bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023‒12‒03
sixty-one papers selected by
Viktor Korolchuk, Newcastle University
  1. Peroxisome Proliferator-Activated Receptor γ Regulates Lipid Metabolism in Sheep Trophoblast Cells through mTOR Pathway-Mediated Autophagy.
  2. Clearance of β-amyloid mediated by autophagy is enhanced by MTORC1 inhibition but not AMPK activation in APP/PSEN1 astrocytes.
  3. Communication between small cytosolic dsDNA and autophagy inhibits CGAS (cyclic GMP-AMP synthase) activation.
  4. CARM1 drives mitophagy and autophagy flux during fasting-induced skeletal muscle atrophy.
  5. Trehalose enhances mitochondria deficits in human NPC1 mutant fibroblasts but disrupts mouse Purkinje cell dendritic growth ex vivo.
  6. Metabolic control of mitophagy.
  7. TRIM22 facilitates autophagosome-lysosome fusion by mediating the association of GABARAPs and PLEKHM1.
  8. TRAF6 triggers Mycobacterium-infected host autophagy through Rab7 ubiquitination.
  9. Hepatocyte-specific regulation of autophagy and inflammasome activation via MyD88 during lethal Ehrlichia infection.
  10. What's in an E3: role of highly curved membranes in facilitating LC3-phosphatidylethanolamine conjugation during autophagy.
  11. Proteostasis and neurodegeneration: a closer look at autophagy in Alzheimer's disease.
  12. HMGB1 in the interplay between autophagy and apoptosis in cancer.
  13. Autophagy promotes cell death induced by hydrogen peroxide in Physcomitrium patens.
  14. Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice.
  15. Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson's disease.
  16. Classical swine fever virus NS5A protein activates autophagy via the PP2A-DAPK3-Beclin 1 axis.
  17. Basal activity of PINK1 and PRKN in cell models and rodent brain.
  18. Not all kidney cysts are created equal: a distinct renal cystogenic mechanism in tuberous sclerosis complex (TSC).
  19. Mitochondrial protein BNIP3 regulates Chikungunya virus replication in the early stages of infection.
  20. Restoring the infected powerhouse: Mitochondrial quality control in sepsis.
  21. The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.
  22. The mTOR pathway and transgenic animals with deletion of the TSC gene in the regeneration of the nervous system and selected models of sciatic nerve damage
  23. Canonical and Non-Canonical Roles of SNX1 and SNX2 in Endosomal Membrane Dynamics.
  24. BNIP3 as a new tool to promote healthy brain aging.
  25. Advances in the investigation of the role of autophagy in the etiology of chronic obstructive pulmonary disease: A review.
  26. Nuclear localization of STING1 competes with canonical signaling to activate AHR for commensal and intestinal homeostasis.
  27. mTORC1 Mediates Biphasic Mechano-Response to Orchestrate Adhesion-Dependent Cell Growth and Anoikis Resistance.
  28. Protein modification regulated autophagy in Bombyx mori and Drosophila melanogaster.
  29. ACO2 deficiency increases vulnerability to Parkinson's disease via dysregulating mitochondrial function and histone acetylation-mediated transcription of autophagy genes.
  30. In vitro anticancer effect of azithromycin targeting hypoxic lung cancer cells via the inhibition of mitophagy.
  31. Coxiella burnetii Pathogenesis: Emphasizing the Role of the Autophagic Pathway.
  32. Mechanistic target of rapamycin in regulating macrophage function in inflammatory cardiovascular diseases.
  33. PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.
  34. Review title: Mechanisms of mitochondrial reorganization.
  35. Mitophagy in human health, ageing and disease.
  36. Analyzing Mitochondrial Function in a Drosophila melanogaster PINK1B9-Null Mutant Using High-resolution Respirometry.
  37. Treatment of calcific arterial disease via enhancement of autophagy using GSK343.
  38. The role of lysosomes as intermediates in betacoronavirus PHEV egress from nerve cells.
  39. LYC inhibits the AKT signaling pathway to activate autophagy and ameliorate TGFB-induced renal fibrosis.
  40. [Research progress on the mechanism of action of mitophagy in the occurrence and development of liver cancer].
  41. Clarithromycin overcomes stromal cell-mediated drug resistance against proteasome inhibitors in myeloma cells via autophagy flux blockage leading to high NOXA expression.
  42. ZNFX1 promotes AMPK-mediated autophagy against Mycobacterium tuberculosis by stabilizing mRNA.
  43. GCN2 mediates access to stored amino acids for somatic maintenance during Drosophila ageing.
  44. Trehalose-Bearing Carriers to Target Impaired Autophagy and Protein Aggregation Diseases.
  45. Melittin kills A549 cells by targeting mitochondria and blocking mitophagy flux.
  46. Genomic profile of Parkinson's disease in Asians.
  47. miR-93 and synaptotagmin-7: two novel players in the regulation of autophagy during cardiac hypertrophy.
  48. Cardiovascular Aging: Spotlight on Mitochondria.
  49. Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype.
  50. Evolutionary arms race between SARS-CoV-2 and interferon signaling via dynamic interaction with autophagy.
  51. Mitochondrial quality control in health and cardiovascular diseases.
  52. Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.
  53. Impairment of Autophagy Mediates the Uric-Acid-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells.
  54. mTOR hypoactivity leads to trophectoderm cell failure by enhancing lysosomal activation and disrupting the cytoskeleton in preimplantation embryo.
  55. Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma.
  56. Restoring autophagic function: a case for type 2 diabetes mellitus drug repurposing in Parkinson's disease.
  57. Nrf1 is not a direct target gene of SREBP1, albeit both are integrated into the rapamycin-responsive regulatory network in human hepatoma cells.
  58. Stress granules plug holes.
  59. Enhanced VEGF secretion and blood-brain barrier disruption: Radiation-mediated inhibition of astrocyte autophagy via PI3K-AKT pathway activation.
  60. Heat Shock Protein 90 in Parkinson's disease: Profile of a serial killer.
  61. Uric Acid Mitigates Cognitive Deficits via TFEB-Mediated Microglial Autophagy in Mice Models of Alzheimer's Disease.
  1. PPAR Res. 2023 ;2023 6422804
    Peroxisome Proliferator-Activated Receptor γ Regulates Lipid Metabolism in Sheep Trophoblast Cells through mTOR Pathway-Mediated Autophagy.
    Kexing Hao, Jing Wang, Hengbin Yu, Lei Chen, Weibin Zeng, Zhengrong Wang, Guangdong Hu.
      Peroxisome proliferator-activated receptor gamma (PPARγ) is a key nuclear receptor transcription factor that is highly expressed in trophoblastic cells during embryonic attachment and is accompanied by rapid cell proliferation and increased lipid accumulation. We previously showed that the autophagy pathway is activated in cells after activation of PPARγ, accompanied by increased lipid accumulation. In this study, we used PPARγ agonist rosiglitazone and inhibitor GW9662, as well as autophagy activator rapamycin and inhibitor 3-methyladenine, to unravel the probable mechanism of PPARγ engaged in lipid metabolism in sheep trophoblast cells (STCs). After 12 h, 24 h, and 48 h of drug treatment, the levels of autophagy-related proteins were detected by Western blot, the triglyceride content and MDA level of cells were detected by colorimetry, and the lipid droplets and lysosomes were localized by immunofluorescence. We found that PPARγ inhibited the activity of mammalian target of rapamycin (mTOR) pathway in STCs for a certain period of time, promoted the increase of autophagy and lysosome formation, and enhanced the accumulation of lipid droplets and triglycerides. Compared with cells whose PPARγ function is activated, blocking autophagy before activating PPARγ will hinder lipid accumulation in STCs. Pretreatment of cells with rapamycin promoted autophagy with results similar to rosiglitazone treatment, while inhibition of autophagy with 3-methyladenine reduced lysosome and lipid accumulation. Based on these observations, we conclude that PPARγ can induce autophagy by blocking the mTOR pathway, thereby promoting the accumulation of lipid droplets and lysosomal degradation, providing an energy basis for the rapid proliferation of trophoblast cells during embryo implantation. In brief, this study partially revealed the molecular regulatory mechanism of PPARγ, mTOR pathway, and autophagy on trophoblast cell lipid metabolism, which provides a theoretical basis for further exploring the functional regulatory network of trophoblast cells during the attachment of sheep embryos.
    DOI:  https://doi.org/10.1155/2023/6422804
  2. Glia. 2023 Nov 27.
    Clearance of β-amyloid mediated by autophagy is enhanced by MTORC1 inhibition but not AMPK activation in APP/PSEN1 astrocytes.
    Marta García-Juan, Lara Ordóñez-Gutiérrez, Francisco Wandosell.
      Proteostasis mechanisms mediated by macroautophagy/autophagy are altered in neurodegenerative diseases such as Alzheimer disease (AD) and their recovery/enhancement has been proposed as a therapeutic approach. From the two central nodes in the anabolism-catabolism balance, it is generally accepted that mechanistic target of rapamycin kinase complex 1 (MTORC1)_ activation leads to the inhibition of autophagy, whereas adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) has the opposite role. In AD, amyloid beta (Aβ) production disturbs the optimal neuronal/glial proteostasis. As astrocytes are essential for brain homeostasis, the purpose of this work was to analyze if the upregulation of autophagy in this cell type, either by MTORC1 inhibition or AMPK activation, could modulate the generation/degradation of β-amyloid. By using primary astrocytes from amyloid beta precursor protein (APP)/Presenilin 1 (PSEN1) mouse model of AD, we confirmed that MTORC1 inhibition reduced Aβ secretion through moderate autophagy induction. Surprisingly, pharmacologically increased activity of AMPK did not enhance autophagy but had different effects on Aβ secretion. Conversely, AMPK inhibition did not affect autophagy but reduced Aβ secretion. These puzzling data were confirmed through the overexpression of different mutant AMPK isoforms: while only the constitutively active AMPK increased autophagy, all versions augmented Aβ secretion. We conclude that AMPK has a significantly different role in primary astrocytes than in other reported cells, similar to our previous findings in neurons. Our data support that perhaps only a basal AMPK activity is needed to maintain autophagy whereas the increased activity, either physiologically or pharmacologically, has no direct effect on autophagy-dependent amyloidosis. These results shed light on the controversy about the therapeutic effect of AMPK activation on autophagy induction.
    Keywords:  AICAR; Alzheimer; amyloid accumulation; autophagy; cultured astrocytes; metformin; rapamycin
    DOI:  https://doi.org/10.1002/glia.24492
  3. Autophagy. 2023 Nov 27. 1-3
    Communication between small cytosolic dsDNA and autophagy inhibits CGAS (cyclic GMP-AMP synthase) activation.
    Yu-Wei Luo, Hongyu Ji, Ai-Long Huang, Kai-Fu Tang.
      The CGAS (cyclic GMP-AMP synthase)-STING1 (stimulator of interferon response cGAMP interactor 1) pathway is an important innate immune pathway that induces proinflammatory cytokine production following stimulation with dsDNA > 45 bp. We recently identified a class of ~ 20-40 bp small cytosolic dsDNA (scDNA) that blocks CGAS-STING1 activation. In this punctum, we discuss the mechanism underlying the inhibition of CGAS-STING1 activation via scDNA. scDNA binds to CGAS but cannot activate its enzymatic activity. It competes with dsDNA > 45 bp for binding with CGAS to inhibit CGAS-STING1 activation. Moreover, scDNA activates macroautophagy/autophagy and induces the autophagic degradation of STING1 and long dsDNA. Autophagy then increases scDNA levels, driving a feedback loop that accelerates the degradation of STING1 and long cytosolic dsDNA. These findings reveal that mutual communication between scDNA and autophagy inhibits CGAS-STING1 activation following stimulation with dsDNA > 45 bp.
    Keywords:  DNA damage; PIK3C3; STING1; interferon-β; small cytosolic double-stranded DNA
    DOI:  https://doi.org/10.1080/15548627.2023.2285612
  4. Autophagy. 2023 Nov 29.
    CARM1 drives mitophagy and autophagy flux during fasting-induced skeletal muscle atrophy.
    Derek W Stouth, Tiffany L vanLieshout, Andrew I Mikhail, Sean Y Ng, Rozhin Raziee, Brittany A Edgett, Goutham Vasam, Erin K Webb, Kevin S Gilotra, Matthew Markou, Hannah C Pineda, Brianna G Bettencourt-Mora, Haleema Noor, Zachary Moll, Megan E Bittner, Brendon J Gurd, Keir J Menzies, Vladimir Ljubicic.
