bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2022‒11‒13
fifty-one papers selected by
Viktor Korolchuk, Newcastle University
  1. How cells recognize and remove the perforated lysosome.
  2. Novel protein complexes containing autophagy and UPS components regulate proteasome-dependent PARK2 recruitment onto mitochondria and PARK2-PARK6 activity during mitophagy.
  3. Defective PTEN-induced kinase 1/Parkin mediated mitophagy and neurodegenerative diseases.
  4. Lysosomal dysfunction, autophagic defects, and CLN5 accumulation underlie the pathogenesis of KCTD7-mutated neuronal ceroid lipofuscinoses.
  5. Fine-Tuning of mTORC1-ULK1-PP2A Regulatory Triangle Is Crucial for Robust Autophagic Response upon Cellular Stress.
  6. Modulating autophagy and mitophagy as a promising therapeutic approach in neurodegenerative disorders.
  7. An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss.
  8. Brain-Derived Neurotrophic Factor stimulates the retrograde pathway for axonal autophagy.
  9. Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.
  10. --Atg9 interactions via its transmembrane domains are required for phagophore expansion during autophagy.
  11. Regulation of autophagy of the heart in ischemia and reperfusion.
  12. Role of mTOR1 signaling in the antidepressant effects of ketamine and the potential of mTORC1 activators as novel antidepressants.
  13. FIP200 Methylation by SETD2 Prevents Trim21-Induced Degradation and Preserves Autophagy Initiation.
  14. The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner.
  15. Autophagy induces mTOR-dependent glucose uptake and mTOR-independent lactate utilization in cadmium-treated A549 cells.
  16. ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation.
  17. Atg9A-mediated mitophagy is required for decidual differentiation of endometrial stromal cells.
  18. Denervation induces mitochondrial decline and exacerbates lysosome dysfunction in middle-aged mice.
  19. Aoatg11 and Aoatg33 are indispensable for mitophagy, and contribute to conidiation, the stress response, and pathogenicity in the nematode-trapping fungus Arthrobotrys oligospora.
  20. Longin domain GAP complexes in nutrient signaling, membrane traffic, and neurodegeneration.
  21. Differential contributions of the proteasome, autophagy, and chaperones to the clearance of arsenite-induced protein aggregates in yeast.
  22. Tegument protein UL21 of alpha-herpesvirus inhibits the innate immunity by triggering CGAS degradation through TOLLIP-mediated selective autophagy.
  23. Ferritinophagy, a form of autophagic ferroptosis: New insights into cancer treatment.
  24. Augmenter of liver regeneration reduces mitochondria-derived ROS and NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy in ischemia-reperfusion-induced renal tubular injury.
  25. Autophagy and Its Association with Genetic Mutations in Parkinson Disease.
  26. Quantitative Metabolomic Analysis of Changes in the Rat Blood Serum during Autophagy Modulation: A Focus on Accelerated Senescence.
  27. Enhanced Sensitivity of Tumor Cells to Autophagy Inhibitors Using Fasting-Mimicking Diet and Targeted Lysosomal Delivery Nanoplatform.
  28. Exploring therapeutic potential of mitophagy modulators using Drosophila models of Parkinson's disease.
  29. Identification and Expression Analysis of the Solanum tuberosum StATG8 Family Associated with the WRKY Transcription Factor.
  30. Palmitate Inhibits Mouse Macrophage Efferocytosis by Activating an mTORC1-Regulated Rho Kinase 1 Pathway: Therapeutic Implications for the Treatment of Obesity.
  31. Editorial: Beclin 1 and autophagy---in memory of Beth Levine (1960-2020).
  32. Anesthetic sevoflurane simultaneously regulates autophagic flux and pyroptotic cell death-associated cellular inflammation in the hypoxic/re-oxygenated cardiomyocytes: Identification of sevoflurane as putative drug for the treatment of myocardial ischemia-reperfusion injury.
  33. Apelin-13 Increases Functional Connexin-43 through Autophagy Inhibition via AKT/mTOR Pathway in the Non-Myocytic Cell Population of the Heart.
  34. Small molecules that enhance mitophagy to delay aging and neurodegeneration.
  35. Redox balance and autophagy regulation in cancer progression and their therapeutic perspective.
  36. Platelet derived growth factor promotes the recovery of traumatic brain injury by inhibiting endoplasmic reticulum stress and autophagy-mediated pyroptosis.
