bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2022‒10‒09
fifty-four papers selected by
Viktor Korolchuk, Newcastle University
  1. Autophagy proteins are essential for aminoglycoside-induced hearing loss.
  2. Autophagy is essential for neural stem cell proliferation promoted by hypoxia.
  3. The Cys-N-degron pathway modulates pexophagy through the N-terminal oxidation and arginylation of ACAD10.
  4. Bifendate inhibits autophagy at multiple steps and attenuates oleic acid-induced lipid accumulation.
  5. MIEAP and ATG5 are tumor suppressors in a mouse model of BRAFV600E-positive thyroid cancer.
  6. The brain-specific splice variant of the CDC42 GTPase works together with the kinase ACK to down-regulate the EGF receptor in promoting neurogenesis.
  7. Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA.
  8. Defective Mitochondrial Quality Control during Dengue Infection Contributes to Disease Pathogenesis.
  9. C-terminal fragment of APP interacts with p62, forms an aggregate, and induces autophagic degradation in Alzheimer's cell model.
  10. V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy.
  11. Autophagy in SARS-CoV-2 infection.
  12. Evaluating mitophagy in embryonic stem cells by using fluorescence-based imaging.
  13. Inhibition of mTOR signaling protects human glioma cells from hypoxia-induced cell death in an autophagy-independent manner.
  14. RHOA, a small G-protein, signals to mitophagy through regulation of PINK1 protein stability and protects cardiomyocytes against ischemia.
  15. The regulatory mechanism and therapeutic potential of transcription factor EB in neurodegenerative diseases.
  16. Calcium transients on the ER surface trigger liquid-liquid phase separation of FIP200 to specify autophagosome initiation sites.
  17. Snake venom induces an autophagic cell death via activation of the JNK pathway in colorectal cancer cells.
  18. Cystine induced-mTORC2 activation through promoting Sin1 phosphorylation to suppress cancer cell ferroptosis.
  19. Destabilization of TP53 by USP10 is essential for neonatal autophagy and survival.
  20. Autophagy in IPF: Predisposition of the Aging Lung to Fibrosis?
  21. V-ATPase a3 Subunit in Secretory Lysosome Trafficking in Osteoclasts.
  22. Aluminum neurotoxicity and autophagy: a mechanistic view.
  23. Protein disulfide isomerase blocks the interaction of LC3II-PHB2 and promotes mTOR signaling to regulate autophagy and radio/chemo-sensitivity.
  24. The functional importance of VCP to maintaining cellular protein homeostasis.
  25. Non-genomic activation of the AKT-mTOR pathway by the mitochondrial stress response in thyroid cancer.
  26. A Noncanonical Autophagy Function of ATG9A for Golgi Integrity and Dynamics.
  27. Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain.
  28. The mechanistic target of rapamycin complex 1 pathway involved in hepatic gluconeogenesis through peroxisome-proliferator-activated receptor γ coactivator-1α.
  29. A long-term high-fat diet influences brain damage and is linked to the activation of HIF-1α/AMPK/mTOR/p70S6K signalling.
  30. Circular RNA-regulated autophagy is involved in cancer progression.
  31. Progress in Parkinson's disease animal models of genetic defects: Characteristics and application.
  32. mTOR-neuropeptide Y signaling sensitizes nociceptors to drive neuropathic pain.
  33. Activation of RhoC by regulatory ubiquitination is mediated by LNX1 and suppressed by LIS1.
  34. A multifaceted evaluation of microgliosis and differential cellular dysregulation of mammalian target of rapamycin signaling in neuronopathic Gaucher disease.
  35. Rapamycin Cannot Reduce Seizure Susceptibility in Infantile Rats with Malformations of Cortical Development Lacking mTORC1 Activation.
  36. Excessive fluoride impairs autophagy flux in ameloblasts which is prevented by the autophagy activator rapamycin.
  37. Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology.
  38. Diesel exhaust particles induce human umbilical vein endothelial cells apoptosis by accumulation of autophagosomes and caspase-8 activation.
  39. Cardio-, hepato- and pneumoprotective effects of autophagy checkpoint inhibition by targeting DBI/ACBP.
  40. Crosstalk between autophagy and the Keap1-Nrf2-ARE pathway regulates realgar-induced neurotoxicity.
  41. New insights into the interplay between autophagy and oxidative and endoplasmic reticulum stress in neuronal cell death and survival.
  42. Suppression of endoplasmic reticulum stress-dependent autophagy enhances cynaropicrin-induced apoptosis via attenuation of the P62/Keap1/Nrf2 pathways in neuroblastoma.
  43. Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons.
  44. Activation of GRP78 ATPase suppresses A549 lung cancer cell migration by promoting ITGB4 degradation.
  45. Fathoming the role of mTOR in diabetes mellitus and its complications.
  46. HIF-1α regulates mTOR signaling pathway during salivary gland development.
  47. The Role of Autophagy in Childhood Central Nervous System Tumors.
  48. RBM3 interacts with Raptor to regulate autophagy and protect cardiomyocytes from ischemia-reperfusion-induced injury.
  49. Mitophagy: A novel perspective for insighting into cancer and cancer treatment.
  50. Mitophagy: A Potential Target for Pressure Overload-Induced Cardiac Remodelling.
  51. ATL1 inhibits the proliferation and invasion of trophoblast cells via inhibition of the mTOR signaling pathway.
  52. Restoration of lysosomal and mitochondrial function through p38 MAPK inhibition ameliorates senescence.
  53. Mitochondrial quality control proteases and their modulation for cancer therapy.
  54. Phosphoinositide signal for lysosomal membrane repair.
  1. Autophagy. 2022 Oct 02. 1-2
    Autophagy proteins are essential for aminoglycoside-induced hearing loss.
    Jinan Li, Chang Liu, Ulrich Müller, Bo Zhao.
      Aminoglycosides (AGs) are widely used to treat severe infections. However, systemically administered AGs preferentially kill cochlear hair cells, resulting in irreversible hearing loss. Recently, we found that AGs bind to RIPOR2 and trigger its rapid translocation in cochlear hair cells. Reducing RIPOR2 expression entirely prevents AG-induced hair cell death and subsequent hearing loss in mice. Next using yeast two-hybrid screening, we found that RIPOR2 interacts with GABARAP, a key macroautophagy/autophagy pathway protein. Following AG treatment, RIPOR2 colocalizes with GABARAP and regulates the activation of autophagy. Remarkably, reducing the expression of GABARAP, or another key autophagy protein MAP1LC3B/LC3B, entirely prevents AG-induced hair cell death and subsequent hearing loss in mice. Furthermore, we found that AGs activate the autophagy pathway specific to mitochondria. Reducing the expression of PINK1 or PRKN/parkin, two key mitophagy proteins, protects hair cells against AG toxicity. Thus, our findings demonstrated that RIPOR2-mediated autophagic dysfunction is essential for AG-induced hearing loss and provided potential therapeutic strategies for preventing AG toxicity.
    Keywords:  GABARAP; RIPOR2; aminoglycoside; autophagy; hair cell; hearing loss; mitophagy; ototoxicity
    DOI:  https://doi.org/10.1080/15548627.2022.2127525
  2. Stem Cells. 2022 Oct 08. pii: sxac076. [Epub ahead of print]
    Autophagy is essential for neural stem cell proliferation promoted by hypoxia.
    Jian Li, Sheng-Hui Gong, Yun-Ling He, Yan Cao, Ying Chen, Guang-Hai Huang, Yu-Fei Wang, Ming Zhao, Xiang Cheng, Yan-Zhao Zhou, Tong Zhao, Yong-Qi Zhao, Ming Fan, Hai-Tao Wu, Ling-Ling Zhu, Li-Ying Wu.
      Hypoxia as a microenvironment or niche stimulates proliferation of neural stem cells (NSCs). However, the underlying mechanisms remain elusive. Autophagy is a protective mechanism by which recycled cellular components and energy are rapidly supplied to the cell under stress. Whether autophagy mediates the proliferation of NSCs under hypoxia and how hypoxia induces autophagy remain unclear. Here, we report that hypoxia facilitates embryonic NSC proliferation through HIF-1/mTORC1 signaling pathway-mediated autophagy. Initially, we found that hypoxia greatly induced autophagy in NSCs, while inhibition of autophagy severely impeded the proliferation of NSCs in hypoxia conditions. Next, we demonstrated that the hypoxia core regulator HIF-1 was necessary and sufficient for autophagy induction in NSCs. Considering that mTORC1 is a key switch that suppresses autophagy, we subsequently analyzed the effect of HIF-1 on mTORC1 activity. Our results showed that the mTORC1 activity was negatively regulated by HIF-1. Finally, we provided evidence that HIF-1 regulated mTORC1 activity via its downstream target gene BNIP3. The increased expression of BNIP3 under hypoxia enhanced autophagy activity and proliferation of NSCs, which was mediated by repressing the activity of mTORC1. We further illustrated that BNIP3 can interact with Rheb, a canonical activator of mTORC1. Thus, we suppose that the interaction of BNIP3 with Rheb reduces the regulation of Rheb towards mTORC1 activity, which relieves the suppression of mTORC1 on autophagy, thereby promoting the rapid proliferation of NSCs. Altogether, this study identified a new HIF-1/BNIP3-Rheb/mTORC1 signaling axis, which regulates the NSC proliferation under hypoxia through induction of autophagy.
    Keywords:  Autophagy; HIF-1; hypoxia; mTORC1; neural stem cells; proliferation
    DOI:  https://doi.org/10.1093/stmcls/sxac076
  3. Autophagy. 2022 Oct 02. 1-20
    The Cys-N-degron pathway modulates pexophagy through the N-terminal oxidation and arginylation of ACAD10.
    Sang Mi Shim, Ha Rim Choi, Soon Chul Kwon, Hye Yeon Kim, Ki Woon Sung, Eui Jung Jung, Su Ran Mun, Tae Hyun Bae, Dong Hyun Kim, Yeon Sung Son, Chan Hoon Jung, Jihoon Lee, Min Jae Lee, Joo-Won Park, Yong Tae Kwon.
      In the N-degron pathway, N-recognins recognize cognate substrates for degradation via the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (hereafter autophagy). We have recently shown that the autophagy receptor SQSTM1/p62 (sequestosome 1) is an N-recognin that binds the N-terminal arginine (Nt-Arg) as an N-degron to modulate autophagic proteolysis. Here, we show that the N-degron pathway mediates pexophagy, in which damaged peroxisomal fragments are degraded by autophagy under normal and oxidative stress conditions. This degradative process initiates when the Nt-Cys of ACAD10 (acyl-CoA dehydrogenase family, member 10), a receptor in pexophagy, is oxidized into Cys sulfinic (CysO2) or sulfonic acid (CysO3) by ADO (2-aminoethanethiol (cysteamine) dioxygenase). Under oxidative stress, the Nt-Cys of ACAD10 is chemically oxidized by reactive oxygen species (ROS). The oxidized Nt-Cys2 is arginylated by ATE1-encoded R-transferases, generating the RCOX N-degron. RCOX-ACAD10 marks the site of pexophagy via the interaction with PEX5 and binds the ZZ domain of SQSTM1/p62, recruiting LC3+-autophagic membranes. In mice, knockout of either Ate1 responsible for Nt-arginylation or Sqstm1/p62 leads to increased levels of peroxisomes. In the cells from patients with peroxisome biogenesis disorders (PBDs), characterized by peroxisomal loss due to uncontrolled pexophagy, inhibition of either ATE1 or SQSTM1/p62 was sufficient to recover the level of peroxisomes. Our results demonstrate that the Cys-N-degron pathway generates an N-degron that regulates the removal of damaged peroxisomal membranes along with their contents. We suggest that tannic acid, a commercially available drug on the market, has a potential to treat PBDs through its activity to inhibit ATE1 R-transferases.Abbreviations: ACAA1, acetyl-Coenzyme A acyltransferase 1; ACAD, acyl-Coenzyme A dehydrogenase; ADO, 2-aminoethanethiol (cysteamine) dioxygenase; ATE1, arginyltransferase 1; CDO1, cysteine dioxygenase type 1; ER, endoplasmic reticulum; LIR, LC3-interacting region; MOXD1, monooxygenase, DBH-like 1; NAC, N-acetyl-cysteine; Nt-Arg, N-terminal arginine; Nt-Cys, N-terminal cysteine; PB1, Phox and Bem1p; PBD, peroxisome biogenesis disorder; PCO, plant cysteine oxidase; PDI, protein disulfide isomerase; PTS, peroxisomal targeting signal; R-COX, Nt-Arg-CysOX; RNS, reactive nitrogen species; ROS, reactive oxygen species; SNP, sodium nitroprusside; UBA, ubiquitin-associated; UPS, ubiquitinproteasome system.