      CARM1 (coactivator associated arginine methyltransferase 1) has recently emerged as a powerful regulator of skeletal muscle biology. However, the molecular mechanisms by which the methyltransferase remodels muscle remain to be fully understood. In this study, carm1 skeletal muscle-specific knockout (mKO) mice exhibited lower muscle mass with dysregulated macroautophagic/autophagic and atrophic signaling, including depressed AMP-activated protein kinase (AMPK) site-specific phosphorylation of ULK1 (unc-51 like autophagy activating kinase 1; Ser555) and FOXO3 (forkhead box O3; Ser588), as well as MTOR (mechanistic target of rapamycin kinase)-induced inhibition of ULK1 (Ser757), along with AKT/protein kinase B site-specific suppression of FOXO1 (Ser256) and FOXO3 (Ser253). In addition to lower mitophagy and autophagy flux in skeletal muscle, carm1 mKO led to increased mitochondrial PRKN/parkin accumulation, which suggests that CARM1 is required for basal mitochondrial turnover and autophagic clearance. carm1 deletion also elicited PPARGC1A (PPARG coactivator 1 alpha) activity and a slower, more oxidative muscle phenotype. As such, these carm1 mKO-evoked adaptations disrupted mitophagy and autophagy induction during food deprivation and collectively served to mitigate fasting-induced muscle atrophy. Furthermore, at the threshold of muscle atrophy during food deprivation experiments in humans, skeletal muscle CARM1 activity decreased similarly to our observations in mice, and was accompanied by site-specific activation of ULK1 (Ser757), highlighting the translational impact of the methyltransferase in human skeletal muscle. Taken together, our results indicate that CARM1 governs mitophagic, autophagic, and atrophic processes fundamental to the maintenance and remodeling of muscle mass. Targeting the enzyme may provide new therapeutic approaches for mitigating skeletal muscle atrophy.
    Keywords:  Atrophy; autophagy; coactivator-associated arginine methyltransferase 1; fasting; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1080/15548627.2023.2288528
  5. PLoS One. 2023 ;18(11): e0294312
    Trehalose enhances mitochondria deficits in human NPC1 mutant fibroblasts but disrupts mouse Purkinje cell dendritic growth ex vivo.
    Collin M MacLeod, Fawad A K Yousufzai, Liam T Spencer, Sarah Kim, Lucianne A Rivera-Rosario, Zerian D Barrera, Lindsay Walsh, Claude Krummenacher, Benjamin Carone, Ileana Soto.
      Lysosomes play important roles in catabolism, nutrient sensing, metabolic signaling, and homeostasis. NPC1 deficiency disrupts lysosomal function by inducing cholesterol accumulation that leads to early neurodegeneration in Niemann-Pick type C (NPC) disease. Mitochondria pathology and deficits in NPC1 deficient cells are associated with impaired lysosomal proteolysis and metabolic signaling. It is thought that activation of the transcription factor TFEB, an inducer of lysosome biogenesis, restores lysosomal-autophagy activity in lysosomal storage disorders. Here, we investigated the effect of trehalose, a TFEB activator, in the mitochondria pathology of NPC1 mutant fibroblasts in vitro and in mouse developmental Purkinje cells ex vivo. We found that in NPC1 mutant fibroblasts, serum starvation or/and trehalose treatment, both activators of TFEB, reversed mitochondria fragmentation to a more tubular mitochondrion. Trehalose treatment also decreased the accumulation of Filipin+ cholesterol in NPC1 mutant fibroblasts. However, trehalose treatment in cerebellar organotypic slices (COSCs) from wild-type and Npc1nmf164 mice caused mitochondria fragmentation and lack of dendritic growth and degeneration in developmental Purkinje cells. Our data suggest, that although trehalose successfully restores mitochondria length and decreases cholesterol accumulation in NPC1 mutant fibroblasts, in COSCs, Purkinje cells mitochondria and dendritic growth are negatively affected possibly through the overactivation of the TFEB-lysosomal-autophagy pathway.
    DOI:  https://doi.org/10.1371/journal.pone.0294312
  6. Eur J Clin Invest. 2023 Dec 01. e14138
    Metabolic control of mitophagy.
    Andreas Zimmermann, Frank Madeo, Abhinav Diwan, Junichi Sadoshima, Simon Sedej, Guido Kroemer, Mahmoud Abdellatif.
      Mitochondrial dysfunction is a major hallmark of ageing and related chronic disorders. Controlled removal of damaged mitochondria by the autophagic machinery, a process known as mitophagy, is vital for mitochondrial homeostasis and cell survival. The central role of mitochondria in cellular metabolism places mitochondrial removal at the interface of key metabolic pathways affecting the biosynthesis or catabolism of acetyl-coenzyme A, nicotinamide adenine dinucleotide, polyamines, as well as fatty acids and amino acids. Molecular switches that integrate the metabolic status of the cell, like AMP-dependent protein kinase, protein kinase A, mechanistic target of rapamycin and sirtuins, have also emerged as important regulators of mitophagy. In this review, we discuss how metabolic regulation intersects with mitophagy. We place special emphasis on the metabolic regulatory circuits that may be therapeutically targeted to delay ageing and mitochondria-associated chronic diseases. Moreover, we identify outstanding knowledge gaps, such as the ill-defined distinction between basal and damage-induced mitophagy, which must be resolved to boost progress in this area.
    Keywords:  AMPK; NAD; acetyl-CoA; ageing; ageing-related disease; metabolism; mitophagy; spermidine
    DOI:  https://doi.org/10.1111/eci.14138
  7. Autophagy. 2023 Nov 27.
    TRIM22 facilitates autophagosome-lysosome fusion by mediating the association of GABARAPs and PLEKHM1.
    Hansol Heo, Hyungsun Park, Myung Shin Lee, Jongyoon Kim, Juyeong Kim, Soon-Young Jung, Sun Kyeon Kim, Seongju Lee, Jaerak Chang.
      Tripartite motif (TRIM) proteins are a large family of E3 ubiquitin ligases implicated in antiviral defense systems, tumorigenesis, and protein quality control. TRIM proteins contribute to protein quality control by regulating the ubiquitin-proteasome system, endoplasmic reticulum-associated degradation, and macroautophagy/autophagy. However, the detailed mechanisms through which various TRIM proteins regulate downstream events have not yet been fully elucidated. Herein, we identified a novel function of TRIM22 in the regulation of autophagy. TRIM22 promotes autophagosome-lysosome fusion by mediating the association of GABARAP family proteins with PLEKHM1, thereby inducing the autophagic clearance of protein aggregates, independent of its E3 ubiquitin ligase activity. Furthermore, a TRIM22 variant associated with early-onset familial Alzheimer disease interferes with autophagosome-lysosome fusion and autophagic clearance. These findings suggest TRIM22 as a critical autophagic regulator that orchestrates autophagosome-lysosome fusion by scaffolding autophagy-related proteins, thus representing a potential therapeutic target in neurodegenerative diseases.
    Keywords:  Alzheimer disease; PLEKHM1; TRIM22; autophagosome-lysosome fusion; autophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2287925
  8. Cell Death Discov. 2023 Nov 28. 9(1): 427
    TRAF6 triggers Mycobacterium-infected host autophagy through Rab7 ubiquitination.
    Qinmei Ma, Jialin Yu, Li Liu, Xiaoyan Ma, Jiaxue Zhang, Jiamei Zhang, Xiaoping Wang, Guangcun Deng, Xiaoling Wu.
      Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase that is extensively involved in the autophagy process by interacting with diverse autophagy initiation and autophagosome maturation molecules. However, whether TRAF6 interacts with lysosomal proteins to regulate Mycobacterium-induced autophagy has not been completely characterized. Herein, the present study showed that TRAF6 interacted with lysosomal key proteins Rab7 through RING domain which caused Rab7 ubiquitination and subsequently ubiquitinated Rab7 binds to STX17 (syntaxin 17, a SNARE protein that is essential for mature autophagosome), and thus promoted the fusion of autophagosomes and lysosomes. Furthermore, TRAF6 enhanced the initiation and formation of autophagosomes in Mycobacterium-induced autophagy in both BMDMs and RAW264.7 cells, as evidenced by autophagic flux, colocalization of LC3 and BCG, autophagy rates, and autophagy-associated protein expression. Noteworthy to mention, TRAF6 deficiency exacerbated lung injury and promoted BCG survival. Taken together, these results identify novel molecular and cellular mechanisms by which TRAF6 positively regulates Mycobacterium-induced autophagy.
    DOI:  https://doi.org/10.1038/s41420-023-01731-4
  9. Front Immunol. 2023 ;14 1212167
    Hepatocyte-specific regulation of autophagy and inflammasome activation via MyD88 during lethal Ehrlichia infection.
    Omid Teymournejad, Aditya Kumar Sharma, Mohammed Abdelwahed, Muhamuda Kader, Ibrahim Ahmed, Hoda Elkafas, Nahed Ismail.
      Hepatocytes play a crucial role in host response to infection. Ehrlichia is an obligate intracellular bacterium that causes potentially life-threatening human monocytic ehrlichiosis (HME) characterized by an initial liver injury followed by sepsis and multi-organ failure. We previously showed that infection with highly virulent Ehrlichia japonica (E. japonica) induces liver damage and fatal ehrlichiosis in mice via deleterious MyD88-dependent activation of CASP11 and inhibition of autophagy in macrophage. While macrophages are major target cells for Ehrlichia, the role of hepatocytes (HCs) in ehrlichiosis remains unclear. We investigated here the role of MyD88 signaling in HCs during infection with E. japonica using primary cells from wild-type (WT) and MyD88-/- mice, along with pharmacologic inhibitors of MyD88 in a murine HC cell line. Similar to macrophages, MyD88 signaling in infected HCs led to deleterious CASP11 activation, cleavage of Gasdermin D, secretion of high mobility group box 1, IL-6 production, and inflammatory cell death, while controlling bacterial replication. Unlike macrophages, MyD88 signaling in Ehrlichia-infected HCs attenuated CASP1 activation but activated CASP3. Mechanistically, active CASP1/canonical inflammasome pathway negatively regulated the activation of CASP3 in infected MyD88-/- HCs. Further, MyD88 promoted autophagy induction in HCs, which was surprisingly associated with the activation of the mammalian target of rapamycin complex 1 (mTORC1), a known negative regulator of autophagy. Pharmacologic blocking mTORC1 activation in E. japonica-infected WT, but not infected MyD88-/- HCs, resulted in significant induction of autophagy, suggesting that MyD88 promotes autophagy during Ehrlichia infection not only in an mTORC1-indpenedent manner, but also abrogates mTORC1-mediated inhibition of autophagy in HCs. In conclusion, this study demonstrates that hepatocyte-specific regulation of autophagy and inflammasome pathway via MyD88 is distinct than MyD88 signaling in macrophages during fatal ehrlichiosis. Understanding hepatocyte-specific signaling is critical for the development of new therapeutics against liver-targeting pathogens such as Ehrlichia.
    Keywords:  Ehrlichia spp.; HMGB1; MyD88; autophagy; inflammasome
    DOI:  https://doi.org/10.3389/fimmu.2023.1212167
  10. Autophagy. 2023 Nov 30. 1-3
    What's in an E3: role of highly curved membranes in facilitating LC3-phosphatidylethanolamine conjugation during autophagy.
    Yansheng Ye, Maria C Bewley, Hong-Gang Wang, Fang Tian, John M Flanagan.
      During autophagosome formation, ATG3, an E2-like enzyme, catalyzes the transfer of LC3-family proteins (including Atg8 in yeast and LC3- and GABARAP-subfamily members in more complex eukaryotes) from the covalent conjugated ATG3-LC3 intermediate to PE lipids in targeted membranes. A recent study has shown that the catalytically important regions of human ATG3 (hereafter referred to as ATG3), including residues 262 to 277 and 291 to 300, in cooperation with its N-terminal curvature-sensing amphipathic helix (NAH), directly interact with the membrane. These membrane interactions are functionally necessary for in vitro conjugation and in vivo cellular assays. They provide a molecular mechanism for how the membrane curvature-sensitive interaction of the NAH of ATG3 is closely coupled to its conjugase activity. Together, the data are consistent with a model in which the highly curved phagophore rims facilitate the recruitment of the ATG3-LC3 complex and promote the conjugation of LC3 to PE lipids. Mechanistically, the highly curved membranes of the phagophore rims act in much the same manner as classical E3 enzymes in the sumo/ubiquitin system, bringing substrates into proximity and rearranging the catalytic center of ATG3. Future studies will investigate how this multifaceted membrane interaction of ATG3 works with the putative E3 complex, ATG12-ATG5-ATG16L1, to promote LC3-PE conjugation.
    Keywords:  ATG3; ATG3-LC3 conjugation; Autophagy; autophagosome biogenesis; membrane curvature
    DOI:  https://doi.org/10.1080/15548627.2023.2288527
  11. Front Aging Neurosci. 2023 ;15 1281338
    Proteostasis and neurodegeneration: a closer look at autophagy in Alzheimer's disease.
    Haleh Barmaki, Alireza Nourazarian, Fatemeh Khaki-Khatibi.
      Alzheimer's disease (AD) is characterized by the accumulation of misfolded amyloid-beta and tau proteins. Autophagy acts as a proteostasis process to remove protein clumps, although it progressively weakens with aging and AD, thus facilitating the accumulation of toxic proteins and causing neurodegeneration. This review examines the impact of impaired autophagy on the progression of AD disease pathology. Under normal circumstances, autophagy removes abnormal proteins and damaged organelles, but any dysfunction in this process can lead to the exacerbation of amyloid and tau pathology, particularly in AD. There is increasing attention to therapeutic tactics to revitalize autophagy, including reduced caloric intake, autophagy-stimulating drugs, and genetic therapy. However, the translation of these strategies into clinical practice faces several hurdles. In summary, this review integrates the understanding of the intricate role of autophagy dysfunction in Alzheimer's disease progression and reinforces the promising prospects of autophagy as a beneficial target for treatments to modify the course of Alzheimer's disease.
