Molecular regulation of autophagy machinery by mTOR‐dependent and ‐independent pathways

Al‐Bari, Md. Abdul Alim; Xu, Pingyong

doi:10.1111/nyas.14305

Cited by 196 publications

(131 citation statements)

References 152 publications

(225 reference statements)

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“…AMPK activity is regulated by phosphorylation at threonine 172 (T172); activation of AMPK in turn negatively regulates the activity of mTOR, a known inhibitor of autophagy initiation (Fig. 4A) (43)(44)(45)(46)(47). Therefore, we investigated whether ITPKB knockdown impacted AMPK or mTOR activity in neurons.…”

Section: Itpkb Inhibition Increases α-Syn Pathology Induced By Preformedmentioning

confidence: 99%

The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

Apicco

Shlevkov

Nezich

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP3, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson’s disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.

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Section: Itpkb Inhibition Increases α-Syn Pathology Induced By Preformedmentioning

confidence: 99%

The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

Apicco

Shlevkov

Nezich

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies have proved the important role of autophagy in tumorigenesis and treatment [ 16 ]. Autophagy is the process of transporting damaged [ 17 ], denatured, or aged proteins and organelles to lysosomes for digestion and degradation, which circulates and degrades intracellular components in response to a lack of nutrients or growth factors to maintain homeostasis [ 18 ]. Therefore, autophagy is important for maintaining genomic stability and overall cell survival.…”

Section: Introductionmentioning

confidence: 99%

Arctigenin Inhibits Glioblastoma Proliferation through the AKT/mTOR Pathway and Induces Autophagy

Jiang

Liu

Wangwang

et al. 2020

BioMed Research International

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Purpose. Arctigenin (ARG) is a natural lignan compound extracted from Arctium lappa and has displayed anticancer function and therapeutic effect in a variety of cancers. Arctigenin is mainly from Arctium lappa extract. It has been shown to induce autophagy in various cancers. However, as for whether arctigenin induces autophagy in gliomas or not, the specific mechanism is still worth exploring. Methods. Using CCK8, the monoclonal experiment was made to detect the proliferation ability. The scratch experiment and the transwell experiment were applied to the migration and invasion ability. PI/RNase and FITC-conjugated anti-annexin V were used to detect the cell cycle and apoptosis. Western blotting was used to determine the specified protein level, and constructed LC3B-GFP plasmid was used for analysis of autophagy.Results. Our research showed that ARG inhibited the growth and proliferation and invasion and migration of glioma cells in a dose-dependent manner (U87MG and T98G) and arrested the cell cycle and induced apoptosis. Interestingly, ARG induced autophagy in a dose-dependent manner. We applied Western blotting to measure the increase in the key autophagy protein LC3B, as well as some other autophagy-related proteins (increase in Beclin-1 and decrease in P62). In order to further explore the mechanism that ARG passed initiating autophagy to inhibit cell growth, we further found by Western blotting that AKT and mTOR phosphorylation proteins (P-AKT, P-mTOR) were reduced after ARG treatment, and we used AKT agonists to rescue, and the phosphorylated proteins of AKT and mTOR increased, and we found that the autophagy-related proteins were also reversed. And interestingly, the protein of apoptosis was also reversed along with autophagy. Conclusions. We thought ARG inhibited the proliferation of glioma cells by inducing autophagy and apoptosis through the AKT/mTOR pathway.

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“…Alteration in Golgi architecture does not affect membrane transport, while organization of the Golgi ribbon has a regulation effect on autophagy via mTOR signaling ( Gosavi et al, 2018 ). mTOR is one of the main regulators of autophagy by controlling activity of the ULK1 complex ( Al-Bari and Xu, 2020 ). Loss of the Golgi ribbon results in dramatic reduction in mTOR activity and induction of autophagy, presumably due to the inability to recruit mTOR to the Golgi pool ( Gosavi et al, 2018 ).…”

Section: Interaction Between the Golgi Apparatus And Autophagymentioning

confidence: 99%

Golgi Apparatus: A Potential Therapeutic Target for Autophagy-Associated Neurological Diseases

Deng

Liu

et al. 2020

Front. Cell Dev. Biol.

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Autophagy has dual effects in human diseases: appropriate autophagy may protect cells from stress, while excessive autophagy may cause cell death. Additionally, close interactions exist between autophagy and the Golgi. This review outlines recent advances regarding the role of the Golgi apparatus in autophagy. The signaling processes of autophagy are dependent on the normal function of the Golgi. Specifically, (i) autophagy-related protein 9 is mainly located in the Golgi and forms new autophagosomes in response to stressors; (ii) Golgi fragmentation is induced by Golgirelated proteins and accompanied with autophagy induction; and (iii) the endoplasmic reticulum-Golgi intermediate compartment and the reticular trans-Golgi network play essential roles in autophagosome formation to provide a template for lipidation of microtubule-associated protein 1A/1B-light chain 3 and induce further ubiquitination. Golgi-related proteins regulate formation of autophagosomes, and disrupted formation of autophagy can influence Golgi function. Notably, aberrant autophagy has been demonstrated to be implicated in neurological diseases. Thus, targeted therapies aimed at protecting the Golgi or regulating Golgi proteins might prevent or ameliorate autophagy-related neurological diseases. Further studies are needed to investigate the potential application of Golgi therapy in autophagy-based neurological diseases.

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Molecular regulation of autophagy machinery by mTOR‐dependent and ‐independent pathways

Cited by 196 publications

References 152 publications

The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

Arctigenin Inhibits Glioblastoma Proliferation through the AKT/mTOR Pathway and Induces Autophagy

Golgi Apparatus: A Potential Therapeutic Target for Autophagy-Associated Neurological Diseases

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