    Keywords:  Acyl-CoA dehydrogenase family, member 10; N-degron pathway; oxidative stress; peroxisomal biogenesis disorders; peroxisome; pexophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2126617
  4. Biochem Biophys Res Commun. 2022 Sep 20. pii: S0006-291X(22)01324-9. [Epub ahead of print]631 115-123
    Bifendate inhibits autophagy at multiple steps and attenuates oleic acid-induced lipid accumulation.
    Weigang Yuan, Fenglei Jian, Yueguang Rong.
      Some traditional Chinese medicines exert roles in the therapy of liver diseases by modulating autophagy. Bifendate (DDB), a synthetic intermediate of Schisandrin C extracted from Schisandrae chinensis, is clinically used to treat hepatitis in China. While DDB is a positive control to research some potential hepatoprotective agents, its related molecular mechanisms are unknown. In this study, we show that DDB inhibited autophagosome-lysosome fusion, lysosome acidification and autophagic lysosome reformation. Moreover, DDB attenuated oleic acid-induced lipid droplet accumulation. These findings reveal the effects of DDB on the autophagy-related processes and lysosomal function, and also provide a possibility to understand the bioactivity mechanism of DDB in the future.
    Keywords:  Autophagy; Bifendate; Lipid droplet; Lysosome
    DOI:  https://doi.org/10.1016/j.bbrc.2022.09.067
  5. Front Endocrinol (Lausanne). 2022 ;13 932754
    MIEAP and ATG5 are tumor suppressors in a mouse model of BRAFV600E-positive thyroid cancer.
    Koichiro Hamada, Tomomi Kurashige, Mika Shimamura, Hirofumi Arakawa, Yasuyuki Nakamura, Yuji Nagayama.
      Mitochondria-eating protein (MIEAP) is a molecule important for non-canonical mitophagy and thought to be a tumor suppressor. Our previous study found that MIEAP expression is defective in thyroid oncocytomas, irrespective of being benign or malignant, and also in non-oncocytic thyroid cancers. Thyroid oncocytomas are composed of large polygonal cells with eosinophilic cytoplasm that is rich in abnormal mitochondria. Thus, our data indicate that, together with increased mitochondrial biogenesis that compensates for the dysfunction of the mitochondria, MIEAP plays a critical role in the accumulation of mitochondria in thyroid oncocytic tumors, whereas a defective MIEAP expression alone is not sufficient for mitochondrial accumulation in non-oncocytic cancers with normal mitochondria. To clarify whether MIEAP is a tumor suppressor in the thyroids and whether MIEAP knockout (KO) alone is sufficient for the oncocytic phenotype and also to extend our effort toward canonical mitophagy (a selective autophagy), we here conducted mouse studies using genetically engineered mice. BrafCA/wt mice developed thyroid cancers 1 year after intrathyroidal injection of adenovirus expressing Cre, while cancer development was observed at 6 months in adenovirus-Cre-injected BrafCA/wt;MieapKO/KO and BrafCA/wt;Atg5flox/flox mice [where autophagy-related 5 (ATG5) is a component of autophagic machinery], although KO of either molecule alone was not sufficient for cancer development. These data demonstrate that MIEAP or ATG5 KO accelerated thyroid cancer development. However, cancers in adenovirus-Cre-injected BrafCA/wt ;MieapKO/KO and BrafCA/wt ;Atg5flox/flox mice were not oncocytic. In conclusion, we here show that MIEAP and ATG5 are both tumor suppressors in thyroid carcinogenesis, but as we have anticipated from our previous data, KO of either molecule does not confer the oncocytic phenotype to BRAFV600E-positive thyroid cancers. The combination of disruptive mitochondrial function and impaired mitochondrial quality control may be necessary to establish a mouse model of thyroid oncocytoma.
    Keywords:  ATG5; MIEAP; mitochondria; oncocytoma; thyroid cancer
    DOI:  https://doi.org/10.3389/fendo.2022.932754
  6. J Biol Chem. 2022 Oct 05. pii: S0021-9258(22)01008-0. [Epub ahead of print] 102564
    The brain-specific splice variant of the CDC42 GTPase works together with the kinase ACK to down-regulate the EGF receptor in promoting neurogenesis.
    Makoto Endo, Richard A Cerione.
      The small GTPase CDC42 plays essential roles in neurogenesis and brain development. Previously, we showed that a CDC42 splice variant that has a ubiquitous tissue distribution specifically stimulates the formation of neural progenitor cells, whereas a brain-specific CDC42 variant, CDC42b, is essential for promoting the transition of neural progenitor cells to neurons. These specific roles of CDC42 and CDC42b in neurogenesis are ascribed to their opposing effects on mTORC1 activity. Specifically, the ubiquitous form of CDC42 stimulates mTORC1 activity and thereby up-regulates tissue-specific transcription factors that are essential for neuroprogenitor formation, whereas CDC42b works together with activated CDC42-associated kinase (ACK) to down-regulate mTOR expression. Here we demonstrate that the EGF receptor (EGFR) is an additional and important target of CDC42b and ACK which is down-regulated by their combined actions in promoting neurogenesis. The activation status of the EGFR determines the timing by which neural progenitor cells derived from P19 embryonal carcinoma terminally differentiate into neurons. By promoting EGFR degradation, we found that CDC42b and ACK stimulate autophagy, which protects emerging neurons from apoptosis and helps trigger neural progenitor cells to differentiate into neurons. Moreover, our results reveal that CDC42b is localized in phosphatidylinositol (3,4,5)-triphosphate (PIP3)-enriched microdomains on the plasma membrane, mediated through its polybasic sequence 185KRK187, which is essential for determining its distinct functions. Overall, these findings now highlight a molecular mechanism by which CDC42b and ACK regulate neuronal differentiation and provide new insights into the functional interplay between EGFR degradation and autophagy which occurs during embryonic neurogenesis.
    Keywords:  ACK; CDC42; EGFR; autophagy; mTOR; neurogenesis
    DOI:  https://doi.org/10.1016/j.jbc.2022.102564
  7. Nat Commun. 2022 Oct 04. 13(1): 5845
    Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA.
    WeiChao Hao, MeiJuan Dian, Ying Zhou, QiuLing Zhong, WenQian Pang, ZiJian Li, YaYan Zhao, JiaCheng Ma, XiaoLin Lin, RenRu Luo, YongLong Li, JunShuang Jia, HongFen Shen, ShiHao Huang, GuanQi Dai, JiaHong Wang, Yan Sun, Dong Xiao.
      Autophagy is crucial for maintaining cellular energy homeostasis and for cells to adapt to nutrient deficiency, and nutrient sensors regulating autophagy have been reported previously. However, the role of eiptranscriptomic modifications such as m6A in the regulation of starvation-induced autophagy is unclear. Here, we show that the m6A reader YTHDF3 is essential for autophagy induction. m6A modification is up-regulated to promote autophagosome formation and lysosomal degradation upon nutrient deficiency. METTL3 depletion leads to a loss of functional m6A modification and inhibits YTHDF3-mediated autophagy flux. YTHDF3 promotes autophagy by recognizing m6A modification sites around the stop codon of FOXO3 mRNA. YTHDF3 also recruits eIF3a and eIF4B to facilitate FOXO3 translation, subsequently initiating autophagy. Overall, our study demonstrates that the epitranscriptome regulator YTHDF3 functions as a nutrient responder, providing a glimpse into the post-transcriptional RNA modifications that regulate metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41467-022-32963-0
  8. J Virol. 2022 Oct 05. e0082822
    Defective Mitochondrial Quality Control during Dengue Infection Contributes to Disease Pathogenesis.
    Bharati Singh, Kiran Avula, Shamim Akhtar Sufi, Nahid Parwin, Sayani Das, Mohd Faraz Alam, Subhashish Samantaray, Leelakrishna Bankapalli, Alankrita Rani, Kokavalla Poornima, Biswajita Prusty, Tareni P Mallick, Shubham K Shaw, Hiren Dodia, Shobhitendu Kabi, Trupti T Pagad, Sriprasad Mohanty, Gulam Hussain Syed.
      Mitochondrial fitness is governed by mitochondrial quality control pathways comprising mitochondrial dynamics and mitochondrial-selective autophagy (mitophagy). Disruption of these processes has been implicated in many human diseases, including viral infections. Here, we report a comprehensive analysis of the effect of dengue infection on host mitochondrial homeostasis and its significance in dengue disease pathogenesis. Despite severe mitochondrial stress and injury, we observed that the pathways of mitochondrial quality control and mitochondrial biogenesis are paradoxically downregulated in dengue-infected human liver cells. This leads to the disruption of mitochondrial homeostasis and the onset of cellular injury and necrotic death in the infected cells. Interestingly, dengue promotes global autophagy but selectively disrupts mitochondrial-selective autophagy (mitophagy). Dengue downregulates the expression of PINK1 and Parkin, the two major proteins involved in tagging the damaged mitochondria for elimination through mitophagy. Mitophagy flux assays also suggest that Parkin-independent pathways of mitophagy are also inactive during dengue infection. Dengue infection also disrupts mitochondrial biogenesis by downregulating the master regulators PPARγ and PGC1α. Dengue-infected cells release mitochondrial damage-associated molecular patterns (mtDAMPs) such as mitochondrial DNA into the cytosol and extracellular milieu. Furthermore, the challenge of naive immune cells with culture supernatants from dengue-infected liver cells was sufficient to trigger proinflammatory signaling. In correlation with our in vitro observations, dengue patients have high levels of cell-free mitochondrial DNA in their blood in proportion to the degree of thrombocytopenia. Overall, our study shows how defective mitochondrial homeostasis in dengue-infected liver cells can drive dengue disease pathogenesis. IMPORTANCE Many viruses target host cell mitochondria to create a microenvironment conducive to viral dissemination. Dengue virus also exploits host cell mitochondria to facilitate its viral life cycle. Dengue infection of liver cells leads to severe mitochondrial injury and inhibition of proteins that regulate mitochondrial quality control and biogenesis, thereby disrupting mitochondrial homeostasis. A defect in mitochondrial quality control leads to the accumulation of damaged mitochondria and promotes cellular injury. This leads to the release of mitochondrial damage-associated molecular patterns (mt-DAMPs) into the cell cytoplasm and extracellular milieu. These mt-DAMPs activate the naive immune cells and trigger proinflammatory signaling, leading to the release of cytokines and chemokines, which may trigger systemic inflammation and contribute to dengue disease pathogenesis. In correlation with this, we observed high levels of cell-free mitochondrial DNA in dengue patient blood. This study provides insight into how the disruption of mitochondrial quality control in dengue-infected cells can trigger inflammation and drive dengue disease pathogenesis.
