealed to interact with the gut microbiota. This review article updates the current body of knowledge on SCFA sensing receptors in the gut and their roles in intestinal health and disease as well as in whole body energy homeostasis. © 2017 American Physiological Society. Compr Physiol 8:1091-1115, 2018.

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Nutrient sensing and metabolic decisions

Cited by 131 publications

References 192 publications

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Leptin and mTOR: Partners in metabolism and inflammation

Role of Short Chain Fatty Acid Receptors in Intestinal Physiology and Pathophysiology

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