  37. A key virulence effector from cyst nematodes targets host autophagy to promote nematode parasitism.
  38. The Genetic Variability of Members of the SLC38 Family of Amino Acid Transporters (SLC38A3, SLC38A7 and SLC38A9) Affects Susceptibility to Type 2 Diabetes and Vascular Complications.
  39. Focusing on the Role of Natural Products in Overcoming Cancer Drug Resistance: An Autophagy-Based Perspective.
  40. Mycobacterium tuberculosis: Implications of Ageing on Infection and Maintaining Protection in the Elderly.
  41. Regulation of autophagy by non-coding RNAs in gastric cancer.
  42. The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy.
  43. Myo1b promotes tumor progression and angiogenesis by inhibiting autophagic degradation of HIF-1α in colorectal cancer.
  44. Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease.
  45. Integration of ER protein quality control mechanisms defines β-cell function and ER architecture.
  46. Nuclear factor erythroid 2-related factor 2 and autophagy regulation in cancer development.
  47. The Novel Lysosomal Autophagy Inhibitor (ROC-325) Ameliorates Experimental Pulmonary Hypertension.
  48. Transthyretin attenuates TDP-43 proteinopathy by autophagy activation via ATF4 in FTLD-TDP.
  49. Cyclodextrins applied to the treatment of lysosomal disorders.
  50. AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
  51. Diversity, equity and inclusion in autophagy research.
  1. Autophagy. 2022 Nov 11. 1-3
    How cells recognize and remove the perforated lysosome.
    Keisuke Tabata, Marika Saeki, Tamotsu Yoshimori, Maho Hamasaki.
      Macroautophagy (hereafter autophagy) is a highly conserved intracellular degradation system to maintain cellular homeostasis by degrading cellular components such as misfolded proteins, nonfunctional organelles, pathogens, and cytosol. Conversely, selective autophagy targets and degrades specific cargo, such as organelles, bacteria, etc. We previously reported that damaged lysosomes are autophagy targets, via a process called lysophagy. However, how cells target damaged lysosomes through autophagy is not known. We performed proteomics analysis followed by siRNA screening to identify genes involved in targeting damaged lysosomes and identified a new E3 ligase complex, involving CUL4A (cullin 4A), as a regulatory complex in lysophagy. We also found that this complex mediates K48-linked poly-ubiquitination on lysosome protein LAMP2 during lysosomal damage; particularly, the lumenal side of LAMP2 is important to recruit the complex to damaged lysosomes. This protein modification is thus critical to initiate the clearance of damaged lysosomes.
    Keywords:  CUL4A; LAMP2; lysophagy; lysosomal membrane damage; selective autophagy; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2022.2138686
  2. Cell Death Dis. 2022 Nov 10. 13(11): 947
    Novel protein complexes containing autophagy and UPS components regulate proteasome-dependent PARK2 recruitment onto mitochondria and PARK2-PARK6 activity during mitophagy.
    Nur Mehpare Kocaturk, Nesibe Peker, Karin Eberhart, Yunus Akkoc, Gamze Deveci, Joern Dengjel, Devrim Gozuacik.
      Autophagy is an evolutionarily conserved eukaryotic cellular mechanism through which cytosolic fragments, misfolded/aggregated proteins and organelles are degraded and recycled. Priming of mitochondria through ubiquitylation is required for the clearance the organelle by autophagy (mitophagy). Familial Parkinson's Disease-related proteins, including the E3-ligase PARK2 (PARKIN) and the serine/threonine kinase PARK6 (PINK1) control these ubiquitylation reactions and contribute to the regulation of mitophagy. Here we describe, novel protein complexes containing autophagy protein ATG5 and ubiquitin-proteasome system (UPS) components. We discovered that ATG5 interacts with PSMA7 and PARK2 upon mitochondrial stress. Results suggest that all three proteins translocate mitochondria and involve in protein complexes containing autophagy, UPS and mitophagy proteins. Interestingly, PARK2 and ATG5 recruitment onto mitochondria requires proteasome components PSMA7 and PSMB5. Strikingly, we discovered that subunit of 20 S proteasome, PSMA7, is required for the progression of PARK2-PARK6-mediated mitophagy and the proteasome activity following mitochondrial stress. Our results demonstrate direct, dynamic and functional interactions between autophagy and UPS components that contribute to the regulation of mitophagy.