    Keywords:  autophagy; dengue virus; inflammation; mitochondria; mitochondrial homeostasis; mitochondrial quality control; mitophagy; mt-DNA; necrosis
    DOI:  https://doi.org/10.1128/jvi.00828-22
  9. Am J Physiol Cell Physiol. 2022 Oct 03.
    C-terminal fragment of APP interacts with p62, forms an aggregate, and induces autophagic degradation in Alzheimer's cell model.
    Keigo Tanaka, Kohei Kuramoto, Tadashi Nakagawa, Yasuyuki Nomura, Koichiro Ozawa, Toru Hosoi.
      Alzheimer's disease is an intractable disease, and the accumulation of amyloid β in the brain is thought to be involved in the onset of the disease. Additionally, abnormal protein accumulation due to autophagic deficiency may also be involved in disease progression. Autophagy involves a mechanism called selective autophagy. However, the relationship between selective autophagy and the amyloid precursor protein (APP) remains unclear. In the present study, we analyzed the interaction between p62, an adapter protein, and an APP-related molecule, and found that p62 interacted with the C-terminal fragment of APP (C60). When C60 and p62 are overexpressed, aggregates are formed, and C60 is degraded by autophagy. These aggregates cannot be easily degraded, even with a reducing agent. We also found that autophagosome- and lysosome-marker-positive vesicles were formed in the C60- and p62-expressing cells. Super resolution technology also revealed that p62-C60-positive autophagosomes were formed in the cells. Overall, these results suggest that p62 may bind with C60 to form aggregates and induce autophagy in autophagosomes. These results reveal one of the mechanisms underlying the progression of Alzheimer's disease, in which selective autophagy may be involved.
    Keywords:  APP transmembrane C-terminal fragments (CTFs); Alzheimer's disease; amyloid precursor protein (APP); autophagy; p62 (sequestosome 1(SQSTM1))
    DOI:  https://doi.org/10.1152/ajpcell.00003.2022
  10. J Cell Biol. 2022 Dec 05. pii: e202206040. [Epub ahead of print]221(12):
    V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy.
    Xiaotong Jia, Anastasia Knyazeva, Yu Zhang, Sergio Castro-Gonzalez, Shuhei Nakamura, Lars-Anders Carlson, Tamotsu Yoshimori, Dale P Corkery, Yao-Wen Wu.
      Pore-forming toxins (PFTs) are important virulence factors produced by many pathogenic bacteria. Here, we show that the Vibrio cholerae toxin MakA is a novel cholesterol-binding PFT that induces non-canonical autophagy in a pH-dependent manner. MakA specifically binds to cholesterol on the membrane at pH < 7. Cholesterol-binding leads to oligomerization of MakA on the membrane and pore formation at pH 5.5. Unlike other cholesterol-dependent cytolysins (CDCs) which bind cholesterol through a conserved cholesterol-binding motif (Thr-Leu pair), MakA contains an Ile-Ile pair that is essential for MakA-cholesterol interaction. Following internalization, endosomal acidification triggers MakA pore-assembly followed by ESCRT-mediated membrane repair and V-ATPase-dependent unconventional LC3 lipidation on the damaged endolysosomal membranes. These findings characterize a new cholesterol-binding toxin that forms pores in a pH-dependent manner and reveals the molecular mechanism of host autophagy manipulation.
    DOI:  https://doi.org/10.1083/jcb.202206040
  11. Curr Opin Physiol. 2022 Sep 27. 100596
    Autophagy in SARS-CoV-2 infection.
    Di Chen, Hong Zhang.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) orchestrates host factors to remodel endomembrane compartments for various steps of the infection cycle. SARS-CoV-2 also intimately intersects with the catabolic autophagy pathway during infection. In response to virus infection, autophagy acts as an innate defensive system by delivering viral components/particles to lysosomes for degradation. Autophagy also elicits antiviral immune responses. SARS-CoV-2, like other positive-stranded RNA viruses, has evolved various mechanisms to escape autophagic destruction and to hijack the autophagic machinery for its own benefit. In this review, we will focus on how the interplay between SARS-CoV-2 viral proteins and autophagy promotes viral replication and transmission. We will also discuss the pathogenic effects of SARS-CoV-2-elicited autophagy dysregulation and pharmacological interventions targeting autophagy for COVID-19 treatment.
    DOI:  https://doi.org/10.1016/j.cophys.2022.100596
  12. Front Cell Dev Biol. 2022 ;10 910464
    Evaluating mitophagy in embryonic stem cells by using fluorescence-based imaging.
    Kun Liu, Xing Li, Zheng Li, Jiani Cao, Xiaoyan Li, Youqing Xu, Lei Liu, Tongbiao Zhao.
      Embryonic stem cells (ESCs), which are characterized by the capacity for self-renewal and pluripotency, hold great promise for regenerative medicine. Increasing evidence points to the essential role of mitophagy in pluripotency regulation. Our recent work showed that PINK1/OPTN take part in guarding ESC mitochondrial homeostasis and pluripotency. Evaluating mitophagy in ESCs is important for exploring the relationships between mitochondrial homeostasis and pluripotency. ESCs are smaller in size than adult somatic cells and the mitophagosomes in ESCs are difficult to observe. Many methods have been employed-for example, detecting colocalization of LC3-II and mitochondria-to evaluate mitophagy in ESCs. However, it is important to define an objective way to detect mitophagy in ESCs. Here, we evaluated two commonly used fluorescence-based imaging methods to detect mitophagy in ESCs. By using autophagy- or mitophagy-defective ESC lines, we showed that the mito-Keima (mt-Keima) system is a suitable and effective way for detecting and quantifying mitophagy in ESCs. Our study provides evidence that mt-Keima is an effective tool to study mitophagy function in ESCs.
    Keywords:  ATG3; LC3; PINK1; mitophagy; mt-keima
    DOI:  https://doi.org/10.3389/fcell.2022.910464
  13. Cell Death Discov. 2022 Oct 06. 8(1): 409
    Inhibition of mTOR signaling protects human glioma cells from hypoxia-induced cell death in an autophagy-independent manner.
    Iris Divé, Kevin Klann, Jonas B Michaelis, Dennis Heinzen, Joachim P Steinbach, Christian Münch, Michael W Ronellenfitsch.
      Although malignant gliomas frequently show aberrant activation of the mammalian target of rapamycin (mTOR), mTOR inhibitors have performed poorly in clinical trials. Besides regulating cell growth and translation, mTOR controls the initiation of autophagy. By recycling cellular components, autophagy can mobilize energy resources, and has thus been attributed cancer-promoting effects. Here, we asked whether the activation of autophagy represents an escape mechanism to pharmacological mTOR inhibition in glioma cells, and explored co-treatment with mTOR and autophagy inhibitors as a therapeutic strategy. Mimicking conditions of the glioma microenvironment, glioma cells were exposed to nutrient starvation and hypoxia. We analyzed autophagic activity, cell growth, viability and oxygen consumption following (co-)treatment with the mTOR inhibitors torin2 or rapamycin, and autophagy inhibitors bafilomycin A1 or MRT68921. Changes in global proteome were quantified by mass spectrometry. In the context of hypoxia and starvation, autophagy was strongly induced in glioma cells and further increased by mTOR inhibition. While torin2 enhanced glioma cell survival, co-treatment with torin2 and bafilomycin A1 failed to promote cell death. Importantly, treatment with bafilomycin A1 alone also protected glioma cells from cell death. Mechanistically, both compounds significantly reduced cell growth and oxygen consumption. Quantitative proteomics analysis showed that bafilomycin A1 induced broad changes in the cellular proteome. More specifically, proteins downregulated by bafilomycin A1 were associated with the mitochondrial respiratory chain and ATP synthesis. Taken together, our results show that activation of autophagy does not account for the cytoprotective effects of mTOR inhibition in our in vitro model of the glioma microenvironment. Our proteomic findings suggest that the pharmacological inhibition of autophagy induces extensive changes in the cellular proteome that can support glioma cell survival under nutrient-deplete and hypoxic conditions. These findings provide a novel perspective on the complex role of autophagy in gliomas.
    DOI:  https://doi.org/10.1038/s41420-022-01195-y
  14. Autophagy. 2022 Oct 06.
    RHOA, a small G-protein, signals to mitophagy through regulation of PINK1 protein stability and protects cardiomyocytes against ischemia.
    Michelle Tu, Shigeki Miyamoto.
      RHOA (ras homolog family member A) is a small G-protein that regulates a range of cellular processes including cell growth and survival. RHOA is a proximal downstream effector of G protein-coupled receptor coupling to GNA12/Gα12-GNA13/Gα13 proteins, and is activated in response to stretch and oxidative stress, functioning as a stress-response molecule. It has been demonstrated that RHOA signaling provides cardioprotection through inhibition of mitochondrial death pathways. Mitochondrial integrity is preserved not only by inhibition of mitochondrial death pathways but also by mitochondrial quality control mechanisms including mitophagy. One of the most well-established mechanisms of mitophagy is the mitochondrial membrane depolarization-dependent PINK1-PRKN/Parkin pathway. However, depolarization of the mitochondrial membrane potential is a late-stage event that occurs just before cell death, and additional intracellular mechanisms that enhance the PINK1-PRKN pathway have not been fully determined. We recently discovered that RHOA activation engages a unique mechanism to regulate PINK1 protein stability without inducing mitochondrial membrane depolarization, leading to increased mitophagy and protection against ischemia in cardiomyocytes. Our results suggest regulation of RHOA signaling as a potential strategy to enhance protective mitophagy against stress without compromising mitochondrial functions.
    Keywords:  Cardiomyocytes; PINK1, RHOA; ischemia; mitophagy, Parkin
    DOI:  https://doi.org/10.1080/15548627.2022.2132707
  15. CNS Neurosci Ther. 2022 Oct 02.
    The regulatory mechanism and therapeutic potential of transcription factor EB in neurodegenerative diseases.
    Fengjuan Jiao, Bojie Zhou, Lingyan Meng.
      The autophagy-lysosomal pathway (ALP) is involved in the degradation of protein aggregates and damaged organelles. Transcription factor EB (TFEB), a major regulator of ALP, has emerged as a leading factor in addressing neurodegenerative disease pathology, including Alzheimer's disease (AD), Parkinson's disease (PD), PolyQ diseases, and Amyotrophic lateral sclerosis (ALS). In this review, we delineate the regulation of TFEB expression and its functions in ALP. Dysfunctions of TFEB and its role in the pathogenesis of several neurodegenerative diseases are reviewed. We summarize the protective effects and molecular mechanisms of some TFEB-targeted agonists in neurodegenerative diseases. We also offer our perspective on analyzing the pros and cons of these agonists in the treatment of neurodegenerative diseases from the perspective of drug development. More studies on the regulatory mechanisms of TFEB in other biological processes will aid our understanding of the application of TFEB-targeted therapy in neurodegeneration.
    Keywords:  TFEB agonist; autophagy; autophagy-lysosomal pathway; neurodegenerative disease; transcription factor EB
    DOI:  https://doi.org/10.1111/cns.13985
  16. Cell. 2022 Sep 30. pii: S0092-8674(22)01123-0. [Epub ahead of print]
    Calcium transients on the ER surface trigger liquid-liquid phase separation of FIP200 to specify autophagosome initiation sites.
    Qiaoxia Zheng, Yong Chen, Di Chen, Hongyu Zhao, Yun Feng, Quan Meng, Yan Zhao, Hong Zhang.