    Keywords:  Alzheimer's disease; autophagy; neurodegeneration; oxidative stress; proteostasis
    DOI:  https://doi.org/10.3389/fnagi.2023.1281338
  12. Cancer Lett. 2023 Nov 24. pii: S0304-3835(23)00445-7. [Epub ahead of print]581 216494
    HMGB1 in the interplay between autophagy and apoptosis in cancer.
    Ruochan Chen, Ju Zou, Xiao Zhong, Jie Li, Rui Kang, Daolin Tang.
      Lysosome-mediated autophagy and caspase-dependent apoptosis are dynamic processes that maintain cellular homeostasis, ensuring cell health and functionality. The intricate interplay and reciprocal regulation between autophagy and apoptosis are implicated in various human diseases, including cancer. High-mobility group box 1 (HMGB1), a nonhistone chromosomal protein, plays a pivotal role in coordinating autophagy and apoptosis levels during tumor initiation, progression, and therapy. The regulation of autophagy machinery and the apoptosis pathway by HMGB1 is influenced by various factors, including the protein's subcellular localization, oxidative state, and interactions with binding partners. In this narrative review, we provide a comprehensive overview of the structure and function of HMGB1, with a specific focus on the interplay between autophagic degradation and apoptotic death in tumorigenesis and cancer therapy. Gaining a comprehensive understanding of the significance of HMGB1 as a biomarker and its potential as a therapeutic target in tumor diseases is crucial for advancing our knowledge of cell survival and cell death.
    Keywords:  Apoptosis; Autophagy; Cancer therapy; HMGB1; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.canlet.2023.216494
  13. Plant Cell Physiol. 2023 Nov 29. pii: pcad149. [Epub ahead of print]
    Autophagy promotes cell death induced by hydrogen peroxide in Physcomitrium patens.
    Md Arif Sakil, Kyosuke Mukae, Junyu Bao, Abhishek Sadhu, Md Shyduzzaman Roni, Yuko Inoue-Aono, Yuji Moriyasu.
      Autophagy-defective mutants (atg5 and atg7) of Physcomitrium patens exhibit strong desiccation tolerance. Here, we examined the effects of H2O2 on wild-type (WT) and autophagy-defective mutants of P. patens, considering that desiccation induces reactive oxygen species (ROS). We found that atg mutants can survive a 30 min treatment with 100 mM H2O2 whereas WT cannot, implying that autophagy promotes cell death induced by H2O2. Concomitant with cell death, vacuole collapse occurred. Intracellular H2O2 levels in both WT and atg5 increased immediately after H2O2 treatment and subsequently reached plateaus, which were higher in WT than in atg5. The ROS scavenger N-acetylcysteine lowered the plateau levels in WT and blocked cell death, suggesting that higher H2O2 plateau caused cell death. The uncoupler of electron transport chain (ETC) carbonyl cyanide m-chlorophenylhydrazone also lowered the H2O2 plateaus, showing that ROS produced in the ETC in mitochondria and/or chloroplasts elevated the H2O2 plateau. The autophagy inhibitor 3-methyladenine lowered the H2O2 plateau and the cell death rate in WT, suggesting that autophagy occurring after H2O2 treatment is involved in the production of ROS. Conversely, the addition of bovine serum albumin, which is endocytosed and supplies amino acids instead of autophagy, elevated the H2O2 plateau in atg5 cells, suggesting that amino acids produced through autophagy promote H2O2 generation. These results clearly show that autophagy causes cell death under certain stress conditions. We propose that autophagy-derived amino acids are catabolized using ETCs in mitochondria and/or chloroplasts and produce H2O2, which in turn promotes the cell death accompanying vacuole collapse.
    Keywords:   Physcomitrium patens (Physcomitrella patens); H2O2; Oxidative stress; autophagic cell death; vacuole collapse
    DOI:  https://doi.org/10.1093/pcp/pcad149
  14. bioRxiv. 2023 Nov 15. pii: 2023.11.11.566707. [Epub ahead of print]
    Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice.
    Tuancheng Feng, Huan Du, Fenghua Hu.
      TMEM106B , a gene encoding a lysosome membrane protein, is tightly associated with brain aging, hypomyelinating leukodystrophy, and multiple neurodegenerative diseases, including frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Recently, TMEM106B polymorphisms have been associated with tauopathy in chronic traumatic encephalopathy (CTE) and FTLD-TDP patients. However, how TMEM106B influences Tau pathology and its associated neurodegeneration, is unclear. Here we show that loss of TMEM106B enhances the accumulation of pathological Tau, especially in the neuronal soma in the hippocampus, resulting in severe neuronal loss in the PS19 Tau transgenic mice. Moreover, Tmem106b -/- PS19 mice develop significantly increased disruption of the neuronal cytoskeleton, autophagy-lysosomal function, and lysosomal trafficking along the axon as well as enhanced gliosis compared with PS19 and Tmem106b -/- mice. Together, our findings demonstrate that loss of TMEM106B drastically exacerbates Tau pathology and its associated disease phenotypes, and provide new insights into the roles of TMEM106B in neurodegenerative diseases.
    DOI:  https://doi.org/10.1101/2023.11.11.566707
  15. Sci Transl Med. 2023 Nov 29. 15(724): eadd0499
    Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson's disease.
    Mohammed Repon Khan, Xiling Yin, Sung-Ung Kang, Jaba Mitra, Hu Wang, Taekyung Ryu, Saurav Brahmachari, Senthilkumar S Karuppagounder, Yasuyoshi Kimura, Aanishaa Jhaldiyal, Hyun Hee Kim, Hao Gu, Rong Chen, Javier Redding-Ochoa, Juan Troncoso, Chan Hyun Na, Taekjip Ha, Valina L Dawson, Ted M Dawson.
      Pathologic α-synuclein plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson's disease (PD). Disruption of proteostasis is thought to be central to pathologic α-synuclein toxicity; however, the molecular mechanism of this deregulation is poorly understood. Complementary proteomic approaches in cellular and animal models of PD were used to identify and characterize the pathologic α-synuclein interactome. We report that the highest biological processes that interacted with pathologic α-synuclein in mice included RNA processing and translation initiation. Regulation of catabolic processes that include autophagy were also identified. Pathologic α-synuclein was found to bind with the tuberous sclerosis protein 2 (TSC2) and to trigger the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which augmented mRNA translation and protein synthesis, leading to neurodegeneration. Genetic and pharmacologic inhibition of mTOR and protein synthesis rescued the dopamine neuron loss, behavioral deficits, and aberrant biochemical signaling in the α-synuclein preformed fibril mouse model and Drosophila transgenic models of pathologic α-synuclein-induced degeneration. Pathologic α-synuclein furthermore led to a destabilization of the TSC1-TSC2 complex, which plays an important role in mTORC1 activity. Constitutive overexpression of TSC2 rescued motor deficits and neuropathology in α-synuclein flies. Biochemical examination of PD postmortem brain tissues also suggested deregulated mTORC1 signaling. These findings establish a connection between mRNA translation deregulation and mTORC1 pathway activation that is induced by pathologic α-synuclein in cellular and animal models of PD.
    DOI:  https://doi.org/10.1126/scitranslmed.add0499
  16. J Virol. 2023 Dec 01. e0098823
    Classical swine fever virus NS5A protein activates autophagy via the PP2A-DAPK3-Beclin 1 axis.
    Jinfu Sun, Haixiao Yu, Yingnan Wang, Liming Li, Jinqi Zhu, Ping Ma, Zezhong Feng, Changchun Tu.
      IMPORTANCE: Autophagy is a conserved degradation process that maintains cellular homeostasis and regulates native and adaptive immunity. Viruses have evolved diverse strategies to inhibit or activate autophagy for their benefit. The paper reveals that CSFV NS5A mediates the dissociation of PP2A from Beclin 1 and the association of PP2A with DAPK3 by interaction with PPP2R1A and DAPK3, PP2A dephosphorylates DAPK3 to activate its protein kinase activity, and activated DAPK3 phosphorylates Beclin 1 to trigger autophagy, indicating that NS5A activates autophagy via the PP2A-DAPK3-Beclin 1 axis. These data highlight a novel mechanism by which CSFV activates autophagy to favor its replication, thereby contributing to the development of antiviral strategies.
    Keywords:  ATG5; LC3B; NS5A; PP2Ac; PPP2R1A; dephosphorylation; phosphorylation
    DOI:  https://doi.org/10.1128/jvi.00988-23
  17. Autophagy. 2023 Dec 02. 1-12
    Basal activity of PINK1 and PRKN in cell models and rodent brain.
    Jens O Watzlawik, Fabienne C Fiesel, Gabriella Fiorino, Bernardo A Bustillos, Zahra Baninameh, Briana N Markham, Xu Hou, Caleb S Hayes, Jenny M Bredenberg, Nicholas W Kurchaba, Dominika Fričová, Joanna Siuda, Zbigniew K Wszolek, Sachiko Noda, Shigeto Sato, Nobutaka Hattori, Asheeta A Prasad, Deniz Kirik, Howard S Fox, Kelly L Stauch, Matthew S Goldberg, Wolfdieter Springer.
      The ubiquitin kinase-ligase pair PINK1-PRKN recognizes and transiently labels damaged mitochondria with ubiquitin phosphorylated at Ser65 (p-S65-Ub) to mediate their selective degradation (mitophagy). Complete loss of PINK1 or PRKN function unequivocally leads to early-onset Parkinson disease, but it is debated whether impairments in mitophagy contribute to disease later in life. While the pathway has been extensively studied in cell culture upon acute and massive mitochondrial stress, basal levels of activation under endogenous conditions and especially in vivo in the brain remain undetermined. Using rodent samples, patient-derived cells, and isogenic neurons, we here identified age-dependent, brain region-, and cell type-specific effects and determined expression levels and extent of basal and maximal activation of PINK1 and PRKN. Our work highlights the importance of defining critical risk and therapeutically relevant levels of PINK1-PRKN signaling which will further improve diagnosis and prognosis and will lead to better stratification of patients for future clinical trials.
    Keywords:  Mitophagy; PINK1; PRKN; Parkinson disease; parkin; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2023.2286414
  18. Front Physiol. 2023 ;14 1289388
    Not all kidney cysts are created equal: a distinct renal cystogenic mechanism in tuberous sclerosis complex (TSC).
    Manoocher Soleimani.
      Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disease caused by mutations in either TSC1 or TSC2 genes. Approximately, two million individuals suffer from this disorder worldwide. TSC1 and TSC2 code for the proteins harmartin and tuberin, respectively, which form a complex that regulates the mechanistic target of rapamycin complex 1 (mTORC1) and prevents uncontrollable cell growth. In the kidney, TSC presents with the enlargement of benign tumors (angiomyolipomas) and cysts whose presence eventually causes kidney failure. The factors promoting cyst formation and tumor growth in TSC are poorly understood. Recent studies on kidney cysts in various mouse models of TSC, including mice with principal cell- or pericyte-specific inactivation of TSC1 or TSC2, have identified a unique cystogenic mechanism. These studies demonstrate the development of numerous cortical cysts that are predominantly comprised of hyperproliferating A-intercalated (A-IC) cells that express both TSC1 and TSC2. An analogous cellular phenotype in cystic epithelium is observed in both humans with TSC and in TSC2+/- mice, confirming a similar kidney cystogenesis mechanism in TSC. This cellular phenotype profoundly contrasts with kidney cysts found in Autosomal Dominant Polycystic Kidney Disease (ADPKD), which do not show any notable evidence of A-IC cells participating in the cyst lining or expansion. RNA sequencing (RNA-Seq) and confirmatory expression studies demonstrate robust expression of Forkhead Box I1 (FOXI1) transcription factor and its downstream targets, including apical H+-ATPase and cytoplasmic carbonic anhydrase 2 (CAII), in the cyst epithelia of Tsc1 (or Tsc2) knockout (KO) mice, but not in Polycystic Kidney Disease (Pkd1) mutant mice. Deletion of FOXI1, which is vital to H+-ATPase expression and intercalated (IC) cell viability, completely inhibited mTORC1 activation and abrogated the cyst burden in the kidneys of Tsc1 KO mice. These results unequivocally demonstrate the critical role that FOXI1 and A-IC cells, along with H+-ATPase, play in TSC kidney cystogenesis. This review article will discuss the latest research into the causes of kidney cystogenesis in TSC with a focus on possible therapeutic options for this devastating disease.
    Keywords:  AVPR1A; FOXI1; c-KIT; intercalated cells; kidney cysts; mTORC1
    DOI:  https://doi.org/10.3389/fphys.2023.1289388
  19. PLoS Negl Trop Dis. 2023 Nov 27. 17(11): e0010751
    Mitochondrial protein BNIP3 regulates Chikungunya virus replication in the early stages of infection.