    DOI:  https://doi.org/10.1038/s41419-022-05339-x
  3. Front Cell Neurosci. 2022 ;16 1031153
    Defective PTEN-induced kinase 1/Parkin mediated mitophagy and neurodegenerative diseases.
    Megan M Braun, Luigi Puglielli.
      The selective degradation of mitochondria through mitophagy is a crucial process for maintaining mitochondrial function and cellular health. Mitophagy is a specialized form of selective autophagy that uses unique machinery to recognize and target damaged mitochondria for mitophagosome- and lysosome-dependent degradation. This process is particularly important in cells with high metabolic activity like neurons, and the accumulation of defective mitochondria is a common feature among neurodegenerative disorders. Here, we describe essential steps involved in the induction and progression of mitophagy, and then highlight the various mechanisms that specifically contribute to defective mitophagy in highly prevalent neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; mitochondria; mitochondrial dysfunction; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3389/fncel.2022.1031153
  4. Autophagy. 2022 Nov 11. 1-3
    Lysosomal dysfunction, autophagic defects, and CLN5 accumulation underlie the pathogenesis of KCTD7-mutated neuronal ceroid lipofuscinoses.
    Yalan Wang, Hongyan Wang, Chenji Wang.
      Lysosomes are essential catabolic organelles responsible for the degradation of biomacromolecules into low-molecular-weight materials for subsequent reuse. Neuronal ceroid lipofuscinoses (NCLs) are a group of fatal neurodegenerative lysosomal storage disorders characterized by the intracellular accumulation of lipoprotein aggregates (called ceroid lipofuscin) in neurons and other tissues. Mutations in KCTD7, which encodes a substrate-binding adaptor for the CUL3-RING E3 (CRL3) ubiquitin ligase complex, are categorized as a unique NCL subtype. However, the molecular mechanisms underlying the KCTD7-mutated NCLs remain unclear. In our recent study, we showed that KCTD7 deficiency leads to the accumulation of lysosomal storage deposits owing to lysosomal dysfunction and macroautophagic/autophagic defects. We identified CLN5 as an authentic substrate of CRL3-KCTD7 E3s. Wild-type KCTD7 targets CLN5 for ubiquitination and proteasomal degradation, whereas NCL patient-derived KCTD7 mutations disrupt the interaction between KCTD7-CUL3 or KCTD7-CLN5 and ultimately lead to excessive CLN5 accumulation in the endoplasmic reticulum. Accumulated CLN5 disrupts the interaction between CLN6-CLN8 and lysosomal enzymes, leading to impaired ER-to-Golgi trafficking of lysosomal enzymes. Thus, our findings indicate that KCTD7 is a key player in maintaining lysosomal and autophagic homeostasis and demonstrate that KCTD7 and CLN5, two NCL causative genes, are biochemically linked and function in a common neurodegenerative pathway.
    Keywords:  Autophagy; lipofuscinoses; lysosome; neurodegeneration; trafficking; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2022.2140882
  5. Biomolecules. 2022 Oct 28. pii: 1587. [Epub ahead of print]12(11):
    Fine-Tuning of mTORC1-ULK1-PP2A Regulatory Triangle Is Crucial for Robust Autophagic Response upon Cellular Stress.
    Bence Hajdú, Marianna Holczer, Gergely Horváth, Gábor Szederkényi, Orsolya Kapuy.
      Autophagy-dependent cellular survival is tightly regulated by both kinases and phosphatases. While mTORC1 inhibits autophagy by phosphorylating ULK1, PP2A is able to remove this phosphate group from ULK1 and promotes the key inducer of autophagosome formation. However, ULK1 inhibits mTORC1, mTORC1 is able to down-regulate PP2A. In addition, the active ULK1 promotes PP2A via phosphorylation. We claim that these double-negative (mTORC1 -| PP2A -| mTORC1, mTORC1 -| ULK1 -| mTORC1) and positive (ULK1 -> PP2A -> ULK1) feedback loops are all necessary for the robust, irreversible decision making process between the autophagy and non-autophagy states. We approach our scientific analysis from a systems biological perspective by applying both theoretical and molecular biological techniques. For molecular biological experiments, HEK293T cell line is used, meanwhile the dynamical features of the regulatory network are described by mathematical modelling. In our study, we explore the dynamical characteristic of mTORC1-ULK1-PP2A regulatory triangle in detail supposing that the positive feedback loops are essential to manage a robust cellular answer upon various cellular stress events (such as mTORC1 inhibition, starvation, PP2A inhibition or ULK1 silencing). We confirm that active ULK1 can up-regulate PP2A when mTORC1 is inactivated. By using theoretical analysis, we explain the importance of cellular PP2A level in stress response mechanism. We proved both experimentally and theoretically that PP2A down-regulation (via addition of okadaic acid) might generate a periodic repeat of autophagy induction. Understanding how the regulation of the cell survival occurs with the precise molecular balance of ULK1-mTORC1-PP2A in autophagy, is highly relevant in several cellular stress-related diseases (such as neurodegenerative diseases or diabetes) and might help to promote advanced therapies in the near future, too.