      The mechanism that initiates autophagosome formation on the ER in multicellular organisms is elusive. Here, we showed that autophagy stimuli trigger Ca2+ transients on the outer surface of the ER membrane, whose amplitude, frequency, and duration are controlled by the metazoan-specific ER transmembrane autophagy protein EPG-4/EI24. Persistent Ca2+ transients/oscillations on the cytosolic ER surface in EI24-depleted cells cause accumulation of FIP200 autophagosome initiation complexes on the ER. This defect is suppressed by attenuating ER Ca2+ transients. Multi-modal SIM analysis revealed that Ca2+ transients on the ER trigger the formation of dynamic and fusion-prone liquid-like FIP200 puncta. Starvation-induced Ca2+ transients on lysosomes also induce FIP200 puncta that further move to the ER. Multiple FIP200 puncta on the ER, whose association depends on the ER proteins VAPA/B and ATL2/3, assemble into autophagosome formation sites. Thus, Ca2+ transients are crucial for triggering phase separation of FIP200 to specify autophagosome initiation sites in metazoans.
    Keywords:  ATG9; Ca(2+) transient; EI24; ER; FIP200; autophagosome formation; liquid-liquid phase separation; lysosome
    DOI:  https://doi.org/10.1016/j.cell.2022.09.001
  17. J Cancer. 2022 ;13(12): 3333-3341
    Snake venom induces an autophagic cell death via activation of the JNK pathway in colorectal cancer cells.
    Ji Eun Yu, In Jun Yeo, Dong Won Lee, Ju Young Chang, Dong Ju Son, Jaesuk Yun, Sang-Bae Han, Jin Tae Hong.
      Snake venom contains many proteins that help treat or prevent thrombosis, cardiovascular disease, and cancer, and many studies have been reported in this regard. It has recently been reported that autophagy exerts anticancer effects by inducing tumor cell death and inhibiting cell growth. In this study, we investigated the effect of snake venom on autophagy. Unlike normal colon cells, LC3-II protein levels and LC3 puncta accumulation are increased in snake venom-treated colorectal cancer cells. Inhibition of autophagy by treating cells with hydroxychloroquine, an autophagy inhibitor, prevented snake venom-induced cell death, indicating that snake venom indeed induces autophagic cell death in human colorectal cancer cells. In addition, we demonstrated that activated JNK, and not mTOR signaling, is an upstream effector controlling autophagy. Pretreatment with SP600125, a JNK inhibitor, reversed snake venom-induced autophagy and cell death, indicating that JNK plays a critical role in snake venom-induced autophagy. This study demonstrated that snake venom can function as an anticarcinogenby induction autophagy.
    Keywords:  Autophagy; JNK; LC3; Snake venom
    DOI:  https://doi.org/10.7150/jca.75791
  18. Mol Nutr Food Res. 2022 Oct 03. e2200186
    Cystine induced-mTORC2 activation through promoting Sin1 phosphorylation to suppress cancer cell ferroptosis.
    GuoYan Wang, Lei Chen, SenLin Qin, YiNing Zheng, Chao Xia, JunHu Yao, Ping Wang, Lu Deng.
      SCOPE: Mechanistic target of rapamycin (mTOR) serves as a central signaling node in the coordination of cell growth and metabolism, and it functions via two distinct complexes, namely, mTORC1 and mTORC2. mTORC1 plays a crucial role in sensing amino acids, whereas mTORC2 involves in sensing growth factors. However, it remains largely unclear whether mTORC2 can sense amino acids and the mechanism by which amino acids regulate mTORC2 has not been studied.METHODS AND RESULTS: After treating cells with indicated concentration of amino acids for different time, it is found that the mTORC2 activation was significantly increased in response to amino acids stimulation, especially cystine. Particularly, knockdown SLC7A11 by siRNA showed that SLC7A11-mediated cystine uptake is responsible for activating mTORC2. Mechanistically, we found that p38 is activated in response to cystine stimulation, and co-immunoprecipitation experiments suggested that p38 regulated the assembly of components within mTORC2 by mediating the phosphorylation of the mTORC2 subunit Sin1 in a cystine-dependent manner. Finally, combined with inducers and inhibitors of ferroptosis and cell viability assay, we observed that cystine-mediated regulation of the p38-Sin1-mTOR-AKT pathway induced resistance to ferroptosis.
    CONCLUSION: These results indicate that cystine-induced activation of the p38-Sin1-mTORC2-AKT pathway suppresses ferroptosis. This article is protected by copyright. All rights reserved.
    Keywords:  Cystine; Ferroptosis; Sin1; mTORC2; p38
    DOI:  https://doi.org/10.1002/mnfr.202200186
  19. Cell Rep. 2022 Oct 04. pii: S2211-1247(22)01276-1. [Epub ahead of print]41(1): 111435
    Destabilization of TP53 by USP10 is essential for neonatal autophagy and survival.
    Hongchang Li, Chaonan Li, Wenjing Zhai, Xin Zhang, Lei Li, Bo Wu, Biyue Yu, Pengfei Zhang, Jie Li, Chun-Ping Cui, Lingqiang Zhang.
      Autophagy is essential for the maintenance of energy homeostasis and for survival during the neonatal starvation period. At birth, the trans-placental nutrient supply is suddenly interrupted, and neonates adapt to this adverse circumstance by activating autophagy. However, the mechanisms underlying the precise regulation of neonatal autophagy remain undefined. Here, we show that the destabilization of TP53 by the deubiquitylase ubiquitin-specific peptidase 10 (USP10) is essential for neonatal autophagy and survival. Usp10 deficiency results in decreased E3 ligase activity of MDM2 and accumulation of cytoplasmic TP53, which interferes with the conjugation of ATG12 and ATG5, the key autophagy-related genes, and ultimately inhibits autophagy in neonatal mice. Combined deletion of Tp53 and Usp10 recovers the nutrition supply and rescues the death phenotype of Usp10-deficient neonates. These findings reveal a role of the USP10-MDM2-TP53 axis in nutrient homeostasis and neonatal viability and provide insights into the long-perplexing mechanism by which cytoplasmic TP53 inhibits autophagy.
    Keywords:  CP: Developmental biology; CP: Molecular biology; TP53; USP10; autophagy; deubiquitination; neonatal survival
    DOI:  https://doi.org/10.1016/j.celrep.2022.111435
  20. Am J Respir Cell Mol Biol. 2022 Oct 06.
    Autophagy in IPF: Predisposition of the Aging Lung to Fibrosis?
    Jaroslaw W Zmijewski, Victor J Thannickal.
      
    Keywords:  IPF, autophagy, Beclin1, aging, alveolar epithelial cells, fibroblasts, lung fibrosis
    DOI:  https://doi.org/10.1165/rcmb.2022-0379ED
  21. Biol Pharm Bull. 2022 ;45(10): 1426-1431
    V-ATPase a3 Subunit in Secretory Lysosome Trafficking in Osteoclasts.
    Mayumi Nakanishi-Matsui, Naomi Matsumoto.
      Vacuolar-type ATPase (V-ATPase) shares its structure and rotational catalysis with F-type ATPase (F-ATPase, ATP synthase). However, unlike subunits of F-ATPase, those of V-ATPase have tissue- and/or organelle-specific isoforms. Structural diversity of V-ATPase generated by different combinations of subunit isoforms enables it to play diverse physiological roles in mammalian cells. Among these various roles, this review focuses on the functions of lysosome-specific V-ATPase in bone resorption by osteoclasts. Lysosomes remain in the cytoplasm in most cell types, but in osteoclasts, secretory lysosomes move toward and fuse with the plasma membrane to secrete lysosomal enzymes, which is essential for bone resorption. Through this process, lysosomal V-ATPase harboring the a3 isoform of the a subunit is relocated to the plasma membrane, where it transports protons from the cytosol to the cell exterior to generate the acidic extracellular conditions required for secreted lysosomal enzymes. In addition to this role as a proton pump, we recently found that the lysosomal a3 subunit of V-ATPase is essential for anterograde trafficking of secretory lysosomes. Specifically, a3 interacts with Rab7, a member of the Rab guanosine 5'-triphosphatase (GTPase) family that regulates organelle trafficking, and recruits it to the lysosomal membrane. These findings revealed the multifunctionality of lysosomal V-ATPase in osteoclasts; V-ATPase is responsible not only for the formation of the acidic environment by transporting protons, but also for intracellular trafficking of secretory lysosomes by recruiting organelle trafficking factors. Herein, we summarize the molecular mechanism underlying secretory lysosome trafficking in osteoclasts, and discuss the possible regulatory role of V-ATPase in organelle trafficking.
    Keywords:  organelle trafficking; osteoclast; proton pump; secretory lysosome; vacuolar-type ATPase
    DOI:  https://doi.org/10.1248/bpb.b22-00371
  22. Neurol Res. 2022 Oct 08. 1-11
    Aluminum neurotoxicity and autophagy: a mechanistic view.
    Sajjad Makhdoomi, Saba Ariafar, Fatemeh Mirzaei, Mojdeh Mohammadi.
      It is strongly believed that aluminum is one of the insalubrious agents because of its neurotoxicity effects and influences on amyloid β (Aβ) production and tau protein hyperphosphorylation following oxidative stress, as one of the initial events in neurotoxicity. The autophagy process plays a considerable role in neurons in preserving intracellular homeostasis and recycling organelles and proteins, especially Aβ and soluble tau. Thus, autophagy is suggested to ameliorate aluminum neurotoxicity effects, and dysfunction of this process can lead to an increase in detrimental proteins. However, the relationship between aluminum neurotoxicity and autophagy dysregulation in some dimensions remains unclear. In the present review, we want to give an overview of the autophagy roles in aluminum neurotoxicity and how dysregulation of autophagy can affect aluminum neurotoxicity.
    Keywords:  Aluminum; Alzheimer’s disease; autophagy; neurotoxicity
    DOI:  https://doi.org/10.1080/01616412.2022.2132727
  23. Cell Death Dis. 2022 Oct 06. 13(10): 851
    Protein disulfide isomerase blocks the interaction of LC3II-PHB2 and promotes mTOR signaling to regulate autophagy and radio/chemo-sensitivity.
    Ruru Wang, Yajing Shang, Bin Chen, Feng Xu, Jie Zhang, Zhaoyang Zhang, Xipeng Zhao, Xiangbo Wan, An Xu, Lijun Wu, Guoping Zhao.
      Protein disulfide isomerase (PDI) is an endoplasmic reticulum (ER) enzyme that mediates the formation of disulfide bonds, and is also a therapeutic target for cancer treatment. Our previous studies found that PDI mediates apoptotic signaling by inducing mitochondrial dysfunction. Considering that mitochondrial dysfunction is a major contributor to autophagy, how PDI regulates autophagy remains unclear. Here, we provide evidence that high expression of PDI in colorectal cancer tumors significantly increases the risk of metastasis and poor prognosis of cancer patients. PDI inhibits radio/chemo-induced cell death by regulating autophagy signaling. Mechanistically, the combination of PDI and GRP78 was enhanced after ER stress, which inhibits the degradation of AKT by GRP78, and eventually activates the mTOR pathway to inhibit autophagy initiation. In parallel, PDI can directly interact with the mitophagy receptor PHB2 in mitochondrial, then competitively blocks the binding of LC3II and PHB2 and inhibits the mitophagy signaling. Collectively, our results identify that PDI can reduce radio/chemo-sensitivity by regulating autophagy, which could be served as a potential target for radio/chemo-therapy.
    DOI:  https://doi.org/10.1038/s41419-022-05302-w
  24. Biochem Soc Trans. 2022 Oct 05. pii: BST20220648. [Epub ahead of print]
    The functional importance of VCP to maintaining cellular protein homeostasis.
    Brittany A Ahlstedt, Rakesh Ganji, Malavika Raman.