    Liliana Echavarria-Consuegra, Nilima Dinesh Kumar, Marleen van der Laan, Mario Mauthe, Denise Van de Pol, Fulvio Reggiori, Jolanda M Smit.
      Chikungunya virus (CHIKV) is a human pathogen causing outbreaks of febrile illness for which vaccines and specific treatments remain unavailable. Autophagy-related (ATG) proteins and autophagy receptors are a set of host factors that participate in autophagy, but have also shown to function in other unrelated cellular pathways. Although autophagy is reported to both inhibit and enhance CHIKV replication, the specific role of individual ATG proteins remains largely unknown. Here, a siRNA screen was performed to evaluate the importance of the ATG proteome and autophagy receptors in controlling CHIKV infection. We observed that 7 out of 50 ATG proteins impact the replication of CHIKV. Among those, depletion of the mitochondrial protein and autophagy receptor BCL2 Interacting Protein 3 (BNIP3) increased CHIKV infection. Interestingly, BNIP3 controls CHIKV independently of autophagy and cell death. Detailed analysis of the CHIKV viral cycle revealed that BNIP3 interferes with the early stages of infection. Moreover, the antiviral role of BNIP3 was found conserved across two distinct CHIKV genotypes and the closely related Semliki Forest virus. Altogether, this study describes a novel and previously unknown function of the mitochondrial protein BNIP3 in the control of the early stages of the alphavirus viral cycle.
    DOI:  https://doi.org/10.1371/journal.pntd.0010751
  20. Redox Biol. 2023 Nov 23. pii: S2213-2317(23)00369-5. [Epub ahead of print]68 102968
    Restoring the infected powerhouse: Mitochondrial quality control in sepsis.
    F M Lira Chavez, L P Gartzke, F E van Beuningen, S E Wink, R H Henning, G Krenning, H R Bouma.
      Sepsis is a dysregulated host response to an infection, characterized by organ failure. The pathophysiology is complex and incompletely understood, but mitochondria appear to play a key role in the cascade of events that culminate in multiple organ failure and potentially death. In shaping immune responses, mitochondria fulfil dual roles: they not only supply energy and metabolic intermediates crucial for immune cell activation and function but also influence inflammatory and cell death pathways. Importantly, mitochondrial dysfunction has a dual impact, compromising both immune system efficiency and the metabolic stability of end organs. Dysfunctional mitochondria contribute to the development of a hyperinflammatory state and loss of cellular homeostasis, resulting in poor clinical outcomes. Already in early sepsis, signs of mitochondrial dysfunction are apparent and consequently, strategies to optimize mitochondrial function in sepsis should not only prevent the occurrence of mitochondrial dysfunction, but also cover the repair of the sustained mitochondrial damage. Here, we discuss mitochondrial quality control (mtQC) in the pathogenesis of sepsis and exemplify how mtQC could serve as therapeutic target to overcome mitochondrial dysfunction. Hence, replacing or repairing dysfunctional mitochondria may contribute to the recovery of organ function in sepsis. Mitochondrial biogenesis is a process that results in the formation of new mitochondria and is critical for maintaining a pool of healthy mitochondria. However, exacerbated biogenesis during early sepsis can result in accumulation of structurally aberrant mitochondria that fail to restore bioenergetics, produce excess reactive oxygen species (ROS) and exacerbate the disease course. Conversely, enhancing mitophagy can protect against organ damage by limiting the release of mitochondrial-derived damage-associated molecules (DAMPs). Furthermore, promoting mitophagy may facilitate the growth of healthy mitochondria by blocking the replication of damaged mitochondria and allow for post sepsis organ recovery through enabling mitophagy-coupled biogenesis. The remaining healthy mitochondria may provide an undamaged scaffold to reproduce functional mitochondria. However, the kinetics of mtQC in sepsis, specifically mitophagy, and the optimal timing for intervention remain poorly understood. This review emphasizes the importance of integrating mitophagy induction with mtQC mechanisms to prevent undesired effects associated with solely the induction of mitochondrial biogenesis.
    Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Sepsis
    DOI:  https://doi.org/10.1016/j.redox.2023.102968
  21. bioRxiv. 2023 Nov 15. pii: 2023.11.11.566693. [Epub ahead of print]
    The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.
    Jace Jones-Tabah, Kathy He, Konstantin Senkevich, Nathan Karpilovsky, Ghislaine Deyab, Yuting Cousineau, Daria Nikanorova, Taylor Goldsmith, Esther Del Cid Pellitero, Carol X-Q Chen, Wen Luo, Zhipeng You, Narges Abdian, Isabella Pietrantonio, Thomas Goiran, Jamil Ahmad, Jennifer A Ruskey, Farnaz Asayesh, Dan Spiegelman, Cheryl Waters, Oury Monchi, Yves Dauvilliers, Nicolas Dupré, Irina Miliukhina, Alla Timofeeva, Anton Emelyanov, Sofya Pchelina, Lior Greenbaum, Sharon Hassin-Baer, Roy N Alcalay, Austen Milnerwood, Thomas M Durcan, Ziv Gan-Or, Edward A Fon.
      Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1 ) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.
    DOI:  https://doi.org/10.1101/2023.11.11.566693
  22. Postepy Biochem. 2023 09 30. 69(3): 159-169
    The mTOR pathway and transgenic animals with deletion of the TSC gene in the regeneration of the nervous system and selected models of sciatic nerve damage
    Natalia Białoń, Krzysztof Suszyński, Mikołaj Górka, Michał Trzęsicki, Dariusz Górka, Kacper Zając, Agata Kupczak.
      Traumatic damage to the nervous system has been a common occurrence for years, reducing patients' quality of life. The mammalian target of rapamycin (mTOR) pathway plays a key role in nervous system physiology, including by controlling nerve cell survival and differentiation. Excessive activation of the mTOR pathway leads to an increase in cell cycle protein activity and apoptosis of nerve cells. Moreover, current findings suggest the involvement of the mTOR pathway in neuroplasticity. The use of transgenic animals with deletion of the TSC gene as well as various models of sciatic nerve damage, allows activation of the mTOR pathway. Currently, the results confirm that inactivation of point mutations in TSC-1 or TSC-2 genes, activates the canonical signaling pathway of the mTORC-1 complex, in turn, reactivation of the mTORC-1 pathway through the absence of the TSC-1 gene in mature neurons induces axonal regeneration. Dysfunction of the mTORC-1 pathway in Schwann cells (SC) inhibits myelination of nerve fibers. The aim of the present study is to understand the physiology and role of the mTOR pathway as well as to demonstrate the impact of TSC gene deletion in the regeneration of the nervous system. Current research on the activity of the mTOR pathway may provide new strategies to intensify peripheral nerve regeneration.
    DOI:  https://doi.org/10.18388/pb.2021_489
  23. Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231217867
    Canonical and Non-Canonical Roles of SNX1 and SNX2 in Endosomal Membrane Dynamics.
    Juliane Da Graça, Etienne Morel.
      Sorting nexins (SNXs) are a family of membrane-binding proteins known to play a critical role in regulating endocytic pathway sorting and endosomal membrane trafficking. Among them, SNX1 and SNX2 are members of the SNX-BAR subfamily and possess a membrane-curvature domain and a phosphoinositide-binding domain, which enables their stabilization at the phosphatidylinositol-3-phosphate (PI3P)-positive surface of endosomes. While their binding to PI3P-positive platforms facilitates interaction with endosomal partners and stabilization at the endosomal membrane, their SNX-BAR region is pivotal for generating membrane tubulation from endosomal compartments. In this context, their primary identified biological roles-and their partnership-are tightly associated with the retromer and endosomal SNX-BAR sorting complex for promoting exit 1 complex trafficking, facilitating the transport of cargoes from early endosomes to the secretory pathway. However, recent literature indicates that these proteins also possess biological functions in other aspects of endosomal features and sorting processes. Notably, SNX2 has been found to regulate endosome-endoplasmic reticulum (ER) contact sites through its interaction with VAP proteins at the ER membrane. Furthermore, data from our laboratory show that SNX1 and SNX2 are involved in the tubulation of early endosomes toward ER sites associated with autophagy initiation during starvation. These findings shed light on a novel role of SNXs in inter-organelle tethering and communication. In this concise review, we will explore the non-retromer functions of SNX1 and SNX2, specifically focusing on their involvement in endosomal membrane dynamics during stress sensing and autophagy-associated processes.
    Keywords:  autophagy; endosomes; membrane dynamics; membrane tubulation; sorting nexins
    DOI:  https://doi.org/10.1177/25152564231217867
  24. Aging Cell. 2023 Nov 29. e14042
    BNIP3 as a new tool to promote healthy brain aging.
    Kit Neikirk, Andrea G Marshall, Monica M Santisteban, Antentor Hinton.
      The article "Neuronal induction of BNIP3-mediated mitophagy slows systemic aging in Drosophila" reveals BCL2-interacting protein 3 as a therapeutic target to counteract brain aging and prolong overall organismal health with age. In this spotlight, we consider the roles of BNIP3, a mitochondrial outer membrane protein, in the adult nervous system, including its induction of mitophagy and prevention of dysfunctional mitochondria in the aged brain. Implications for other tissue types to reduce the burden of aging are further considered.
    Keywords:  BNIP3; age-related pathology; aging; mitochondria; neuronal
    DOI:  https://doi.org/10.1111/acel.14042
  25. Medicine (Baltimore). 2023 Nov 24. 102(47): e36390
    Advances in the investigation of the role of autophagy in the etiology of chronic obstructive pulmonary disease: A review.
    Qianxinhong Wang, Wenlong Su, Junnan Liu, Dongkai Zhao.
      Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory illness. It arises from emphysema and chronic bronchitis and is characterized by progressive and irreversible airflow limitation and chronic inflammation of the lungs, which eventually progresses to pulmonary hypertension, chronic pulmonary heart disease and respiratory failure. Autophagy is a highly conserved cellular homeostasis maintenance mechanism that involves the transport of damaged organelles and proteins to lysosomes for destruction. Dysregulation of autophagy is one of the pathogenic mechanisms of many diseases and is strongly associated with the development of COPD, although the precise mechanisms are unknown. In this paper, we focus on macroautophagy, a type of autophagy that has been thoroughly studied, and describe the characteristics, processes, regulatory pathways, and functions of autophagy, and discuss its relationship with COPD from the perspectives of inflammation, emphysema, mucus hypersecretion, cilia structure and function, airway remodeling, vascular remodeling, and bacterial infections, with a view to searching for the therapeutic targets of COPD from the perspective of autophagy, which is hoped to be helpful for the clinical treatment.
    DOI:  https://doi.org/10.1097/MD.0000000000036390
  26. Immunity. 2023 Nov 15. pii: S1074-7613(23)00458-2. [Epub ahead of print]
    Nuclear localization of STING1 competes with canonical signaling to activate AHR for commensal and intestinal homeostasis.
    Ruoxi Zhang, Chunhua Yu, Herbert J Zeh, Haichao Wang, Guido Kroemer, Daniel J Klionsky, Timothy R Billiar, Rui Kang, Daolin Tang.
      Extensive studies demonstrate the importance of the STING1 (also known as STING) protein as a signaling hub that coordinates immune and autophagic responses to ectopic DNA in the cytoplasm. Here, we report a nuclear function of STING1 in driving the activation of the transcription factor aryl hydrocarbon receptor (AHR) to control gut microbiota composition and homeostasis. This function was independent of DNA sensing and autophagy and showed competitive inhibition with cytoplasmic cyclic guanosine monophosphate (GMP)-AMP synthase (CGAS)-STING1 signaling. Structurally, the cyclic dinucleotide binding domain of STING1 interacted with the AHR N-terminal domain. Proteomic analyses revealed that STING1-mediated transcriptional activation of AHR required additional nuclear partners, including positive and negative regulatory proteins. Although AHR ligands could rescue colitis pathology and dysbiosis in wild-type mice, this protection was abrogated by mutational inactivation of STING1. These findings establish a key framework for understanding the nuclear molecular crosstalk between the microbiota and the immune system.
    Keywords:  AHR; STING1; gut microbiota; inflammatory bowel disease; innate immunity
    DOI:  https://doi.org/10.1016/j.immuni.2023.11.001
  27. Adv Sci (Weinh). 2023 Dec 02. e2307206
    mTORC1 Mediates Biphasic Mechano-Response to Orchestrate Adhesion-Dependent Cell Growth and Anoikis Resistance.
    Chunlei Zhang, Yuan Wang, Zifeng Zhen, Jiayi Li, Jing Su, Congying Wu.
      Cells constantly sense and respond to not only biochemical but also biomechanical changes in their microenvironment, demanding for dynamic metabolic adaptation. ECM stiffening is a hallmark of cancer aggressiveness, while survival under substrate detachment also associates with poor prognosis. Mechanisms underlying this, non-linear mechano-response of tumor cells may reveal potential double-hit targets for cancers. Here, an integrin-GSK3β-FTO-mTOR axis is reported, that can integrate stiffness sensing to ensure both the growth advantage endowed by rigid substrate and cell death resistance under matrix detachment. It is demonstrated that substrate stiffening can activate mTORC1 and elevate mTOR level through integrins and GSK3β-FTO mediated mRNA m6 A modification, promoting anabolic metabolism. Inhibition of this axis upon ECM detachment enhances autophagy, which in turn conveys resilience of tumor cells to anoikis, as it is demonstrated in human breast ductal carcinoma in situ (DCIS) and mice malignant ascites. Collectively, these results highlight the biphasic mechano-regulation of cellular metabolism, with implications in tumor growth under stiffened conditions such as fibrosis, as well as in anoikis-resistance during cancer metastasis.