    Keywords:  PP2A; ULK1; autophagy; feedback loop; mTORC1; systems biology
    DOI:  https://doi.org/10.3390/biom12111587
  6. Life Sci. 2022 Nov 04. pii: S0024-3205(22)00853-0. [Epub ahead of print] 121153
    Modulating autophagy and mitophagy as a promising therapeutic approach in neurodegenerative disorders.
    Jayapriya Mishra, Gurjit Kaur Bhatti, Abhishek Sehrawat, Charan Singh, Arti Singh, Arubala P Reddy, P Hemachandra Reddy, Jasvinder Singh Bhatti.
      The high prevalence of neurodegenerative diseases has become a major public health challenge and is associated with a tremendous burden on individuals, society and federal governments worldwide. Protein misfolding and aggregation are the major pathological hallmarks of several neurodegenerative disorders. The cells have evolved several regulatory mechanisms to deal with aberrant protein folding, namely the classical ubiquitin pathway, where ubiquitination of protein aggregates marks their degradation via lysosome and the novel autophagy or mitophagy pathways. Autophagy is a catabolic process in eukaryotic cells that allows the lysosome to recycle the cell's own contents, such as organelles and proteins, known as autophagic cargo. Their most significant role is to keep cells alive in distressed situations. Mitophagy is also crucial for reducing abnormal protein aggregation and increasing organelle clearance and partly accounts for maintaining cellular homeostasis. Furthermore, substantial data indicate that any disruption in these homeostatic mechanisms leads to the emergence of several age-associated metabolic and neurodegenerative diseases. So, targeting autophagy and mitophagy might be a potential therapeutic strategy for a variety of health conditions.
    Keywords:  Aggregation; Autophagic cargo; Autophagy; Functional foods; Homeostasis; Misfolding; Mitophagy; Neurodegenerative disorders
    DOI:  https://doi.org/10.1016/j.lfs.2022.121153
  7. Nat Commun. 2022 Nov 10. 13(1): 6808
    An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss.
    Kaushal Asrani, Juhyung Woo, Adrianna A Mendes, Ethan Schaffer, Thiago Vidotto, Clarence Rachel Villanueva, Kewen Feng, Lia Oliveira, Sanjana Murali, Hans B Liu, Daniela C Salles, Brandon Lam, Pedram Argani, Tamara L Lotan.
      The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in renal cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null renal cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in renal cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.
    DOI:  https://doi.org/10.1038/s41467-022-34617-7
  8. J Biol Chem. 2022 Nov 03. pii: S0021-9258(22)01116-4. [Epub ahead of print] 102673
    Brain-Derived Neurotrophic Factor stimulates the retrograde pathway for axonal autophagy.
    David Kader Sidibe, Vineet Vinay Kulkarni, Audrey Dong, Jessica Brandt Herr, Maria Chalokh Vogel, Max Henry Stempel, Sandra Maday.
      Autophagy is a lysosomal degradative pathway important for neuronal development, function, and survival. How autophagy in axons is regulated by neurotrophins to impact neuronal viability and function is poorly understood. Here, we use live-cell imaging in primary neurons to investigate the regulation of axonal autophagy by the neurotrophin Brain-Derived Neurotrophic Factor (BDNF), and elucidate whether autophagosomes carry BDNF-mediated signaling information. We find that BDNF induces autophagic flux in primary neurons by stimulating the retrograde pathway for autophagy in axons. We observed an increase in autophagosome density and retrograde flux in axons, and a corresponding increase in autophagosome density in the soma. However, we find little evidence of autophagosomes co-migrating with BDNF. In contrast, BDNF effectively engages its cognate receptor TrkB to undergo retrograde transport in the axon. These compartments, however, are distinct from LC3-positive autophagic organelles in the axon. Together, we find that BDNF stimulates autophagy in the axon, but retrograde autophagosomes do not appear to carry BDNF cargo. Thus, autophagosomes likely do not play a major role in relaying neurotrophic signaling information across the axon in the form of active BDNF/TrkB complexes. Rather, BDNF likely stimulates autophagy as a consequence of BDNF-induced processes that require canonical roles for autophagy in degradation.