      The AAA-ATPase (ATPases associated with diverse cellular activities) valosin-containing protein (VCP), is essential for many cellular pathways including but not limited to endoplasmic reticulum-associated degradation (ERAD), DNA damage responses, and cell cycle regulation. VCP primarily identifies ubiquitylated proteins in these pathways and mediates their unfolding and degradation by the 26S proteasome. This review summarizes recent research on VCP that has uncovered surprising new ways that this ATPase is regulated, new aspects of recognition of substrates and novel pathways and substrates that utilize its activity.
    Keywords:  autophagy; neurodegeneration; organelles; protein quality control; ubiquitin
    DOI:  https://doi.org/10.1042/BST20220648
  25. Oncogene. 2022 Oct 04.
    Non-genomic activation of the AKT-mTOR pathway by the mitochondrial stress response in thyroid cancer.
    Woo Kyung Lee Doolittle, Sunmi Park, Seul Gi Lee, Seonhyang Jeong, Gibbeum Lee, Dongryeol Ryu, Kristina Schoonjans, Johan Auwerx, Jandee Lee, Young Suk Jo.
      Cancer progression is associated with metabolic reprogramming and causes significant intracellular stress; however, the mechanisms that link cellular stress and growth signalling are not fully understood. Here, we identified a mechanism that couples the mitochondrial stress response (MSR) with tumour progression. We demonstrated that the MSR is activated in a significant proportion of human thyroid cancers via the upregulation of heat shock protein D family members and the mitokine, growth differentiation factor 15. Our study also revealed that MSR triggered AKT/S6K signalling by activating mTORC2 via activating transcription factor 4/sestrin 2 activation whilst promoting leucine transporter and nutrient-induced mTORC1 activation. Importantly, we found that an increase in mtDNA played an essential role in MSR-induced mTOR activation and that crosstalk between MYC and MSR potentiated mTOR activation. Together, these findings suggest that the MSR could be a predictive marker for aggressive human thyroid cancer as well as a useful therapeutic target.
    DOI:  https://doi.org/10.1038/s41388-022-02484-7
  26. Autophagy. 2022 Oct 05.
    A Noncanonical Autophagy Function of ATG9A for Golgi Integrity and Dynamics.
    Yuanyuan Meng, Qian Luo, Quan Chen, Yushan Zhu.
      In mammalian cells, the Golgi apparatus serves as the central hub for membrane trafficking. Notably, the membrane trafficking and Golgi integrity are tightly regulated by reversible post-translational modifications, such as glycosylation, phosphorylation and ubiquitination. Nonetheless, how the Golgi apparatus responses to stress to ensure appropriate membrane assembly and distribution of cargo is poorly understood. The Golgi resident protein ATG9A is the only multi-spanning membrane protein in the ATG family, and has been demonstrated to traffic through the plasma membrane, endosomes, and Golgi to deliver materials for the initiation of macroautophagy/autophagy. Our recent work reveals a noncanonical function of ATG9A for Golgi dynamics and identifies a pathway for sensing Golgi stress via the MARCHF9-ATG9A axis.
    Keywords:  ATG9A; Golgi dynamics; Golgi stress response; MARCHF9; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2022.2131244
  27. Eur J Pharmacol. 2022 Sep 30. pii: S0014-2999(22)00562-3. [Epub ahead of print] 175301
    Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain.
    Martina P Morawe, Fan Liao, Willi Amberg, Jeroen van Bergeijk, Rui Chang, Mary Gulino, Caitlin Hamilton, Carolin Hoft, Casey Lumpkin, Bryan Mastis, Emily McGlame, Judith Nuber, Christian Plaas, Brinda Ravikumar, Kaushambi Roy, Marion Schanzenbächer, Joseph Tierno, Viktor Lakics, Tammy Dellovade, Matthew Townsend.
      In this study we aimed to reduce tau pathology, a hallmark of Alzheimer's Disease (AD), by activating mTOR-dependent autophagy in a transgenic mouse model of tauopathy by long-term dosing of animals with mTOR-inhibitors. Rapamycin treatment reduced the burden of hyperphosphorylated and aggregated pathological tau in the cerebral cortex only when applied to young mice, prior to the emergence of pathology. Conversely, PQR530 which exhibits better brain exposure and superior pharmacokinetic properties, reduced tau pathology even when the treatment started after the onset of pathology. Our results show that dosing animals twice per week with PQR530 resulted in intermittent, rather than sustained target engagement. Nevertheless, this pulse-like mTOR inhibition followed by longer intervals of re-activation was sufficient to reduce tau pathology in the cerebral cortex in P301S tau transgenic mice. This suggests that balanced therapeutic dosing of blood-brain-barrier permeable mTOR-inhibitors can result in a disease-modifying effect in AD and at the same time prevents toxic side effects due to prolonged over activation of autophagy.
    Keywords:  Alzheimer's disease; Autophagy; Mechanistic target of rapamycin (mTOR); PQR530; Rapamycin; Tau
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175301
  28. Anim Nutr. 2022 Dec;11 121-131
    The mechanistic target of rapamycin complex 1 pathway involved in hepatic gluconeogenesis through peroxisome-proliferator-activated receptor γ coactivator-1α.
    Guoyan Wang, Jun Zhang, Shengru Wu, Senlin Qin, Yining Zheng, Chao Xia, Huijun Geng, Junhu Yao, Lu Deng.
      Cattle can efficiently perform de novo generation of glucose through hepatic gluconeogenesis to meet post-weaning glucose demand. Substantial evidence points to cattle and non-ruminant animals being characterized by phylogenetic features in terms of their differing capacity for hepatic gluconeogenesis, a process that is highly efficient in cattle yet the underlying mechanism remains unclear. Here we used a variety of transcriptome data, as well as tissue and cell-based methods to uncover the mechanisms of high-efficiency hepatic gluconeogenesis in cattle. We showed that cattle can efficiently convert propionate into pyruvate, at least partly, via high expression of acyl-CoA synthetase short-chain family member 1 (ACSS1), propionyl-CoA carboxylase alpha chain (PCCA), methylmalonyl-CoA epimerase (MCEE), methylmalonyl-CoA mutase (MMUT), and succinate-CoA ligase (SUCLG2) genes in the liver (P < 0.01). Moreover, higher expression of the rate-limiting enzymes of gluconeogenesis, such as phosphoenolpyruvate carboxykinase (PCK) and fructose 1,6-bisphosphatase (FBP), ensures the efficient operation of hepatic gluconeogenesis in cattle (P < 0.01). Mechanistically, we found that cattle liver exhibits highly active mechanistic target of rapamycin complex 1 (mTORC1), and the expressions of PCCA, MMUT, SUCLG2, PCK, and FBP genes are regulated by the activation of mTORC1 (P < 0.001). Finally, our results showed that mTORC1 promotes hepatic gluconeogenesis in a peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) dependent manner. Collectively, our results not only revealed an important mechanism responsible for the quantitative differences in the efficiency of hepatic gluconeogenesis in cattle versus non-ruminant animals, but also established that mTORC1 is indeed involved in the regulation of hepatic gluconeogenesis through PGC-1α. These results provide a novel potential insight into promoting hepatic gluconeogenesis through activated mTORC1 in both ruminants and mammals.
    Keywords:  Cattle; Hepatic gluconeogenesis; Peroxisome-proliferator-activated receptor γ coactivator-1α; mTORC1
    DOI:  https://doi.org/10.1016/j.aninu.2022.07.010
  29. Front Neurosci. 2022 ;16 978431
    A long-term high-fat diet influences brain damage and is linked to the activation of HIF-1α/AMPK/mTOR/p70S6K signalling.
    Fei Chen, Wen-Min Yi, Sheng-Yuan Wang, Ming-Hao Yuan, Jie Wen, Hong-Yan Li, Qian Zou, Shu Liu, Zhi-You Cai.
      High-fat diets (HFDs) are related to the incidence of obesity and diabetes, but the effect of high-fat diet-induced brain damage remains to be clarified. In our study, we found that 24 weeks of a HFD effectively induced obesity and a change in fur color in mice. In addition, the mice also exhibited deficits in learning and memory. We further found that autophagic flux was impaired in mice after HFD feeding. Hypoxia-inducible factor 1α (HIF-1α) expression was significantly increased in HFD-fed mice, and HFD feeding inhibited adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and induced mechanistic target of rapamycin (mTOR) phosphorylation and p70S6K expression. Treatment of HFD-induced BV2 cell model with palmitic acid (PA) was used to further verify a similar result. We concluded that improving tissue hypoxia or enhancing autophagy through the AMPK/mTOR/p70S6K pathway may be a relevant strategy for improving obesity- and ageing-related disorders.
    Keywords:  AMPK/m TOR pathway; HIF-1α; ageing; autophagy; high-fat (HF) diet; obesity
    DOI:  https://doi.org/10.3389/fnins.2022.978431
  30. Front Cell Dev Biol. 2022 ;10 961983
    Circular RNA-regulated autophagy is involved in cancer progression.
    Xuejian Zhou, Juntao Lin, Feifan Wang, Xianwu Chen, Yan Zhang, Zhenghui Hu, Xiaodong Jin.
      Circular RNAs (circRNAs) are a sort of long, non-coding RNA molecules with a covalently closed continuous ring structure without 5'-3' polarity and poly-A tail. The modulative role of circRNAs in malignant diseases has been elucidated by many studies in recent years via bioinformatics and high-throughput sequencing technologies. Generally, circRNA affects the proliferative, invasive, and migrative capacity of malignant cells via various mechanisms, exhibiting great potential as novel biomarkers in the diagnoses or treatments of malignancies. Meanwhile, autophagy preserves cellular homeostasis, serving as a vital molecular process in tumor progression. Mounting studies have demonstrated that autophagy can not only contribute to cancer cell survival but can also induce autophagic cell death in specific conditions. A growing number of research studies have indicated that there existed abundant associations between circRNAs and autophagy. Herein, we systemically reviewed and discussed recent studies on this topic in different malignancies and concluded that the circRNA-autophagy axis played crucial roles in the proliferation, metastasis, invasion, and drug or radiation resistance of different tumor cells.
    Keywords:  autophagy; cancer; circRNAs; progression; regulation
    DOI:  https://doi.org/10.3389/fcell.2022.961983
  31. Biomed Pharmacother. 2022 Sep 28. pii: S0753-3322(22)01157-X. [Epub ahead of print]155 113768
    Progress in Parkinson's disease animal models of genetic defects: Characteristics and application.
    Chutian Zhang, Shiya Chen, Xiyu Li, Qian Xu, Yao Lin, Fan Lin, Mingzhou Yuan, Yong Zi, Jing Cai.
      Parkinson's disease (PD) is the second major progressive neurodegenerative disease, which critically impacts patients' quality of life. Based on genetics, animal models of genetic defects created by gene editing technology have clear advantages in reflecting PD's pathogenesis and pathological characteristics and exploring potential therapeutic targets for PD. In this review, we summarized animal models of genetic defects in various pathogenesis of PD, including α-synuclein abnormal encoding, autophagy-lysosome system defects, ubiquitin protease system defects, and mitochondria-related dysfunction, and discuss their respective advantages, limitations, and application directions to provide a reference for the application of animal models of PD and research on anti-PD therapy.
    Keywords:  Autophagy-lysosome pathway; Gene editing; Mitochondrial dysfunction; Parkinson's disease; Ubiquitin-proteasome system; α-synuclein
    DOI:  https://doi.org/10.1016/j.biopha.2022.113768
  32. JCI Insight. 2022 Oct 04. pii: e159247. [Epub ahead of print]
    mTOR-neuropeptide Y signaling sensitizes nociceptors to drive neuropathic pain.