    Keywords:  autophagy; cell adhesion; mTORC1; mechano-transduction
    DOI:  https://doi.org/10.1002/advs.202307206
  28. Front Physiol. 2023 ;14 1281555
    Protein modification regulated autophagy in Bombyx mori and Drosophila melanogaster.
    Wenmei Wu, Luobin Lin, Yuntao Zhao, Huaqin Li, Rongxin Zhang.
      Post-translational modifications refer to the chemical alterations of proteins following their biosynthesis, leading to changes in protein properties. These modifications, which encompass acetylation, phosphorylation, methylation, SUMOylation, ubiquitination, and others, are pivotal in a myriad of cellular functions. Macroautophagy, also known as autophagy, is a major degradation of intracellular components to cope with stress conditions and strictly regulated by nutrient depletion, insulin signaling, and energy production in mammals. Intriguingly, in insects, 20-hydroxyecdysone signaling predominantly stimulates the expression of most autophagy-related genes while concurrently inhibiting mTOR activity, thereby initiating autophagy. In this review, we will outline post-translational modification-regulated autophagy in insects, including Bombyx mori and Drosophila melanogaster, in brief. A more profound understanding of the biological significance of post-translational modifications in autophagy machinery not only unveils novel opportunities for autophagy intervention strategies but also illuminates their potential roles in development, cell differentiation, and the process of learning and memory processes in both insects and mammals.
    Keywords:  Bombyx mori; Drosophila melanogaster; autophagy; insects; protein modification
    DOI:  https://doi.org/10.3389/fphys.2023.1281555
  29. Commun Biol. 2023 Nov 25. 6(1): 1201
    ACO2 deficiency increases vulnerability to Parkinson's disease via dysregulating mitochondrial function and histone acetylation-mediated transcription of autophagy genes.
    Junge Zhu, Fanxi Xu, Hong Lai, Huiyao Yuan, Xu-Ying Li, Junya Hu, Wei Li, Lei Liu, Chaodong Wang.
      Parkinson's disease (PD) is characterized by α-synuclein aggregation in dopaminergic (DA) neurons, which are sensitive to oxidative stress. Mitochondria aconitase 2 (ACO2) is an essential enzyme in the tricarboxylic acid cycle that orchestrates mitochondrial and autophagic functions to energy metabolism. Though widely linked to diseases, its relation to PD has not been fully clarified. Here we revealed that the peripheral ACO2 activity was significantly decreased in PD patients and associated with their onset age and disease durations. The knock-in mouse and Drosophila models with the A252T variant displayed aggravated motor deficits and DA neuron degeneration after 6-OHDA and rotenone-induction, and the ACO2 knockdown or blockade cells showed features of mitochondrial and autophagic dysfunction. Moreover, the transcription of autophagy-related genes LC3 and Atg5 was significantly downregulated via inhibited histone acetylation at the H3K9 and H4K5 sites. These data provided multi-dimensional evidences supporting the essential roles of ACO2, and as a potential early biomarker to be used in clinical trials for assessing the effects of antioxidants in PD. Moreover, ameliorating energy metabolism by targeting ACO2 could be considered as a potential therapeutic strategy for PD and other neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s42003-023-05570-y
  30. Oncol Lett. 2024 Jan;27(1): 12
    In vitro anticancer effect of azithromycin targeting hypoxic lung cancer cells via the inhibition of mitophagy.
    Kazutoshi Toriyama, Takashi Okuma, Shinji Abe, Hiroyuki Nakamura, Kazutetsu Aoshiba.
      Solid tumors are predisposed to hypoxia, which induces tumor progression, and causes resistance to treatment. Hypoxic tumor cells exploit auto- and mitophagy to facilitate metabolism and mitochondrial renewal. Azithromycin (AZM), a widely used macrolide, inhibits autophagy in cancer cells. The aim of the present study was to determine whether AZM targeted hypoxic cancer cells by inhibiting mitophagy. Lung cancer cell lines (A549, H1299 and NCI-H441) were cultured for up to 72 h under normoxic (20% O2) or hypoxic (0.3% O2) conditions in the presence or absence of AZM (≤25 µM), and the cell survival, autophagy flux and mitophagy flux were evaluated. AZM treatment reduced cell survival under hypoxic conditions, caused mitolysosome dysfunction with raised lysosomal pH and impaired the efficient removal of hypoxia-damaged mitochondria, eventually inducing apoptosis in the cancer cells. The cytotoxic effect of AZM under hypoxic conditions was abolished in mitochondria-deficient A549 cells (ρ° cells). The present study demonstrated that AZM reduced lung cancer cell survival under hypoxic conditions by interfering with the efficient removal of damaged mitochondria through mitophagy inhibition. Thus, AZM may be considered as a promising anticancer drug that targets the mitochondrial vulnerability of hypoxic lung cancer cells.
    Keywords:  AZM; TME; autophagy; hypoxia; mitophagy
    DOI:  https://doi.org/10.3892/ol.2023.14146
  31. Arch Razi Inst. 2023 Jun;78(3): 785-796
    Coxiella burnetii Pathogenesis: Emphasizing the Role of the Autophagic Pathway.
    M Kodori, J Amani, Z Meshkat, A Ahmadi.
      Coxiella burnetii (C. burnetii), the etiological agent of the Q fever disease, ranks among the most sporadic and persistent global public health concerns. Ruminants are the principal source of human infections and diseases present in both acute and chronic forms. This bacterium is an intracellular pathogen that can survive and reproduce under acidic (pH 4 to 5) and harsh circumstances that contain Coxiella-containing vacuoles. By undermining the autophagy defense system of the host cell, C. burnetii is able to take advantage of the autophagy pathway, which allows it to improve the movement of nutrients and the membrane, thereby extending the vacuole of the reproducing bacteria. For this method to work, it requires the participation of many bacterial effector proteins. In addition, the precise and prompt identification of the causative agent of an acute disease has the potential to delay the onset of its chronic form. Moreover, to make accurate and rapid diagnoses, it is necessary to create diagnostic devices. This review summarizes the most recent research on the epidemiology, pathogenesis, and diagnosis approaches of C. burnetii. This study also explored the complicated relationships between C. burnetii and the autophagic pathway, which are essential for intracellular reproduction and survival in host cells for the infection to be effective.
    Keywords:   Autophagy pathway; Epidemiology; Intracellular replication; Pathogenesis; Q fever; Coxiella burnetii; Coxiella-containing vacuoles
    DOI:  https://doi.org/10.22092/ARI.2023.361161.2636
  32. J Mol Cell Cardiol. 2023 Nov 30. pii: S0022-2828(23)00166-9. [Epub ahead of print]186 111-124
    Mechanistic target of rapamycin in regulating macrophage function in inflammatory cardiovascular diseases.
    MariaSanta C Mangione, Jinhua Wen, Dian J Cao.
      The mechanistic target of rapamycin (mTOR) is evolutionarily conserved from yeast to humans and is one of the most fundamental pathways of living organisms. Since its discovery three decades ago, mTOR has been recognized as the center of nutrient sensing and growth, homeostasis, metabolism, life span, and aging. The role of dysregulated mTOR in common diseases, especially cancer, has been extensively studied and reported. Emerging evidence supports that mTOR critically regulates innate immune responses that govern the pathogenesis of various cardiovascular diseases. This review discusses the regulatory role of mTOR in macrophage functions in acute inflammation triggered by ischemia and in atherosclerotic cardiovascular disease (ASCVD) and heart failure with preserved ejection fraction (HFpEF), in which chronic inflammation plays critical roles. Specifically, we discuss the role of mTOR in trained immunity, immune senescence, and clonal hematopoiesis. In addition, this review includes a discussion on the architecture of mTOR, the function of its regulatory complexes, and the dual-arm signals required for mTOR activation to reflect the current knowledge state. We emphasize future research directions necessary to understand better the powerful pathway to take advantage of the mTOR inhibitors for innovative applications in patients with cardiovascular diseases associated with aging and inflammation.
    Keywords:  Atherosclerosis; Inflammation; Ischemia; Macrophage; mTOR
    DOI:  https://doi.org/10.1016/j.yjmcc.2023.10.011
  33. Cell Metab. 2023 Nov 16. pii: S1550-4131(23)00411-4. [Epub ahead of print]
    PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.
    Cong Jiang, Jing Liu, Shaohui He, Wei Xu, Runzhi Huang, Weijuan Pan, Xiaolong Li, Xiaoming Dai, Jianping Guo, Tao Zhang, Hiroyuki Inuzuka, Ping Wang, John M Asara, Jianru Xiao, Wenyi Wei.
      Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive. Here, we report that PRMT1 senses methionine/SAM by utilizing SAM as a cofactor for an enzymatic activity-based regulation of mTORC1 signaling. Under methionine-sufficient conditions, elevated cytosolic SAM releases SAMTOR from GATOR1, which confers the association of PRMT1 with GATOR1. Subsequently, SAM-loaded PRMT1 methylates NPRL2, the catalytic subunit of GATOR1, thereby suppressing its GAP activity and leading to mTORC1 activation. Notably, genetic or pharmacological inhibition of PRMT1 impedes hepatic methionine sensing by mTORC1 and improves insulin sensitivity in aged mice, establishing the role of PRMT1-mediated methionine sensing at physiological levels. Thus, PRMT1 coordinates with SAMTOR to form the methionine-sensing apparatus of mTORC1 signaling.
    Keywords:  GATOR1; NPRL2; PRMT1; arginine methylation; mTOR; methionine sensing; nutrient sensing
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.001
  34. J Biochem. 2023 Nov 28. pii: mvad098. [Epub ahead of print]
    Review title: Mechanisms of mitochondrial reorganization.
    Tatsuro Maruyama, Yutaro Hama, Nobuo N Noda.
      The cytoplasm of eukaryotes is dynamically zoned by membrane-bound and membraneless organelles. Cytoplasmic zoning allows various biochemical reactions to take place at the right time and place. Mitochondrion is a membrane-bound organelle that provides a zone for intracellular energy production and metabolism of lipids and iron. A key feature of mitochondria is their high dynamics: mitochondria constantly undergo fusion and fission, and excess or damaged mitochondria are selectively eliminated by mitophagy. Therefore, mitochondria are appropriate model systems to understand dynamic cytoplasmic zoning by membrane organelles. In this review, we summarize the molecular mechanisms of mitochondrial fusion and fission as well as mitophagy unveiled through studies using yeast and mammalian models.
    Keywords:  cytoplasmic zoning; mitochondria; mitochondrial fission; mitochondrial fusion; mitophagy
    DOI:  https://doi.org/10.1093/jb/mvad098
  35. Nat Metab. 2023 Nov 30.
    Mitophagy in human health, ageing and disease.
    Anna Picca, Julie Faitg, Johan Auwerx, Luigi Ferrucci, Davide D'Amico.
      Maintaining optimal mitochondrial function is a feature of health. Mitophagy removes and recycles damaged mitochondria and regulates the biogenesis of new, fully functional ones preserving healthy mitochondrial functions and activities. Preclinical and clinical studies have shown that impaired mitophagy negatively affects cellular health and contributes to age-related chronic diseases. Strategies to boost mitophagy have been successfully tested in model organisms, and, recently, some have been translated into clinics. In this Review, we describe the basic mechanisms of mitophagy and how mitophagy can be assessed in human blood, the immune system and tissues, including muscle, brain and liver. We outline mitophagy's role in specific diseases and describe mitophagy-activating approaches successfully tested in humans, including exercise and nutritional and pharmacological interventions. We describe how mitophagy is connected to other features of ageing through general mechanisms such as inflammation and oxidative stress and forecast how strengthening research on mitophagy and mitophagy interventions may strongly support human health.
    DOI:  https://doi.org/10.1038/s42255-023-00930-8
  36. J Vis Exp. 2023 Nov 10.
    Analyzing Mitochondrial Function in a Drosophila melanogaster PINK1B9-Null Mutant Using High-resolution Respirometry.
    Paula Michelotti, Tâmie Duarte, Cristiane L Dalla Corte.
