New Insights into the Regulation of mTOR Signaling via Ca2+-Binding Proteins

Amemiya, Yuna; Maki, Masatoshi; Shibata, Hideki; Takahara, Taishi

doi:10.3390/ijms24043923

Cited by 15 publications

(6 citation statements)

References 139 publications

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“…Ca homeostasis was critical for regulating the lysosome function as one of the main storage compartments for Ca . mTORC1 played a key role in the regulation of lysosomal pH and catabolic activity, , while the activation of mTORC1 highly depended on the Ca-binding proteins. , Compared with Ca, Zn homeostasis also regulated the lysosome function. Rivera et al found that the loss of Zn transporter inhibited the assembly of the proton transporter vacuolar ATPase on lysosomes, which thereby affected the lysosome acidification.…”

Section: Resultsmentioning

confidence: 99%

Tracking the Cellular Degradation of Silver Nanoparticles: Development of a Generic Kinetic Model

Wang,

Wang

2024

ACS Nano

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Understanding the degradation of nanoparticles (NPs) after crossing the cell plasma membrane is crucial in drug delivery designs and cytotoxicity assessment. However, the key factors controlling the degradable kinetics remain unclear due to the absence of a quantification model. In this study, subcellular imaging of silver nanoparticles (AgNPs) was used to determine the intracellular transfer of AgNPs, and single particle ICP-MS was utilized to track the degradation process. A cellular kinetic model was subsequently developed to describe the uptake, transfer, and degradation behaviors of AgNPs. Our model demonstrated that the intracellular degradation efficiency of AgNPs was much higher than that determined by mimicking testing, and the degradation of NPs was highly influenced by cellular factors. Specifically, deficiencies in Ca or Zn primarily decreased the kinetic dissolution of NPs, while a Ca deficiency also resulted in the retardation of NP transfer. The biological significance of these kinetic parameters was strongly revealed. Our model indicated that the majority of internalized AgNPs dissolved, with the resulting ions being rapidly depurated. The release of Ag ions was largely dependent on the microvesicle-mediated route. By changing the coating and size of AgNPs, the model results suggested that size influenced the transfer of NPs into the degradation process, whereas coating affected the degradation kinetics. Overall, our developed model provides a valuable tool for understanding and predicting the impacts of the physicochemical properties of NPs and the ambient environment on nanotoxicity and therapeutic efficacy.

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Section: Resultsmentioning

confidence: 99%

Tracking the Cellular Degradation of Silver Nanoparticles: Development of a Generic Kinetic Model

Wang,

Wang

2024

ACS Nano

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“…A recent bioRxiv preprint study by Kazyken and colleagues reported that alkaline intracellular pH can activate the AMPK/mTORC2 pathway and inhibit mTORC1 activity [165]. This links the role of SGLT2is to AMPK activation and subsequent mTORC2 activity via NHE-mediated pH homeostasis and Ca i 2+ modulation [64]. From another perspective, SGLT2 inhibitors have been shown in some studies to promote ketogenesis, lipid oxidation, and erythrocytosis, which can reflect a fasting-like transcriptional paradigm by mimicking nutrient deprivation and hypoxia [166] but can also be responsible for the moderate adverse effects in SGLT2i clinical trials (Table 2).…”

Section: Moderate Genital Infectionsmentioning

confidence: 98%

“…mTOR signaling is involved in diverse biological pathways by regulating ionic homeostasis, specifically by regulating the activity and expression of various Ca 2+ channels [61][62][63]. Intertwined links between sarcoplasmic reticulum calcium homeostasis and mTORC1 signaling are critical for physiological and pathological cardiac hypertrophy [64,65]. Inhibition of mTORC1 with rapamycin induces Ca 2+ release from lysosomes through the activation of two-pore segment channel 2, TPC2 [66].…”

Section: Differential Role Of Mtorc1 and Mtorc2 In Diabetic Cardiomyo...mentioning

confidence: 99%

mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy

Saha,

Fang,

Green

et al. 2023

IJMS

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Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium–glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.

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“…Despite varying modes of regulation, the different family members are modulated by mTORC2. Whether the signals that activate PKC could play a role in modulating mTORC2 remains a possibility given that mTORC2 components can bind to different lipids and that this complex is regulated by calcium/calmodulin [ 132 , 189 , 250 ]. The TM and HM phosphorylation of PKC occurs in an mTORC2-dependent manner as disruption or pharmacological inhibition of mTORC2 abolishes their phosphorylation.…”

Section: Targets and Cellular Functions Of Mtorc2mentioning

confidence: 99%

The mTORC2 signaling network: targets and cross-talks

Ragupathi,

Kim,

Jacinto

2024

Biochemical Journal

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The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.

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New Insights into the Regulation of mTOR Signaling via Ca2+-Binding Proteins

Cited by 15 publications

References 139 publications

Tracking the Cellular Degradation of Silver Nanoparticles: Development of a Generic Kinetic Model

Tracking the Cellular Degradation of Silver Nanoparticles: Development of a Generic Kinetic Model

mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy

The mTORC2 signaling network: targets and cross-talks

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