    Lunhao Chen, Yaling Hu, Siyuan Wang, Kelei Cao, Weihao Mai, Weilin Sha, Huan Ma, Ling-Hui Zeng, Zhen-Zhong Xu, Yong-Jing Gao, Shumin Duan, Yue Wang, Zhihua Gao.
      Neuropathic pain is a refractory condition that involves de novo protein synthesis in the nociceptive pathway. The mechanistic target of rapamycin (mTOR) is a master regulator of protein translation; however, mechanisms underlying its role in neuropathic pain remain elusive. Using the spared nerve injury-induced neuropathic pain model, we found that mTOR was preferentially activated in large-diameter dorsal root ganglion (DRG) neurons and spinal microglia. However, selective ablation of mTOR in DRG neurons, rather than microglia, alleviated acute neuropathic pain in mice. We showed that injury-induced mTOR activation promoted the transcriptional induction of Npy likely via signal transducer and activator of transcription 3 (STAT3) phosphorylation. NPY further acted primarily on Y2 receptors (Y2R) to enhance neuronal excitability. Peripheral replenishment of NPY reversed pain alleviation upon mTOR removal, whereas Y2R antagonists prevented pain restoration. Our findings reveal an unexpected link between mTOR and NPY/Y2R in promoting nociceptor sensitization and neuropathic pain.
    Keywords:  NPY; Neuroscience; Pain
    DOI:  https://doi.org/10.1172/jci.insight.159247
  33. Sci Rep. 2022 Oct 03. 12(1): 16493
    Activation of RhoC by regulatory ubiquitination is mediated by LNX1 and suppressed by LIS1.
    Stanislav Kholmanskikh, Shawn Singh, M Elizabeth Ross.
      Regulation of Rho GTPases remains a topic of active investigation as they are essential participants in cell biology and the pathophysiology of many human diseases. Non-degrading ubiquitination (NDU) is a critical regulator of the Ras superfamily, but its relevance to Rho proteins remains unknown. We show that RhoC, but not RhoA, is a target of NDU by E3 ubiquitin ligase, LNX1. Furthermore, LNX1 ubiquitination of RhoC is negatively regulated by LIS1 (aka, PAFAH1B1). Despite multiple reports of functional interaction between LIS1 and activity of Rho proteins, a robust mechanism linking the two has been lacking. Here, LIS1 inhibition of LNX1 effects on RhoGDI-RhoC interaction provides a molecular mechanism underpinning the enhanced activity of Rho proteins observed upon reduction in LIS1 protein levels. Since LNX1 and RhoC are only found in vertebrates, the LIS1-LNX1-RhoC module represents an evolutionarily acquired function of the highly conserved LIS1. While these nearly identical proteins have several distinct RhoA and RhoC downstream effectors, our data provide a rare example of Rho-isoform specific, upstream regulation that opens new therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41598-022-19740-1
  34. Front Mol Neurosci. 2022 ;15 944883
    A multifaceted evaluation of microgliosis and differential cellular dysregulation of mammalian target of rapamycin signaling in neuronopathic Gaucher disease.
    Zhenting Zhang, Xiaohong Wang, Yi Lin, Dao Pan.
      Neuronopathic Gaucher disease (nGD) is an inherited neurodegenerative disease caused by mutations in GBA1 gene and is associated with premature death. Neuroinflammation plays a critical role in disease pathogenesis which is characterized by microgliosis, reactive astrocytosis, and neuron loss, although molecular mechanisms leading to neuroinflammation are not well-understood. In this report, we developed a convenient tool to quantify microglia proliferation and activation independently and uncovered abnormal proliferation of microglia (∼2-fold) in an adult genetic nGD model. The nGD-associated pattern of inflammatory mediators pertinent to microglia phenotypes was determined, showing a unique signature favoring pro-inflammatory chemokines and cytokines. Moreover, highly polarized (up or down) dysregulations of mTORC1 signaling with varying lysosome dysfunctions (numbers and volume) were observed among three major cell types of nGD brain. Specifically, hyperactive mTORC1 signaling was detected in all disease-associated microglia (Iba1high) with concurrent increase in lysosome function. Conversely, the reduction of neurons presenting high mTORC1 activity was implicated (including Purkinje-like cells) which was accompanied by inconsistent changes of lysosome function in nGD mice. Undetectable levels of mTORC1 activity and low Lamp1 puncta were noticed in astrocytes of both diseased and normal mice, suggesting a minor involvement of mTORC1 pathway and lysosome function in disease-associated astrocytes. These findings highlight the differences and complexity of molecular mechanisms that are involved within various cell types of the brain. The quantifiable parameters established and nGD-associated pattern of neuroinflammatory mediators identified would facilitate the efficacy evaluation on microgliosis and further discovery of novel therapeutic target(s) in treating neuronopathic Gaucher disease.
    Keywords:  Gaucher disease; Lamp1; Tmem119; disease-associated microglia; mTOR; neurodegenerative disorders; neuroinflammation; reactive astrocytes
    DOI:  https://doi.org/10.3389/fnmol.2022.944883
  35. Mol Neurobiol. 2022 Oct 04.
    Rapamycin Cannot Reduce Seizure Susceptibility in Infantile Rats with Malformations of Cortical Development Lacking mTORC1 Activation.
    Minyoung Lee, Eun-Jin Kim, Min-Jee Kim, Mi-Sun Yum.
      The mechanistic target of the rapamycin (mTOR) pathway is involved in cortical development. However, the efficacy of mTOR inhibitors in malformations of cortical dysplasia (MCD) outside of the tuberous sclerosis complex is unknown. We selected the MCD rat model with prenatal MAM exposure to test the efficacy of mTOR inhibitors in MCDs. We explored the early cortical changes of mTOR pathway protein expression in rats aged P15. We also monitored the early treatment effect of the mTOR inhibitor, rapamycin, on N-methyl-D-aspartate (NMDA)-induced spasms at P15 and their behavior in the juvenile stage. In vivo MR spectroscopy was performed after rapamycin treatment and compared with vehicle controls. There was no difference in mTORC1 pathway protein expression between MAM-exposed MCD rats and controls at P15, and prolonged treatment of rapamycin had no impact on NMDA-induced spasms despite poor weight gain. Prenatal MAM-exposed juvenile rats treated with rapamycin showed increased social approaching and freezing behavior during habituation. MR spectroscopy showed altered neurometabolites, including Gln, Glu+Gln, Tau, and Cr. Despite behavioral changes and in vivo neurometabolic alteration with early prolonged rapamycin treatment, rapamycin had no effect on spasms susceptibility in prenatal MAM-exposed infantile rats with MCD without mTORC1 activation. For MAM-exposed MCD rats without mTORC1 activation, treatment options outside of mTOR pathway inhibitors should be explored.
    Keywords:  Malformations of cortical development (MCD); Methylazoxymethanol (MAM); N-methyl-D-aspartate (NMDA); Rapamycin; mTOR
    DOI:  https://doi.org/10.1007/s12035-022-03033-9
  36. Environ Toxicol. 2022 Oct 03.
    Excessive fluoride impairs autophagy flux in ameloblasts which is prevented by the autophagy activator rapamycin.
    Shuran Yao, Qingqing Weng, Yiying Zhu, Jialiang Liu, Yinyue Luo, Dongxin Da, Ying Zhang.
      Excessive fluoride intake can cause dental fluorosis during teeth development and growth. However, the mechanisms underlying fluoride-induced enamel damage are still not fully elucidated. Previously, we observed fluoride-induced autophagy in ameloblasts, but the effects of fluoride on autophagy flux in ameloblasts remain unclear. Hence, this study aimed to clarify the effects of fluoride and rapamycin, an autophagy activator, on autophagy flux in ameloblasts. This in vitro study used the murine ameloblast-derived cell line LS8. Cells were treated with different concentrations of sodium fluoride (NaF) to evaluate NaF-induced cytotoxicity. Using transmission electron microscopy, we observed an increase in the number of autophagosomes with increasing fluoride concentrations. Western blot analyses showed increases in microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1 (p62) expression after NaF treatment and an increase in LC3II expression after bafilomycin A1 administration. Together with changes in RFP-GFP-LC3 lentivirus expression, this demonstrated that fluoride impaired autophagy flux. Furthermore, we evaluated whether rapamycin can alleviate fluoride-induced cytotoxicity by restoring autophagy flux. Compared to the NaF-treated group, LS8 cells cotreated with NaF and rapamycin grew considerably better and had significantly decreased p62 expression. Taken together, these data suggest that fluoride-induced impaired autophagosome degradation may damage ameloblasts. This provides experimental in vitro evidence and an explanation for the observed NaF-induced toxicity of ameloblasts. Rapamycin probably alleviates this impairment by decreasing the expression of p62, thereby preventing autophagy defects.
    Keywords:  ameloblasts; autophagy; dental fluorosis; fluoride; rapamycin
    DOI:  https://doi.org/10.1002/tox.23677
  37. NPJ Parkinsons Dis. 2022 Oct 06. 8(1): 126
    Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology.
    Alba Navarro-Romero, Irene Fernandez-Gonzalez, Jordi Riera, Marta Montpeyo, Merce Albert-Bayo, Tresa Lopez-Royo, Pablo Castillo-Sanchez, Clara Carnicer-Caceres, Jose Antonio Arranz-Amo, Laura Castillo-Ribelles, Eddie Pradas, Josefina Casas, Miquel Vila, Marta Martinez-Vicente.
      Mutations in the GBA gene that encodes the lysosomal enzyme β-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations as well as GBA knockout cell lines as a in vitro disease modeling system to study the relationship between mutant GBA and the abnormal accumulation of α-synuclein. We performed a deep analysis of the consequences triggered by the presence of mutant GBA protein and the loss of GCase activity in different cellular compartments, focusing primarily on the lysosomal compartment, and analyzed in detail the lysosomal activity, composition, and integrity. The loss of GCase activity generates extensive lysosomal dysfunction, promoting the loss of activity of other lysosomal enzymes, affecting lysosomal membrane stability, promoting intralysosomal pH changes, and favoring the intralysosomal accumulation of sphingolipids and cholesterol. These local events, occurring only at a subcellular level, lead to an impairment of autophagy pathways, particularly chaperone-mediated autophagy, the main α-synuclein degradative pathway. The findings of this study highlighted the role of lysosomal function and lipid metabolism in PD and allowed us to describe a molecular mechanism to understand how mutations in GBA can contribute to an abnormal accumulation of different α-synuclein neurotoxic species in PD pathology.
    DOI:  https://doi.org/10.1038/s41531-022-00397-6
  38. Sci Rep. 2022 Oct 03. 12(1): 16492
    Diesel exhaust particles induce human umbilical vein endothelial cells apoptosis by accumulation of autophagosomes and caspase-8 activation.
    Geun-Young Kim, Inkyo Jung, Minhan Park, Kihong Park, Seung Hee Lee, Won-Ho Kim.
      Diesel exhaust particles (DEP) are risk factors for endothelial cells (ECs) dysfunction. However, the mechanism by which DEP induce ECs apoptosis remains unclear. Here, we investigated how DEP induce death of human umbilical vein ECs (HUVECs), with a focus on the autophagy-mediated apoptotic pathway. DEP induced dose-dependent HUVECs death and exposure to the IC50 concentration of DEP (70 µg/ml) led to apoptosis. DEP phosphorylated Beclin-1 (Ser93) and increased protein levels of p62 and LC3BII and the number of LC3B puncta, indicating autophagy initiation. DEP increased expression of pro- and mature forms of cathepsin D, which increases lysosomal activity. However, DEP suppressed expression of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins (STX17, VAMP8, SNAP29, YKT6, and STX7) to inhibit autolysosome formation, resulting in accumulation of autophagosomes. LC3B, p62, and caspase-8 form a tertiary complex in accumulated autophagosomes, which is known to serve as a platform for caspase-8 activation. Indeed, DEP activates caspase-8 and pretreatment with a caspase-8 inhibitor suppressed DEP-induced apoptosis. Furthermore, depletion of p62 decreased caspase-8 and caspase-3 activation and inhibited the DEP-induced apoptosis. Taken together, these findings demonstrated that DEP induced HUVECs apoptosis by inhibiting autophagosome maturation and identified caspase-8 as a novel mediator of DEP-induced ECs apoptosis.