      Neurodegenerative diseases, including Parkinson's Disease (PD), and cellular disturbances such as cancer are some of the disorders that disrupt energy metabolism with impairment of mitochondrial functions. Mitochondria are organelles that control both energy metabolism and cellular processes involved in cell survival and death. For this reason, approaches to evaluate mitochondrial function can offer important insights into cellular conditions in pathological and physiological processes. In this regard, high-resolution respirometry (HRR) protocols allow evaluation of the whole mitochondrial respiratory chain function or the activity of specific mitochondrial complexes. Furthermore, studying mitochondrial physiology and bioenergetics requires genetically and experimentally tractable models such as Drosophila melanogaster. This model presents several advantages, such as its similarity to human physiology, its rapid life cycle, easy maintenance, cost-effectiveness, high throughput capabilities, and a minimized number of ethical concerns. These attributes collectively establish it as an invaluable tool for dissecting complex cellular processes. The present work explains how to analyze mitochondrial function using the Drosophila melanogaster PINK1B9-null mutant. The pink1 gene is responsible for encoding PTEN-induced putative kinase 1, through a process recognized as mitophagy, which is crucial for the removal of dysfunctional mitochondria from the mitochondrial network. Mutations in this gene have been associated with an autosomal recessive early-onset familial form of PD. This model can be used to study mitochondrial dysfunction involved in the pathophysiology of PD.
    DOI:  https://doi.org/10.3791/65664
  37. iScience. 2023 Nov 17. 26(11): 108360
    Treatment of calcific arterial disease via enhancement of autophagy using GSK343.
    Christian L Lino Cardenas, Wanlin Jiang, Lova P Kajuluri, Kuldeep Singh, Katrina Ostrom, Rebecca Li, Francois Cherbonneau, Sophie Boerboom, Claire Birchenough, Kangsan Roh, Elizabeth L Chou, Zarbafian Shahrooz, Christopher Nicholson, Adam L Johnson, Sujin Lee, Fumito Ichinose, Donald B Bloch, Sagar Nigwekar, Patrick T Ellinor, Patricia Musolino, Mark E Lindsay, Zhixun Dou, Clint L Miller, Rajeev Malhotra.
      Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp-/-) and small (Abcc6-/-) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.
    Keywords:  Cardiovascular medicine; Human Genetics; Molecular physiology
    DOI:  https://doi.org/10.1016/j.isci.2023.108360
  38. J Virol. 2023 Nov 27. e0133823
    The role of lysosomes as intermediates in betacoronavirus PHEV egress from nerve cells.
    Zhenzhen Wang, Wenqi He, Caili Li, Yuzhu Chen, Zi Li, Yubo Jiao, Jing Zhang, Junchao Shi, Gaili Wang, Jiyu Guan, Kui Zhao, Deguang Song, Feng Gao, Yungang Lan.
      IMPORTANCE: Betacoronaviruses, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and mouse hepatitis virus (MHV), exploit the lysosomal exocytosis pathway for egress. However, whether all betacoronaviruses members use the same pathway to exit cells remains unknown. Here, we demonstrated that porcine hemagglutinating encephalomyelitis virus (PHEV) egress occurs by Arl8b-dependent lysosomal exocytosis, a cellular egress mechanism shared by SARS-CoV-2 and MHV. Notably, PHEV acidifies lysosomes and activates lysosomal degradative enzymes, while SARS-CoV-2 and MHV deacidify lysosomes and limit the activation of lysosomal degradative enzymes. In addition, PHEV release depends on V-ATPase-mediated lysosomal pH. Furthermore, this is the first study to evaluate βCoV using lysosome for spreading through the body, and we have found that lysosome played a critical role in PHEV neural transmission and brain damage caused by virus infection in the central nervous system. Taken together, different betacoronaviruses could disrupt lysosomal function differently to exit cells.
    Keywords:  CNS; PHEV; V-ATPase; betacoronaviruses; lysosome; virus egress
    DOI:  https://doi.org/10.1128/jvi.01338-23
  39. Autophagy. 2023 Nov 30. 1-20
    LYC inhibits the AKT signaling pathway to activate autophagy and ameliorate TGFB-induced renal fibrosis.
    Yu Wang, Zhenlei Ping, Hongxin Gao, Zhihui Liu, Qingyang Xv, Xiaowen Jiang, Wenhui Yu.
      Renal fibrosis is a typical pathological change in chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) is the predominant stage. Activation of macroautophagy/autophagy plays a crucial role in the process of EMT. Lycopene (LYC) is a highly antioxidant carotenoid with pharmacological effects such as anti-inflammation, anti-apoptosis and mediation of autophagy. In this study, we demonstrated the specific mechanism of LYC in activating mitophagy and improving renal fibrosis. The enrichment analysis results of GO and KEGG showed that LYC had high enrichment values with autophagy. In this study, we showed that LYC alleviated aristolochic acid I (AAI)-induced intracellular expression of PINK1, TGFB/TGF-β, p-SMAD2, p-SMAD3, and PRKN/Parkin, recruited expression of MAP1LC3/LC3-II and SQSTM1/p62, decreased mitochondrial membrane potential (MMP), and ameliorated renal fibrosis in mice. When we simultaneously intervened NRK52E cells using bafilomycin A1 (Baf-A1), AAI, and LYC, intracellular MAP1LC3-II and SQSTM1 expression was significantly increased. A similar result was seen in renal tissue and cells when treated in vitro and in vivo with CQ, AAI, and LYC, and the inhibitory effect of LYC on the AAI-activated SMAD2-SMAD3 signaling pathway was attenuated. Molecular docking simulation experiments showed that LYC stably bound to the AKT active site. After intervention of cells with AAI and GSK-690693, the expression of PINK1, PRKN, MAP1LC3-II, BECN1, p-SMAD2 and p-SMAD3 was increased, and the expression of SQSTM1 was decreased. However, SC79 inhibited autophagy and reversed the inhibitory effect of LYC on EMT. The results showed that LYC could inhibit the AKT signaling pathway to activate mitophagy and reduce renal fibrosis.Abbreviation: AA: aristolochic acid; ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB: actin beta; AKT/protein kinase B: thymoma viral proto-oncogene; BAF-A1: bafilomycin A1; BECN1: beclin 1, autophagy related; CCN2/CTGF: cellular communication network factor 2; CDH1/E-Cadherin: cadherin 1; CKD: chronic kidney disease; COL1: collagen, type I; COL3: collagen, type III; CQ: chloroquine; ECM: extracellular matrix; EMT: epithelial-mesenchymal transition; FN1: fibronectin 1; LYC: lycopene; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase ; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced putative kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PPI: protein-protein interaction; SMAD2: SMAD family member 2; SMAD3: SMAD family member 3; SQSTM1/p62: sequestosome 1; TGFB/TGFβ: transforming growth factor, beta; VIM: vimentin.
    Keywords:  AKT; TGFB; lycopene; mitophagy; renal fibrosis
    DOI:  https://doi.org/10.1080/15548627.2023.2287930
  40. Zhonghua Gan Zang Bing Za Zhi. 2023 Oct 20. 31(10): 1113-1116
    [Research progress on the mechanism of action of mitophagy in the occurrence and development of liver cancer].
    X Y Fu, X Zhang, K S Dong, J Yu.
      Mitophagy, as an important link in maintaining mitochondrial homeostasis and environmental homeostasis in the liver, can remove damaged mitochondria and provide energy through autophagy and other processes. Additionally, it plays a dual role in the occurrence and development of liver cancer and can affect the therapeutic effect of liver cancer through a variety of signaling pathways. This article reviews the relationship between mitophagy and hepatitis B virus infection, liver cancer occurrence and development, liver cancer stem cells, mitochondrial division and fusion, therapeutic resistance and invasiveness of liver cancer, and other aspects.
    Keywords:  Hepatocellular carcinoma
    DOI:  https://doi.org/10.3760/cma.j.cn501113-20220915-00470
  41. PLoS One. 2023 ;18(12): e0295273
    Clarithromycin overcomes stromal cell-mediated drug resistance against proteasome inhibitors in myeloma cells via autophagy flux blockage leading to high NOXA expression.
    Shota Moriya, Hiromi Kazama, Hirotsugu Hino, Naoharu Takano, Masaki Hiramoto, Shin Aizawa, Keisuke Miyazawa.
      We previously reported that macrolide antibiotics, such as clarithromycin (CAM), blocked autophagy flux, and simultaneous proteasome and autophagy inhibition by bortezomib (BTZ) plus CAM resulted in enhanced apoptosis induction in multiple myeloma (MM) cells via increased endoplasmic reticulum (ER) stress loading. However, in actual therapeutic settings, cell adhesion-mediated drug resistance between bone marrow stromal cells (BMSC) and MM cells has been known to be a barrier to treatment. To investigate whether CAM could enhance BTZ-induced cytotoxicity in MM cells under direct cell adhesion with BMSC, we established a co-culture system of EGFP-labeled MM cells with BMSC. The cytotoxic effect of BTZ on MM cells was diminished by its interaction with BMSC; however, the attenuated cytotoxicity was recovered by the co-administration of CAM, which upregulates ER stress loading and NOXA expression. Knockout of NOXA in MM cells canceled the enhanced cell death by CAM, indicating that NOXA is a key molecule for cell death induction by the co-administration of CAM. Since NOXA is degraded by autophagy as well as proteasomes, blocking autophagy with CAM resulted in the sustained upregulation of NOXA in MM cells co-cultured with BMSC in the presence of BTZ. Our data suggest that BMSC-associated BTZ resistance is mediated by the attenuation of ER stress loading. However, the addition of CAM overcomes BMSC-associated resistance via upregulation of NOXA by concomitantly blocking autophagy-mediated NOXA degradation and transcriptional activation of NOXA by ER stress loading.
    DOI:  https://doi.org/10.1371/journal.pone.0295273
  42. JCI Insight. 2023 Nov 28. pii: e171850. [Epub ahead of print]
    ZNFX1 promotes AMPK-mediated autophagy against Mycobacterium tuberculosis by stabilizing mRNA.
    Honglin Liu, Zhenyu Han, Liru Chen, Jing Zhang, Zhanqing Zhang, Yaoxin Chen, Feichang Liu, Ke Wang, Jieyu Liu, Na Sai, Xinying Zhou, Chaoying Zhou, Shengfeng Hu, Qian Wen, Li Ma.
      Tuberculosis, a chronic infectious disease caused by a single pathogen, holds the highest mortality rate worldwide. RNA-binding proteins (RBPs) are involved in autophagy - a key defense mechanism against Mycobacterium tuberculosis (Mtb) infection - by modulating RNA stability and forming intricate regulatory networks. However, the functions of host RBPs during Mtb infection remain relatively unexplored. ZNFX1, a conserved RBP critically involved in immune deficiency diseases and mycobacterial infections, is significantly upregulated in Mtb-infected macrophages. Here, we aimed to explore the immune regulatory functions of ZNFX1 during Mtb infection. We observed that Znfx1 knockout markedly compromised the multifaceted immune responses mediated by macrophages. This compromise resulted in reduced phagocytosis, suppressed macrophage activation, increased Mtb burden, progressive lung tissue injury, and chronic inflammation in Mtb-infected mice. Mechanistic investigations revealed that the absence of ZNFX1 inhibited autophagy, consequently mediating immune suppression. ZNFX1 critically maintained AMPK-regulated autophagic flux by stabilizing Prkaa2 mRNA, which encodes a key catalytic α subunit of AMPK, through its zinc finger region. This process contributed to Mtb growth suppression. These findings reveal a function of ZNFX1 in establishing anti-Mtb immune responses, enhancing our understanding of the roles of RBPs in tuberculosis immunity and providing a promising approach to bolster anti-tuberculosis immunotherapy.
    Keywords:  Autophagy; Immunology; Infectious disease; RNA processing; Tuberculosis
    DOI:  https://doi.org/10.1172/jci.insight.171850
  43. bioRxiv. 2023 Nov 14. pii: 2023.11.14.566972. [Epub ahead of print]
    GCN2 mediates access to stored amino acids for somatic maintenance during Drosophila ageing.
    Joshua N Johnstone, Christen K Mirth, Travis K Johnson, Ralf B Schittenhelm, Matthew D W Piper.
      Many mechanistic theories of ageing argue that a progressive failure of somatic maintenance, the use of energy and resources to prevent and repair damage to the cell, underpins ageing. To sustain somatic maintenance an organism must acquire dozens of essential nutrients from the diet, including essential amino acids (EAAs), which are physiologically limiting for many animals. In Drosophila , adulthood deprivation of each individual EAA yields vastly different lifespan trajectories, and adulthood deprivation of one EAA, phenylalanine (Phe), has no associated lifespan cost; this is despite each EAA being strictly required for growth and reproduction. Moreover, survival under any EAA deprivation depends entirely on the conserved AA sensor GCN2, a component of the integrated stress response (ISR), suggesting that a novel ISR-mediated mechanism sustains lifelong somatic maintenance during EAA deprivation. Here we investigated this mechanism, finding that flies chronically deprived of dietary Phe continue to incorporate Phe into new proteins, and that challenging flies to increase the somatic requirement for Phe shortens lifespan under Phe deprivation. Further, we show that autophagy is required for full lifespan under Phe deprivation, and that activation of the ISR can partially rescue the shortened lifespan of GCN2 -nulls under Phe deprivation. We therefore propose a mechanism by which GCN2, via the ISR, activates autophagy during EAA deprivation, breaking down a larvally-acquired store of EAAs to support somatic maintenance. These data refine our understanding of the strategies by which flies sustain lifelong somatic maintenance, which determines length of life in response to changes in the nutritional environment.
