mTORC1 inhibitor rapamycin and ER stressor tunicamycin induce differential patterns of ER-mitochondria coupling

Bravo-Sagua, Roberto; López-Crisosto, Camila; Parra, Valentina; Rodriguez–Peña, Marcelo; Rothermel, Beverly A.; Quest, Andrew F. G.; Lavandero, Sergio

doi:10.1038/srep36394

Cited by 33 publications

(42 citation statements)

References 47 publications

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“…Recent reports show that ER stress can positively regulate ER-mitochondria communication in HeLa cells 55 , 56 . In our experimental system, acute ER stress promoted a clear disruption of ER-mitochondria communication, and its AKT-mTOR-dependent re-establishment clearly correlated with the dynamics of UPR signaling.…”

Section: Discussionmentioning

confidence: 99%

AKT-mTOR signaling modulates the dynamics of IRE1 RNAse activity by regulating ER-mitochondria contacts

Sánchez-Álvarez

Pozo

Bakal

2017

Sci Rep

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Inositol Requiring Enzyme-1 (IRE1) is the most conserved transducer of the Unfolded Protein Response (UPR), a surveillance mechanism that ensures homeostasis of the endoplasmic reticulum (ER) in eukaryotes. IRE1 activation orchestrates adaptive responses, including lipid anabolism, metabolic reprogramming, increases in protein folding competency, and ER expansion/remodeling. However, we still know surprisingly little regarding the principles by which this ER transducer is deactivated upon ER stress clearance. Here we show that Protein Kinase B-mechanistic Target of Rapamycin (PKB/AKT-mTOR) signaling controls the dynamics of IRE1 deactivation by regulating ER-mitochondria physical contacts and the autophosphorylation state of IRE1. AKT-mTOR-mediated attenuation of IRE1 activity is important for ER remodelling dynamics and cell survival in the face of recursive, transient ER stress. Our observations suggest that IRE1 attenuation is an integral component of anabolic programmes regulated by AKT-mTOR. We suggest that AKT-mTOR activity is part of a ‘timing mechanism’ to deactivate IRE1 immediately following engagement of the UPR, in order to limit prolonged IRE1 RNAse activity that could lead to damaging inflammation or apoptosis.

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Section: Discussionmentioning

confidence: 99%

AKT-mTOR signaling modulates the dynamics of IRE1 RNAse activity by regulating ER-mitochondria contacts

Sánchez-Álvarez

Pozo

Bakal

2017

Sci Rep

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“…Bravo-Sagua and coworkers [63] showed that ER stress, during its early stage, increases the ER-mitochondria contacts, thus leading to an adaptive increase in mitochondrial energetics. This appears to be a generic response to acute stress, as we similarly observed such changes upon inhibition of the nutrient-sensing kinase mammalian target of rapamycin complex 1 (mTORC1) [80]. In fact, RM enables lysate treated cells to maintain a high mitochondrial membrane potential, accordingly to the decrease of the apoptotic process.…”

Section: Discussionmentioning

confidence: 60%

Rapamycin Re-Directs Lysosome Network, Stimulates ER-Remodeling, Involving Membrane CD317 and Affecting Exocytosis, in Campylobacter Jejuni-Lysate-Infected U937 Cells

Canonico

Cesarini

Montanari

et al. 2020

IJMS

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The Gram-negative Campylobacter jejuni is a major cause of foodborne gastroenteritis in humans worldwide. The cytotoxic effects of Campylobacter have been mainly ascribed to the actions of the cytolethal distending toxin (CDT): it is mandatory to put in evidence risk factors for sequela development, such as reactive arthritis (ReA) and Guillain–Barré syndrome (GBS). Several researches are directed to managing symptom severity and the possible onset of sequelae. We found for the first time that rapamycin (RM) is able to largely inhibit the action of C. jejuni lysate CDT in U937 cells, and to partially avoid the activation of specific sub-lethal effects. In fact, we observed that the ability of this drug to redirect lysosomal compartment, stimulate ER-remodeling (highlighted by ER–lysosome and ER–mitochondria contacts), protect mitochondria network, and downregulate CD317/tetherin, is an important component of membrane microdomains. In particular, lysosomes are involved in the process of the reduction of intoxication, until the final step of lysosome exocytosis. Our results indicate that rapamycin confers protection against C. jejuni bacterial lysate insults to myeloid cells.

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“…ER stress induced by thapsigargin in human cancer cells 67 or tunicamycin in HeLa cells 68 promoted cell death involving mitochondrial swelling, dissipation of the electrochemical gradient and opening of the mPTP. However, in HT22 cells ER stress induced by brefeldin A, thapsigargin or tunicamycin induced caspase-dependent cell death through enhanced ER-Ca 2+ release that was independent of mitochondrial damage.…”

Section: Discussionmentioning

confidence: 99%

Glucose-regulated protein 75 determines ER–mitochondrial coupling and sensitivity to oxidative stress in neuronal cells

et al. 2017

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The crosstalk between different organelles allows for the exchange of proteins, lipids and ions. Endoplasmic reticulum (ER) and mitochondria are physically linked and signal through the mitochondria-associated membrane (MAM) to regulate the transfer of Ca2+ from ER stores into the mitochondrial matrix, thereby affecting mitochondrial function and intracellular Ca2+ homeostasis. The chaperone glucose-regulated protein 75 (GRP75) is a key protein expressed at the MAM interface which regulates ER–mitochondrial Ca2+ transfer. Previous studies revealed that modulation of GRP75 expression largely affected mitochondrial integrity and vulnerability to cell death. In the present study, we show that genetic ablation of GRP75, by weakening ER–mitochondrial junctions, provided protection against mitochondrial dysfunction and cell death in a model of glutamate-induced oxidative stress. Interestingly, GRP75 silencing attenuated both cytosolic and mitochondrial Ca2+ overload in conditions of oxidative stress, blocked the formation of reactive oxygen species and preserved mitochondrial respiration. These data revealed a major role for GRP75 in regulating mitochondrial function, Ca2+ and redox homeostasis. In line, GRP75 overexpression enhanced oxidative cell death induced by glutamate. Overall, our findings suggest weakening ER–mitochondrial connectivity by GRP75 inhibition as a novel protective approach in paradigms of oxidative stress in neuronal cells.

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mTORC1 inhibitor rapamycin and ER stressor tunicamycin induce differential patterns of ER-mitochondria coupling

Cited by 33 publications

References 47 publications

AKT-mTOR signaling modulates the dynamics of IRE1 RNAse activity by regulating ER-mitochondria contacts

AKT-mTOR signaling modulates the dynamics of IRE1 RNAse activity by regulating ER-mitochondria contacts

Rapamycin Re-Directs Lysosome Network, Stimulates ER-Remodeling, Involving Membrane CD317 and Affecting Exocytosis, in Campylobacter Jejuni-Lysate-Infected U937 Cells

Glucose-regulated protein 75 determines ER–mitochondrial coupling and sensitivity to oxidative stress in neuronal cells

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