    DOI:  https://doi.org/10.1038/s41598-022-21044-3
  39. Autophagy. 2022 Oct 05.
    Cardio-, hepato- and pneumoprotective effects of autophagy checkpoint inhibition by targeting DBI/ACBP.
    Omar Motiño, Flavia Lambertucci, Gerasimos Anagnostopoulos, Sijing Li, Isabelle Martins, Guido Kroemer.
      DBI/ACBP (diazepam binding inhibitor, also known as acyl coenzyme A binding protein), acts as a paracrine inhibitor of macroautophagy/autophagy. We characterized a monoclonal antibody neutralizing mouse DBI/ACBP (a-DBI) for its cytoprotective effects on several organs (heart, liver and lung) that were damaged by surgical procedures (ligation of coronary and hepatic arteries or bile duct ligation), a variety of different toxins (acetaminophen, bleomycin, carbon tetrachloride or concanavalin A) or a methionine/choline-deficient diet (MCD). In all these models of organ damage, a-DBI prevents cell loss, inflammation and fibrosis through pathways that are blocked by pharmacological or genetic inhibition of autophagy. The hepatoprotective effects of a-DBI against MCD are mimicked by three alternative strategies to block DBI/ACBP signaling, in particular (i) induction of DBI/ACBP-specific autoantibodies, (ii) tamoxifen-inducible knockout of the Dbi gene, and (iii) a point mutation in Gabrg2 (gamma-aminobutyric acid (GABA) A receptor, subunit gamma 2; Gabrg2F77I) that abolishes binding of DBI/ACBP. We conclude that a-DBI-mediated neutralization of extracellular DBI/ACBP mediates potent autophagy-dependent organ protection by on-target effects, hence unravelling a novel and potentially useful strategy for autophagy enhancement. "Autophagy checkpoint inhibition" (ACI) can be achieved by targeting DBI/ACBP.
    Keywords:  acute liver damage; cirrhosis; cytoprotection; fibrosis; inflammation; lung fibrosis; metabolism; myocardial infarction; non-alcoholic steatohepatitis
    DOI:  https://doi.org/10.1080/15548627.2022.2131241
  40. J Ethnopharmacol. 2022 Sep 30. pii: S0378-8741(22)00815-7. [Epub ahead of print] 115776
    Crosstalk between autophagy and the Keap1-Nrf2-ARE pathway regulates realgar-induced neurotoxicity.
    Weiwei Zhang, Xu Geng, Qing Dong, Xiuhan Li, Ping Ye, Mengyuan Lin, Bin Xu, Hong Jiang.
      ETHNOPHARMACOLOGICAL RELEVANCE: Realgar, the main component of which is As2S2 or As4S4 (≥90%), is a traditional Chinese natural medicine that has been used to treat carbuncles, furuncles, snake and insect bites, abdominal pain caused by parasitic worms, and epilepsy in China for many years. Because realgar contains arsenic, chronic or excessive use of single-flavor realgar and realgar-containing Chinese patent medicine can lead to drug-induced arsenic poisoning, but the exact mechanism underlying its toxicity to the central nervous system is unclear.AIM OF THE STUDY: The aim of this study was to clarify the mechanism of realgar-induced neurotoxicity and to investigate the effects of realgar on autophagy and the Keap1-Nrf2-ARE pathway.
    MATERIALS AND METHODS: We used rats treated with the autophagy inhibitor 3-methyladenine (3-MA) or adeno-associated virus (AAV2/9-r-shRNA-Sqstm1, sh-p62) to investigate realgar-induced neurotoxicity and explore the specific relationship between autophagy and the Keap1-Nrf2-ARE pathway (the Nrf2 pathway) in the cerebral cortex. Molecular docking analysis was used to assess the interactions among the Nrf2, p62 and Keap1 proteins.
    RESULTS: Our results showed that arsenic from realgar accumulated in the brain and blood to cause neuronal and synaptic damage, decrease exploratory behavior and spontaneous movement, and impair memory ability in rats. The mechanism may have involved realgar-mediated autophagy impairment and continuous activation of the Nrf2 pathway via the LC3-p62-Keap1-Nrf2 axis. However, because this activation of the Nrf2 pathway was not sufficient to counteract oxidative damage, apoptosis was aggravated in the cerebral cortex.
    CONCLUSIONS: This study revealed that autophagy, the Nrf2 pathway, and apoptosis are involved in realgar-induced central nervous system toxicity and identified p62 as the hub of the LC3-p62-Keap1-Nrf2 axis in the regulation of autophagy, the Nrf2 pathway, and apoptosis.
    Keywords:  Autophagy; LC3-p62-Keap1-Nrf2 axis; Neurotoxicity; Nrf2 pathway; Realgar
    DOI:  https://doi.org/10.1016/j.jep.2022.115776
  41. Front Cell Dev Biol. 2022 ;10 994037
    New insights into the interplay between autophagy and oxidative and endoplasmic reticulum stress in neuronal cell death and survival.
    Yahao Gao, Changshui Wang, Di Jiang, Gang An, Feng Jin, Junchen Zhang, Guangkui Han, Changmeng Cui, Pei Jiang.
      Autophagy is a dynamic process that maintains the normal homeostasis of cells by digesting and degrading aging proteins and damaged organelles. The effect of autophagy on neural tissue is still a matter of debate. Some authors suggest that autophagy has a protective effect on nerve cells, whereas others suggest that autophagy also induces the death of nerve cells and aggravates nerve injury. In mammals, oxidative stress, autophagy and endoplasmic reticulum stress (ERS) constitute important defense mechanisms to help cells adapt to and survive the stress conditions caused by physiological and pathological stimuli. Under many pathophysiological conditions, oxidative stress, autophagy and ERS are integrated and amplified in cells to promote the progress of diseases. Over the past few decades, oxidative stress, autophagy and ERS and their interactions have been a hot topic in biomedical research. In this review, we summarize recent advances in understanding the interactions between oxidative stress, autophagy and ERS in neuronal cell death and survival.
    Keywords:  autophagy; endoplasmic reticulum stress; neuronal cell death; neuronal cell injury; neuronal cell survival; oxidative stress
    DOI:  https://doi.org/10.3389/fcell.2022.994037
  42. Front Pharmacol. 2022 ;13 977622
    Suppression of endoplasmic reticulum stress-dependent autophagy enhances cynaropicrin-induced apoptosis via attenuation of the P62/Keap1/Nrf2 pathways in neuroblastoma.
    Randong Yang, Shurong Ma, Ran Zhuo, Lingqi Xu, Siqi Jia, Pengcheng Yang, Ye Yao, Haibo Cao, Liya Ma, Jian Pan, Jian Wang.
      Autophagy has dual roles in cancer, resulting in cellular adaptation to promote either cell survival or cell death. Modulating autophagy can enhance the cytotoxicity of many chemotherapeutic and targeted drugs and is increasingly considered to be a promising cancer treatment approach. Cynaropicrin (CYN) is a natural compound that was isolated from an edible plant (artichoke). Previous studies have shown that CYN exhibits antitumor effects in several cancer cell lines. However, it anticancer effects against neuroblastoma (NB) and the underlying mechanisms have not yet been investigated. More specifically, the regulation of autophagy in NB cells by CYN has never been reported before. In this study, we demonstrated that CYN induced apoptosis and protective autophagy. Further mechanistic studies suggested that ER stress-induced autophagy inhibited apoptosis by activating the p62/Keap1/Nrf2 pathways. Finally, in vivo data showed that CYN inhibited tumour growth in xenografted nude mice. Overall, our findings suggested that CYN may be a promising candidate for the treatment of NB, and the combination of pharmacological inhibitors of autophagy may hold novel therapeutic potential for the treatment of NB. Our paper will contribute to the rational utility and pharmacological studies of CYN in future anticancer research.
    Keywords:  apoptosis; autophagy; cynaropicrin; neuroblastoma; p62/Keap1/Nrf2
    DOI:  https://doi.org/10.3389/fphar.2022.977622
  43. Life Sci Alliance. 2022 Nov;pii: e202201530. [Epub ahead of print]5(11):
    Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons.
    Susanne Bauer, Lars Dittrich, Lech Kaczmarczyk, Melvin Schleif, Rui Benfeitas, Walker S Jackson.
      Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, including fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD), different mutations in the Prnp gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice. To define affected cell types, we analyzed cell type-specific translatomes from six neuron types of 9 mo old FFI and CJD mice. Somatostatin (SST) neurons responded the strongest in both diseases, with unexpectedly high overlap in genes and pathways. Functional analyses revealed up-regulation of neurodegenerative disease pathways and ribosome and mitochondria biogenesis, and down-regulation of synaptic function and small GTPase-mediated signaling in FFI, implicating down-regulation of mTOR signaling as the root of these changes. In contrast, responses in glutamatergic cerebellar neurons were disease-specific. The high similarity in SST neurons of FFI and CJD mice suggests that a common therapy may be beneficial for multiple genetic prion diseases.
    DOI:  https://doi.org/10.26508/lsa.202201530
  44. Cell Adh Migr. 2022 Dec;16(1): 107-114
    Activation of GRP78 ATPase suppresses A549 lung cancer cell migration by promoting ITGB4 degradation.
    Junya Ning, Xiaoling Cui, Nan Li, Na Li, Baoxiang Zhao, Junying Miao, Zhaomin Lin.
      Hypochlorous acid (HOCl) is an essential signal molecule in cancer cells. Activated GRP78 ATPase by a HOCl probe named ZBM-H inhibits lung cancer cell growth. However, the role and underlying mechanism of GRP78 ATPase in lung cancer cell migration have not been established. Here, we reported that activation of GRP78 ATPase by ZBM-H suppressed A549 cell migration and inhibited EMT process. Notably, ZBM-H time-dependently decreased the protein level of integrin β4 (ITGB4) in A549 cells. Combinatorial treatment of 3BDO (an autophagy inhibitor) and ZBM-H partially rescued the protein level of ITGB4. Consistently, 3BDO partially reversed ZBM-H-inhibited cell migration. Furthermore, ZBM-H promoted the interaction between ANXA7 and Hsc70, which participated in the regulation of selective autophagy and degradation of ITGB4.
    Keywords:  Integrin β4; cell migration; glucose-regulated protein 78; hypochlorous acid probe; lung cancer cells
    DOI:  https://doi.org/10.1080/19336918.2022.2130415
  45. Curr Mol Pharmacol. 2022 Oct 05.
    Fathoming the role of mTOR in diabetes mellitus and its complications.
    Faheem, S Shanthi.
      Mechanistic/Mammalian target of rapamycin (mTOR) orchestrates cellular homeostasis by controlling cell growth, proliferation, metabolism, and survival by integrating various growth factors, nutrients, amino acids. Eccentric synchronization of mTOR has been incriminated in various diseases/disorders like cancer, neurodegenerative disorders, and diabetes mellitus and its complications. Recent reports also highlight the role of mTOR in diabetes and its associated complications. This review tries to fathom the role of mTOR signaling in diabetes mellitus and its complications- diabetic cardiomyopathy, diabetic nephropathy, and diabetic retinopathy and highlights mTOR as a putative target for the development of novel anti-diabetic drug candidates.