    DOI:  https://doi.org/10.1101/2023.11.14.566972
  44. J Med Chem. 2023 Nov 29.
    Trehalose-Bearing Carriers to Target Impaired Autophagy and Protein Aggregation Diseases.
    Ali Maruf, Małgorzata Milewska, Máté Varga, Ilona Wandzik.
      In recent years, trehalose, a natural disaccharide, has attracted growing attention because of the discovery of its potential to induce autophagy. Trehalose has also been demonstrated to preserve the protein's structural integrity and to limit the aggregation of pathologically misfolded proteins. Both of these properties have made trehalose a promising therapeutic candidate to target autophagy-related disorders and protein aggregation diseases. Unfortunately, trehalose has poor bioavailability due to its hydrophilic nature and susceptibility to enzymatic degradation. Recently, trehalose-bearing carriers, in which trehalose is incorporated either by chemical conjugation or physical entrapment, have emerged as an alternative option to free trehalose to improve its efficacy, particularly for the treatment of neurodegenerative diseases, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and cancers. In the current Perspective, we discuss all existing literature in this emerging field and try to identify key challenges for researchers intending to develop trehalose-bearing carriers to stimulate autophagy or inhibit protein aggregation.
    DOI:  https://doi.org/10.1021/acs.jmedchem.3c01442
  45. Redox Rep. 2023 Dec;28(1): 2284517
    Melittin kills A549 cells by targeting mitochondria and blocking mitophagy flux.
    Xuan Li, Zheng Li, Yu-Qi Meng, Hui Qiao, Ke-Rong Zhai, Zhen-Qing Li, Shi-Lin Wei, Bin Li.
      Melittin, a naturally occurring polypeptide found in bee venom, has been recognized for its potential anti-tumor effects, particularly in the context of lung cancer. Our previous study focused on its impact on human lung adenocarcinoma cells A549, revealing that melittin induces intracellular reactive oxygen species (ROS) burst and oxidative damage, resulting in cell death. Considering the significant role of mitochondria in maintaining intracellular redox levels and ROS, we further examined the involvement of mitochondrial damage in melittin-induced apoptosis in lung cancer cells. Our findings demonstrated that melittin caused changes in mitochondrial membrane potential (MMP), triggered mitochondrial ROS burst (Figure 1), and activated the mitochondria-related apoptosis pathway Bax/Bcl-2 by directly targeting mitochondria in A549 cells (Figure 2). Further, we infected A549 cells using a lentivirus that can express melittin-Myc and confirmed that melittin can directly target binding to mitochondria, causing the biological effects described above (Figure 2). Notably, melittin induced mitochondrial damage while inhibiting autophagy, resulting in abnormal degradation of damaged mitochondria (Figure 5). To summarize, our study unveils that melittin targets mitochondria, causing mitochondrial damage, and inhibits the autophagy-lysosomal degradation pathway. This process triggers mitoROS burst and ultimately activates the mitochondria-associated Bax/Bcl-2 apoptotic signaling pathways in A549 cells.
    Keywords:  A549 cells; Melittin; ROS; apoptosis; autophagy; mitochondria damage; mitophagy; mitophagy flux
    DOI:  https://doi.org/10.1080/13510002.2023.2284517
  46. Clin Chim Acta. 2023 Nov 26. pii: S0009-8981(23)00484-9. [Epub ahead of print]552 117682
    Genomic profile of Parkinson's disease in Asians.
    Valentinus Besin, Farizky Martriano Humardani, Trilis Yulianti, Matthew Justyn.
      Parkinson's Disease (PD) has witnessed an alarming rise in prevalence, highlighting the suboptimal nature of early diagnostic and therapeutic strategies. To address this issue, genetic testing has emerged as a potential avenue. In this comprehensive review, we have meticulously summarized the variants associated with PD in Asian populations. Our review reveals that these variants exert their influence on diverse biological pathways, encompassing the autophagy-lysosome pathway, cholesterol metabolism, circadian rhythm regulation, immune system response, and synaptic function. Conventionally, PD has been linked to other diseases; however, our findings shed light on a shared genetic susceptibility among these conditions, implying an underlying pathophysiological mechanism that unifies them. Moreover, it is noteworthy that these PD-associated variants can significantly impact drug responses during therapeutic interventions. This review not only provides a consolidated overview of the genetic variants associated with PD in Asian populations but also contributes novel insights into the intricate relationships between PD and other diseases by elucidating shared genetic components. These findings underscore the importance of personalized approaches in diagnosing and treating PD based on individual genetic profiles to optimize patient outcomes.
    Keywords:  Asian populations; Drug response; Genetic sharing; Genetic variant; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.cca.2023.117682
  47. FEBS J. 2023 Dec 01.
    miR-93 and synaptotagmin-7: two novel players in the regulation of autophagy during cardiac hypertrophy.
    Maurizio Forte, Gianmarco Sarto, Sebastiano Sciarretta.
      The molecular mechanisms involved in the transition of cardiac hypertrophy to heart failure (HF) are not fully characterized. Autophagy is a catabolic, self-renewal intracellular mechanism, which protects the heart during HF. In the heart of a mouse model of angiotensin-II-induced hypertrophy, Sun and colleagues demonstrated that reduced levels of miR-93 lead to synaptotagmin-7 (Syt-7) upregulation and consequent inhibition of autophagy. miR-93 overexpression or syt-7 inhibition rescues autophagy and maladaptive hypertrophy. This research identifies new players in the pathophysiology of cardiac hypertrophy, opening innovative therapeutic perspectives. miR-93 may also be considered in the future as a novel circulating biomarker for patients at high risk to develop HF.
    Keywords:  angiotensin II; autophagy; cardiac hypertrophy; cardiovascular diseases; heart failure; miRNAs
    DOI:  https://doi.org/10.1111/febs.17008
  48. Am J Physiol Heart Circ Physiol. 2023 Dec 01.
    Cardiovascular Aging: Spotlight on Mitochondria.
    Md Akkas Ali, Rachel Gioscia-Ryan, Dongli Yang, Nadia R Sutton, Daniel J Tyrrell.
      Mitochondria are cellular organelles critical for ATP production and are particularly relevant to cardiovascular diseases including heart failure, atherosclerosis, ischemia reperfusion injury, and cardiomyopathies. With advancing age, even in the absence of clinical disease, mitochondrial homeostasis becomes disrupted (e.g. redox balance, mitochondrial DNA damage, oxidative metabolism, and mitochondrial quality control). Mitochondrial dysregulation leads to the accumulation of damaged and dysfunctional mitochondria, producing excessive reactive oxygen species and perpetuating mitochondrial dysfunction. Additionally, mitochondrial DNA, cardiolipin, and N-formyl peptides are potent activators of cell-intrinsic and extrinsic inflammatory pathways. These age-related mitochondrial changes contribute to development of cardiovascular diseases. This review covers the impact of aging on mitochondria and links these mechanisms to therapeutic implications for age-associated cardiovascular diseases.
    Keywords:  Cardiovascular; aging; metabolism; mitochondria; senescence
    DOI:  https://doi.org/10.1152/ajpheart.00632.2023
  49. Nat Commun. 2023 Nov 30. 14(1): 7908
    Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype.
    Gang Xue, Jianing Xie, Matthias Hinterndorfer, Marko Cigler, Lara Dötsch, Hana Imrichova, Philipp Lampe, Xiufen Cheng, Soheila Rezaei Adariani, Georg E Winter, Herbert Waldmann.
      Targeted proteasomal and autophagic protein degradation, often employing bifunctional modalities, is a new paradigm for modulation of protein function. In an attempt to explore protein degradation by means of autophagy we combine arylidene-indolinones reported to bind the autophagy-related LC3B-protein and ligands of the PDEδ lipoprotein chaperone, the BRD2/3/4-bromodomain containing proteins and the BTK- and BLK kinases. Unexpectedly, the resulting bifunctional degraders do not induce protein degradation by means of macroautophagy, but instead direct their targets to the ubiquitin-proteasome system. Target and mechanism identification reveal that the arylidene-indolinones covalently bind DCAF11, a substrate receptor in the CUL4A/B-RBX1-DDB1-DCAF11 E3 ligase. The tempered α, β-unsaturated indolinone electrophiles define a drug-like DCAF11-ligand class that enables exploration of this E3 ligase in chemical biology and medicinal chemistry programs. The arylidene-indolinone scaffold frequently occurs in natural products which raises the question whether E3 ligand classes can be found more widely among natural products and related compounds.
    DOI:  https://doi.org/10.1038/s41467-023-43657-6
  50. bioRxiv. 2023 Nov 16. pii: 2023.11.13.566859. [Epub ahead of print]
    Evolutionary arms race between SARS-CoV-2 and interferon signaling via dynamic interaction with autophagy.
    Jae Seung Lee, Mark Dittmar, Jesse Miller, Minghua Li, Kasirajan Ayyanathan, Max Ferretti, Jesse Hulahan, Kanupriya Whig, Zienab Etwebi, Trevor Griesman, David C Schultz, Sara Cherry.
      SARS-CoV-2 emerged, and is evolving to efficiently infect humans worldwide. SARS-CoV-2 evades early innate recognition, interferon signaling activated only in bystander cells. This balance of innate activation and viral evasion has important consequences, but the pathways involved are incompletely understood. Here we find that autophagy genes regulate innate immune signaling, impacting the basal set point of interferons, and thus permissivity to infection. Mechanistically, autophagy genes negatively regulate MAVS, and this low basal level of MAVS is efficiently antagonized by SARS-CoV-2 ORF9b, blocking interferon activation in infected cells. However, upon loss of autophagy increased MAVS overcomes ORF9b-mediated antagonism suppressing infection. This has led to the evolution of SARS-CoV-2 variants to express higher levels of ORF9b, allowing SARS-CoV-2 to replicate under conditions of increased MAVS signaling. Altogether, we find a critical role of autophagy in the regulation of innate immunity and uncover an evolutionary trajectory of SARS-CoV-2 ORF9b to overcome host defenses.
    DOI:  https://doi.org/10.1101/2023.11.13.566859
  51. Front Cell Dev Biol. 2023 ;11 1290046
    Mitochondrial quality control in health and cardiovascular diseases.
    Asli E Atici, Timothy R Crother, Magali Noval Rivas.
      Cardiovascular diseases (CVDs) are one of the primary causes of mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy demand, such as the cardiovascular system. In addition to producing ATP as a power source, mitochondria are also heavily involved in adaptation to environmental stress and fine-tuning tissue functions. Mitochondrial quality control (MQC) through fission, fusion, mitophagy, and biogenesis ensures the clearance of dysfunctional mitochondria and preserves mitochondrial homeostasis in cardiovascular tissues. Furthermore, mitochondria generate reactive oxygen species (ROS), which trigger the production of pro-inflammatory cytokines and regulate cell survival. Mitochondrial dysfunction has been implicated in multiple CVDs, including ischemia-reperfusion (I/R), atherosclerosis, heart failure, cardiac hypertrophy, hypertension, diabetic and genetic cardiomyopathies, and Kawasaki Disease (KD). Thus, MQC is pivotal in promoting cardiovascular health. Here, we outline the mechanisms of MQC and discuss the current literature on mitochondrial adaptation in CVDs.
    Keywords:  ROS; cardiovascular disease; mitobiogenesis; mitochondria; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2023.1290046
  52. J Immunol. 2023 Dec 01. pii: ji2200835. [Epub ahead of print]
    Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.
    Maximilian Nickenig, Matthew S J Mangan, Hye Eun Lee, Konstantinos Symeonidis, Antonia Henne, Romina Kaiser, Eike Geißmar, Hendrikus Garritsen, Zeinab Abdullah, Karsten Hiller, Eicke Latz, Mario A Lauterbach.
      The 2'3'-cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of IFN genes (STING) pathway can sense infection and cellular stress by detecting cytosolic DNA. Upon ligand binding, cGAS produces the cyclic dinucleotide messenger cGAMP, which triggers its receptor STING. Active STING initiates gene transcription through the transcription factors IFN regulatory factor 3 (IRF3) and NF-κB and induces autophagy, but whether STING can cause changes in the metabolism of macrophages is unknown. In this study, we report that STING signaling activates ATP-citrate lyase (ACLY) by phosphorylation in human macrophages. Using genetic and pharmacologic perturbation, we show that STING targets ACLY via its prime downstream signaling effector TANK (TRAF family member-associated NF-κB activator)-binding kinase 1 (TBK1). We further identify that TBK1 alters cellular metabolism upon cGAMP treatment. Our results suggest that STING-mediated metabolic reprogramming adjusts the cellular response to DNA sensing in addition to transcription factor activation and autophagy induction.
    DOI:  https://doi.org/10.4049/jimmunol.2200835
  53. Pharmacology. 2023 Nov 27. 1-9
    Impairment of Autophagy Mediates the Uric-Acid-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells.
    Yan Lu, Hanlin Zhang, Min Han, Ping Wang, Liping Meng.
      INTRODUCTION: Hyperuricemia may be involved in the phenotypic transformation of vascular smooth muscle cells, thus promoting the occurrence of atherosclerosis, and autophagy may be one of the important links, but little is known about the specific molecular mechanism.METHODS: We established a mouse model of hyperuricemia and studied the relationship between changes in autophagy levels and the phenotypic transformation of muscle cells.
    RESULTS: Our study found that high uric acid levels promote the phenotypic transformation of muscle cells by inhibiting autophagy, thus enhancing their proliferation and migration abilities. If autophagy is restored, phenotypic transformation can be reversed by reducing the levels of the transcription factor Kruppel-like factor 4.
    CONCLUSION: Uric acid may induce the phenotypic transformation of muscle cells and promote the occurrence of atherosclerosis by disrupting normal autophagy.
    Keywords:  Atherosclerosis; Autophagy; Kruppel-like factor 4; Uric acid; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1159/000534929
  54. Cell Biosci. 2023 Nov 30. 13(1): 219
    mTOR hypoactivity leads to trophectoderm cell failure by enhancing lysosomal activation and disrupting the cytoskeleton in preimplantation embryo.
    Chiyuan Ma, Qin Li, Yuxin Yang, Lei Ge, Jiaxuan Cai, Juan Wang, Maoxian Zhu, Yue Xiong, Wenya Zhang, Jingtong Xie, Yujing Cao, Huashan Zhao, Qing Wei, Chen Huang, Junchao Shi, Jian V Zhang, Enkui Duan, Xiaohua Lei.
      BACKGROUND: Metabolic homeostasis is closely related to early impairment of cell fate determination and embryo development. The protein kinase mechanistic target of rapamycin (mTOR) is a key regulator of cellular metabolism in the body. Inhibition of mTOR signaling in early embryo causes postimplantation development failure, yet the mechanisms are still poorly understood.METHODS: Pregnancy mice and preimplantation mouse embryo were treated with mTOR inhibitor in vivo and in vitro respectively, and subsequently examined the blastocyst formation, implantation, and post-implantation development. We used immunofluorescence staining, RNA-Seq smart2, and genome-wide bisulfite sequencing technologies to investigate the impact of mTOR inhibitors on the quality, cell fate determination, and molecular alterations in developing embryos.
    RESULTS: We showed mTOR suppression during preimplantation decreases the rate of blastocyst formation and the competency of implantation, impairs the post implantation embryonic development. We discovered that blocking mTOR signaling negatively affected the transformation of 8-cell embryos into blastocysts and caused various deficiencies in blastocyst quality. These included problems with compromised trophectoderm cell differentiation, as well as disruptions in cell fate specification. mTOR suppression significantly affected the transcription and DNA methylation of embryos. Treatment with mTOR inhibitors increase lysosomal activation and disrupts the organization and dynamics of the actin cytoskeleton in blastocysts.
    CONCLUSIONS: These results demonstrate that mTOR plays a crucial role in 8-cell to blastocyst transition and safeguards embryo quality during early embryo development.
    Keywords:  Actin cytoskeleton disruption; DNA methylation; Lysosomal activation; Transcriptome; Trophectoderm cell failure; mTOR
    DOI:  https://doi.org/10.1186/s13578-023-01176-3
  55. EMBO Mol Med. 2023 Nov 27. e18028
    Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma.
    Jelle Verhoeven, Kathryn A Jacobs, Francesca Rizzollo, Francesca Lodi, Yichao Hua, Joanna Poźniak, Adhithya Narayanan Srinivasan, Diede Houbaert, Gautam Shankar, Sanket More, Marco B Schaaf, Nikolina Dubroja Lakic, Maarten Ganne, Jochen Lamote, Johan Van Weyenbergh, Louis Boon, Oliver Bechter, Francesca Bosisio, Yasuo Uchiyama, Mathieu Jm Bertrand, Jean Christophe Marine, Diether Lambrechts, Gabriele Bergers, Madhur Agrawal, Patrizia Agostinis.
      Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T-cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched InflammatoryHigh /AutophagyLow TEC phenotype in correlation with clinical responses to immunotherapy, and responders exhibit an increased presence of inflamed vessels interfacing with infiltrating CD8+ T-cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, our study identifies autophagy as a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.
    Keywords:  autophagy; cancer; immunotherapy; inflammation; tumor endothelial cells
    DOI:  https://doi.org/10.15252/emmm.202318028
  56. Front Neurosci. 2023 ;17 1244022
    Restoring autophagic function: a case for type 2 diabetes mellitus drug repurposing in Parkinson's disease.
    Marco Greco, Anas Munir, Debora Musarò, Chiara Coppola, Michele Maffia.
      Parkinson's disease (PD) is a predominantly idiopathic pathological condition characterized by protein aggregation phenomena, whose main component is alpha-synuclein. Although the main risk factor is ageing, numerous evidence points to the role of type 2 diabetes mellitus (T2DM) as an etiological factor. Systemic alterations classically associated with T2DM like insulin resistance and hyperglycemia modify biological processes such as autophagy and mitochondrial homeostasis. High glucose levels also compromise protein stability through the formation of advanced glycation end products, promoting protein aggregation processes. The ability of antidiabetic drugs to act on pathways impaired in both T2DM and PD suggests that they may represent a useful tool to counteract the neurodegeneration process. Several clinical studies now in advanced stages are looking for confirmation in this regard.
    Keywords:  Parkinson’s disease; alpha-synuclein; autophagy; hyperglycemia; insulin-resistance; islet amyloid peptide protein; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3389/fnins.2023.1244022
  57. PLoS One. 2023 ;18(11): e0294508
    Nrf1 is not a direct target gene of SREBP1, albeit both are integrated into the rapamycin-responsive regulatory network in human hepatoma cells.
    Keli Liu, Shaofan Hu, Lu Qiu, Meng Wang, Zhengwen Zhang, Guiyin Sun, Yiguo Zhang.
      The essential role of protein degradation by ubiquitin-proteasome system is exerted primarily for maintaining cellular protein homeostasis. The transcriptional activation of proteasomal genes by mTORC1 signaling depends on Nrf1, but whether this process is directly via SREBP1 remains elusive. In this study, our experiment evidence revealed that Nrf1 is not a direct target of SREBP1, although both are involved in the rapamycin-responsive regulatory networks. Closely scrutinizing two distinct transcriptomic datasets unraveled no significant changes in transcriptional expression of Nrf1 and almost all proteasomal subunits in either siSREBP2-silencing cells or SREBP1-∕-MEFs, when compared to equivalent controls. However, distinct upstream signaling to Nrf1 dislocation by p97 and its processing by DDI1/2, along with downstream proteasomal expression, may be monitored by mTOR signaling, to various certain extents, depending on distinct experimental settings in different types of cells. Our further evidence has been obtained from DDI1-∕-(DDI2insC) cells, demonstrating that putative effects of mTOR on the rapamycin-responsive signaling to Nrf1 and proteasomes may also be executed partially through a DDI1/2-independent mechanism, albeit the detailed regulatory events remain to be determined.
    DOI:  https://doi.org/10.1371/journal.pone.0294508
  58. Sci Signal. 2023 Nov 28. 16(813): eadn0652
    Stress granules plug holes.
    John F Foley.
      Ruptures in lysosomal membranes stimulate the formation of stress granules that plug the holes to enable repair.
    DOI:  https://doi.org/10.1126/scisignal.adn0652
  59. Glia. 2023 Nov 27.
    Enhanced VEGF secretion and blood-brain barrier disruption: Radiation-mediated inhibition of astrocyte autophagy via PI3K-AKT pathway activation.
    Shifeng Zhang, Mingping Li, Yuemin Qiu, Junyu Wu, Xue Xu, Qian Ma, Zhihui Zheng, Gengxin Lu, Zhezhi Deng, Haiwei Huang.
      Radiation-induced damage to the blood-brain barrier (BBB) is the recognized pathological basis of radiation-induced brain injury (RBI), a side effect of head and neck cancer treatments. There is currently a lack of therapeutic approaches for RBI due to the ambiguity of its underlying mechanisms. Therefore, it is essential to identify these mechanisms in order to prevent RBI or provide early interventions. One crucial factor contributing to BBB disruption is the radiation-induced activation of astrocytes and oversecretion of vascular endothelial growth factor (VEGF). Mechanistically, the PI3K-AKT pathway can inhibit cellular autophagy, leading to pathological cell aggregation. Moreover, it acts as an upstream pathway of VEGF. In this study, we observed the upregulation of the PI3K-AKT pathway in irradiated cultured astrocytes through bioinformatics analysis, we then validated these findings in animal brains and in vitro astrocytes following radiation exposure. Additionally, we also found the inhibition of autophagy and the oversecretion of VEGF in irradiated astrocytes. By inhibiting the PI3K-AKT pathway or promoting cellular autophagy, we observed a significant amelioration of the inhibitory effect on autophagy, leading to reductions in VEGF oversecretion and BBB disruption. In conclusion, our study suggests that radiation can inhibit autophagy and promote VEGF oversecretion by upregulating the PI3K-AKT pathway in astrocytes. Blocking the PI3K pathway can alleviate both of these effects, thereby mitigating damage to the BBB in patients undergoing radiation treatment.
    Keywords:  PI3K-AKT; astrocyte; autophagy; blood-brain barrier; radiation
    DOI:  https://doi.org/10.1002/glia.24491
  60. Neuroscience. 2023 Nov 29. pii: S0306-4522(23)00532-8. [Epub ahead of print]
    Heat Shock Protein 90 in Parkinson's disease: Profile of a serial killer.
    Heba M Mansour, Ahmed F Mohamed, Mahmoud M Khattab, Aiman S El-Khatib.
      Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by abnormal α-synuclein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, as well as progressive death of dopaminergic neurons in the substantia nigra. Molecular chaperones play a role in stabilizing proteins and helping them achieve their proper structure. Previous studies have shown that overexpression of heat shock protein 90 (HSP90) can lead to the death of dopaminergic neurons associated with PD. Inhibiting HSP90 is considered a potential treatment approach for neurodegenerative disorders, as it may reduce protein aggregation and related toxicity, as well as suppress various forms of regulated cell death (RCD). This review provides an overview of HSP90 and its role in PD, focusing on its modulation of proteostasis and quality control of LRRK2. The review also explores the effects of HSP90 on different types of RCD, such as apoptosis, chaperone-mediated autophagy (CMA), necroptosis, and ferroptosis. Additionally, it discusses HSP90 inhibitors that have been tested in PD models. We will highlight the under-investigated neuroprotective effects of HSP90 inhibition, including modulation of oxidative stress, mitochondrial dysfunction, PINK/PARKIN, heat shock factor 1 (HSF1), histone deacetylase 6 (HDAC6), and the PHD2-HSP90 complex-mediated mitochondrial stress pathway. By examining previous literature, this review uncovers overlooked neuroprotective mechanisms and emphasizes the need for further research on HSP90 inhibitors as potential therapeutic strategies for PD. Finally, the review discusses the potential limitations and possibilities of using HSP90 inhibitors in PD therapy.
    Keywords:  Chaperones; Heat shock protein 90; Parkinson's disease; Regulated cell death; chaperone-mediated autophagy
    DOI:  https://doi.org/10.1016/j.neuroscience.2023.11.031
  61. Mol Neurobiol. 2023 Nov 27.
    Uric Acid Mitigates Cognitive Deficits via TFEB-Mediated Microglial Autophagy in Mice Models of Alzheimer's Disease.
    Qian Xiao, Jiaojiao Wang, Qiuyun Tian, Na Tian, Qi Tian, Xin He, Yutian Wang, Zhifang Dong.
      Clinical trials have demonstrated the potential neuroprotective effects of uric acid (UA) in Alzheimer's disease (AD). However, the specific mechanism underlying the neuroprotective effect of UA remains unclear. In the present study, we investigated the neuroprotective effect and underlying mechanism of UA in AD mouse models. Various behavioral tests including an elevated plus maze, Barnes maze, and Morris water maze were conducted to evaluate the impact of UA on cognitive function in β-amyloid (Aβ) microinjection and APP23/PS45 double transgenic mice models of AD. Immunohistochemical staining was employed to visualize pathological changes in the brains of AD model mice. Western blotting and immunofluorescence techniques were used to assess levels of autophagy-related proteins and transcription factor EB (TFEB)-related signaling pathways. BV2 cells were used to investigate the association between UA and microglial autophagy. We reported that UA treatment significantly alleviated memory decline in Aβ-induced AD model mice and APP23/PS45 double transgenic AD model mice. Furthermore, UA activated microglia and upregulated the autophagy-related proteins such as LC3II/I ratio, Beclin-1, and LAMP1 in the hippocampus of AD model mice. Similarly, UA protected BV2 cells from Aβ toxicity by upregulating the expressions of Beclin-1, LAMP1, and the LC3II/I ratio, whereas genetic inhibition of TFEB completely abolished these protective effects. Our results indicate that UA may serve as a novel activator of TFEB to induce microglia autophagy and facilitate Aβ degradation, thereby improving cognitive function in AD model mice. Therefore, these findings suggest that UA may be a novel therapeutic agent for AD treatment.
    Keywords:  Alzheimer’s disease; Autophagy; Neuroprotection; Transcription factor EB; Uric acid
    DOI:  https://doi.org/10.1007/s12035-023-03818-6
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