    Keywords:  Apoptosis; Diabetes mellitus; Diabetic cardiomyopathy; Diabetic nephropathy; Diabetic retinopathy; Insulin resistance; mTOR
    DOI:  https://doi.org/10.2174/1874467215666221005123919
  46. Biochem Biophys Res Commun. 2022 Sep 24. pii: S0006-291X(22)01334-1. [Epub ahead of print]631 130-137
    HIF-1α regulates mTOR signaling pathway during salivary gland development.
    Tomomasa Kimura, Manabu Sakai, Nao Gojo, Mikio Watanabe, Narikazu Uzawa, Takayoshi Sakai.
      The mammalian target of rapamycin (mTOR)-composed of multiple complexes, including mTOR complex 1/2 (mTORC1/2)-is a serine-threonine kinase that regulates embryonic development. The transcription factor, hypoxia-inducible factor-1α (HIF-1α), is also involved in embryonic development. As the relationship between mTOR and HIF-1α during embryonic development remains unclear, we investigated the relationship between the two using ex vivo submandibular salivary gland organ cultures. When the expression of HIF-1α increased under hypoxic conditions (1% O2), the expression of mTOR signaling pathway-related proteins decreased. Conversely, when the expression of HIF-1α decreased, the expression of mTOR signaling pathway-related proteins increased. These results indicate a strong relationship between HIF-1α and the mTOR signaling pathway. For the first time, we clarified that HIF-1α negatively regulates the mTOR signaling pathway and suppresses salivary gland development under 1% O2 using small molecules. Our research provides new insights into the relationship between HIF-1α and the mTOR signaling pathway in embryonic organ development.
    Keywords:  Development; HIF-1α; Hypoxia; Salivary glands; mTOR signaling
    DOI:  https://doi.org/10.1016/j.bbrc.2022.09.078
  47. Curr Treat Options Oncol. 2022 Oct 05.
    The Role of Autophagy in Childhood Central Nervous System Tumors.
    Yafeng Wang, Yiran Xu, Changlian Zhu.
      OPINION STATEMENT: Autophagy is a physiological process that occurs in normal tissues. Under external environmental pressure or internal environmental changes, cells can digest part of their contents through autophagy in order to reduce metabolic pressure or remove damaged organelles. In cancer, autophagy plays a paradoxical role, acting as a tumor suppressor-by removing damaged organelles and inhibiting inflammation or by promoting genome stability and the tumor-adaptive responses-as a pro-survival mechanism to protect cells from stress. In this article, we review the autophagy-dependent mechanisms driving childhood central nervous system tumor cell death, malignancy invasion, chemosensitivity, and radiosensitivity. Autophagy inhibitors and inducers have been developed, and encouraging results have been achieved in autophagy modulation, suggesting that these might be potential therapeutic agents for the treatment of pediatric central nervous system (CNS) tumors.
    Keywords:  Autophagy; Cell death; Central nervous system tumors; Chemosensitivity; Children; Radiosensitivity
    DOI:  https://doi.org/10.1007/s11864-022-01015-6
  48. J Physiol Biochem. 2022 Oct 04.
    RBM3 interacts with Raptor to regulate autophagy and protect cardiomyocytes from ischemia-reperfusion-induced injury.
    Nan Wang, Limeiting Wang, Changyan Li, Peng Rao, Xun Wang, Yazhou Xu, Lin Yang, Lin Sun, Di Lu.
      Acute myocardial infarction (AMI) is a common disease with high morbidity and mortality worldwide. However, postinfarction pathogenesis remains unclear, and it is particularly important to identify new therapeutic targets. The RNA-binding motif protein RBM3 (also known as cold-inducible protein) is known to promote translation and is associated with tumor proliferation and neuroprotection. However, little is known about the biological effects of RBM3 on myocardial infarction. In the present study, we found that RBM3 expression was significantly upregulated in ischemia-reperfusion (I/R) condition and downregulation of RBM3 inhibited autophagy and promoted apoptosis in cardiomyocytes. We confirmed that RBM3 interacts with Raptor to regulate the autophagy pathway. Taken together, these findings illustrate the protective effects of RBM3 against I/R-induced myocardial apoptosis through the autophagy pathway.
    Keywords:  Acute myocardial infarction; Apoptosis; Autophagy; Ischemia–reperfusion; RNA-binding motif protein 3
    DOI:  https://doi.org/10.1007/s13105-022-00919-z
  49. Cell Prolif. 2022 Oct 05. e13327
    Mitophagy: A novel perspective for insighting into cancer and cancer treatment.
    Congkuan Song, Shize Pan, Jinjin Zhang, Ning Li, Qing Geng.
      BACKGROUND: Mitophagy refers to the selective self-elimination of mitochondria under damaged or certain developmental conditions. As an important regulatory mechanism to remove damaged mitochondria and maintain the internal and external cellular balance, mitophagy plays pivotal roles in carcinogenesis and progression as well as treatment.MATERIALS AND METHODS: Here, we combined data from recent years to comprehensively describe the regulatory mechanisms of mitophagy and its multifaceted significance in cancer, and discusse the potential of targeted mitophagy as a cancer treatment strategy.
    RESULTS: The molecular mechanisms regulating mitophagy are complex, diverse, and cross-talk. Inducing or blocking mitophagy has the same or completely different effects in different cancer contexts. Mitophagy plays an indispensable role in regulating cancer metabolic reprogramming, cell stemness, and chemotherapy resistance for better adaptation to tumor microenvironment. In cancer cell biology, mitophagy is considered to be a double-edged sword. And to fully understand the role of mitophagy in cancer development can provide new targets for cancer treatment in clinical practice.
    CONCLUSIONS: This review synthesizes a large body of data to comprehensively describe the molecular mechanisms of mitophagy and its multidimensional significance in cancer and cancer treatment, which will undoubtedly deepen the understanding of mitophagy.
    DOI:  https://doi.org/10.1111/cpr.13327
  50. Oxid Med Cell Longev. 2022 ;2022 2849985
    Mitophagy: A Potential Target for Pressure Overload-Induced Cardiac Remodelling.
    Ruochen Shao, Junli Li, Tianyi Qu, Yanbiao Liao, Mao Chen.
      The pathological mechanisms underlying cardiac remodelling and cardiac dysfunction caused by pressure overload are poorly understood. Mitochondrial damage and functional dysfunction, including mitochondrial bioenergetic disorder, oxidative stress, and mtDNA damage, contribute to heart injury caused by pressure overload. Mitophagy, an important regulator of mitochondrial homeostasis and function, is triggered by mitochondrial damage and participates in the pathological process of cardiovascular diseases. Recent studies indicate that mitophagy plays a critical role in the pressure overload model, but evidence on the causal relationship between mitophagy abnormality and pressure overload-induced heart injury is inconclusive. This review summarises the mechanism, role, and regulation of mitophagy in the pressure overload model. It also pays special attention to active compounds that may regulate mitophagy in pressure overload, which provide clues for possible clinical applications.
    DOI:  https://doi.org/10.1155/2022/2849985
  51. J Biochem Mol Toxicol. 2022 Oct 03. e23237
    ATL1 inhibits the proliferation and invasion of trophoblast cells via inhibition of the mTOR signaling pathway.
    Guanli Zhang, Yan Feng, Min Wang, Xin Liu.
      Pre-eclampsia (PE) is a major cause of hypertension in maternal and fetal. Atlastin-1 (ATL1), one regulator of endoplasmic reticulum (ER) morphology, participates in tubular ER formation and protein synthesis. The objective of this study is to investigate the role and molecular mechanism of ATL1 in PE. GEO databases showed that ATL1 was upregulated in PE patients. Our data also found that ATL1 was highly expressed in PE placental tissues. The cell viability, proliferation, migration, and invasion of HTR-8/SVneo cells increased/decreased after the downregulation/upregulation of ATL1. The mTOR pathway is the downstream pathway of ATL1. The levels of p-p70S6K and p-mTOR were increased/decreased after the downregulation/upregulation of ATL1. Moreover, rapamycin, an inhibitor of mTOR pathway, reversed the promotive effect of siATL1 on proliferation, migration, and invasion in HTR-8/SVneo cells. In conclusion, ATL1 inhibits the proliferation and invasion of trophoblast cells via the inhibition of the mTOR signaling pathway in HTR-8/SVneo cells.
    Keywords:  invasion; mTOR pathway; migration; pre-eclampsia; proliferation
    DOI:  https://doi.org/10.1002/jbt.23237
  52. Rejuvenation Res. 2022 Oct 07.
    Restoration of lysosomal and mitochondrial function through p38 MAPK inhibition ameliorates senescence.
    Ji Yun Park, Haneur Lee, Eun Seon Song, Yun Haeng Lee, Myeong Uk Kuk, Gahyun Ko, Hyung Wook Kwon, Youngjoo Byun, Joon Tae Park.
      Oncogene-induced senescence (OIS), characterized by irreversible cell cycle arrest by oncogene activation, plays an important role in the pathogenesis of aging and age-related diseases. Recent research indicates that OIS is driven by activation of mitogen-activated protein kinase (MAPK). However, it is not apparent whether MAPK inhibition helps to recover senescence. In our previous study, we uncovered p38 MAPK inhibitor, SB203580, as an effective agent to reduce ROS and increase proliferation in premature senescent cells. In this study, we evaluated whether SB203580 could ameliorate senescence in normal senescent cells. The senescence-improving effect was observed in the results that SB203580 treatment restored lysosomal function, as evidenced by a decrease in lysosomal mass and an increase in autophagic vacuoles. Then, SB203580-mediated lysosomal function restoration triggered the clearance of damaged mitochondria, leading to metabolic reprogramming necessary for amelioration of senescence. Indeed, p38 MAPK inhibition by SB203580 improved key senescent phenotypes. Our findings suggest a novel mechanism by which modulation of p38 MAPK activity leads to senescence improvement through functional restoration of lysosome and mitochondria.
    DOI:  https://doi.org/10.1089/rej.2022.0043
  53. Med Res Rev. 2022 Oct 08.
    Mitochondrial quality control proteases and their modulation for cancer therapy.
    Jiangnan Zhang, Wenliang Qiao, Youfu Luo.
      Mitochondria, the main provider of energy in eukaryotic cells, contains more than 1000 different proteins and is closely related to the development of cells. However, damaged proteins impair mitochondrial function, further contributing to several human diseases. Evidence shows mitochondrial proteases are critically important for protein maintenance. Most importantly, quality control enzymes exert a crucial role in the modulation of mitochondrial functions by degrading misfolded, aged, or superfluous proteins. Interestingly, cancer cells thrive under stress conditions that damage proteins, so targeting mitochondrial quality control proteases serves as a novel regulator for cancer cells. Not only that, mitochondrial quality control proteases have been shown to affect mitochondrial dynamics by regulating the morphology of optic atrophy 1 (OPA1), which is closely related to the occurrence and progression of cancer. In this review, we introduce mitochondrial quality control proteases as promising targets and related modulators in cancer therapy with a focus on caseinolytic protease P (ClpP), Lon protease (LonP1), high-temperature requirement protein A2 (HrtA2), and OMA-1. Further, we summarize our current knowledge of the advances in clinical trials for modulators of mitochondrial quality control proteases. Overall, the content proposed above serves to suggest directions for the development of novel antitumor drugs.
    Keywords:  activator; cancer therapy; inhibitor; mitochondrial proteases; quality control
    DOI:  https://doi.org/10.1002/med.21929
  54. Nat Rev Mol Cell Biol. 2022 Oct 07.
    Phosphoinositide signal for lysosomal membrane repair.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s41580-022-00550-2
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