    Keywords:  Autophagy; Axon; BDNF; Neurons; Neurotrophin
    DOI:  https://doi.org/10.1016/j.jbc.2022.102673
  9. Nat Commun. 2022 Nov 07. 13(1): 6704
    Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.
    Ayesha Sen, Sebastian Kallabis, Felix Gaedke, Christian Jüngst, Julia Boix, Julian Nüchel, Kanjanamas Maliphol, Julia Hofmann, Astrid C Schauss, Marcus Krüger, Rudolf J Wiesner, David Pla-Martín.
      Understanding the mechanisms governing selective turnover of mutation-bearing mtDNA is fundamental to design therapeutic strategies against mtDNA diseases. Here, we show that specific mtDNA damage leads to an exacerbated mtDNA turnover, independent of canonical macroautophagy, but relying on lysosomal function and ATG5. Using proximity labeling and Twinkle as a nucleoid marker, we demonstrate that mtDNA damage induces membrane remodeling and endosomal recruitment in close proximity to mitochondrial nucleoid sub-compartments. Targeting of mitochondrial nucleoids is controlled by the ATAD3-SAMM50 axis, which is disrupted upon mtDNA damage. SAMM50 acts as a gatekeeper, influencing BAK clustering, controlling nucleoid release and facilitating transfer to endosomes. Here, VPS35 mediates maturation of early endosomes to late autophagy vesicles where degradation occurs. In addition, using a mouse model where mtDNA alterations cause impairment of muscle regeneration, we show that stimulation of lysosomal activity by rapamycin, selectively removes mtDNA deletions without affecting mtDNA copy number, ameliorating mitochondrial dysfunction. Taken together, our data demonstrates that upon mtDNA damage, mitochondrial nucleoids are eliminated outside the mitochondrial network through an endosomal-mitophagy pathway. With these results, we unveil the molecular players of a complex mechanism with multiple potential benefits to understand mtDNA related diseases, inherited, acquired or due to normal ageing.
    DOI:  https://doi.org/10.1038/s41467-022-34205-9
  10. Autophagy. 2022 Nov 10. 1-20
    --Atg9 interactions via its transmembrane domains are required for phagophore expansion during autophagy.
    Sabrina Chumpen Ramirez, Rubén Gómez-Sánchez, Pauline Verlhac, Ralph Hardenberg, Eleonora Margheritis, Katia Cosentino, Fulvio Reggiori, Christian Ungermann.
      During macroautophagy/autophagy, precursor cisterna known as phagophores expand and sequester portions of the cytoplasm and/or organelles, and subsequently close resulting in double-membrane transport vesicles called autophagosomes. Autophagosomes fuse with lysosomes/vacuoles to allow the degradation and recycling of their cargoes. We previously showed that sequential binding of yeast Atg2 and Atg18 to Atg9, the only conserved transmembrane protein in autophagy, at the extremities of the phagophore mediates the establishment of membrane contact sites between the phagophore and the endoplasmic reticulum. As the Atg2-Atg18 complex transfers lipids between adjacent membranes in vitro, it has been postulated that this activity and the scramblase activity of the trimers formed by Atg9 are required for the phagophore expansion. Here, we present evidence that Atg9 indeed promotes Atg2-Atg18 complex-mediated lipid transfer in vitro, although this is not the only requirement for its function in vivo. In particular, we show that Atg9 function is dramatically compromised by a F627A mutation within the conserved interface between the transmembrane domains of the Atg9 monomers. Although Atg9F627A self-interacts and binds to the Atg2-Atg18 complex, the F627A mutation blocks the phagophore expansion and thus autophagy progression. This phenotype is conserved because the corresponding human ATG9A mutant severely impairs autophagy as well. Importantly, Atg9F627A has identical scramblase activity in vitro like Atg9, and as with the wild-type protein enhances Atg2-Atg18-mediated lipid transfer. Collectively, our data reveal that interactions of Atg9 trimers via their transmembrane segments play a key role in phagophore expansion beyond Atg9's role as a lipid scramblase.Abbreviations: BafA1: bafilomycin A1; Cvt: cytoplasm-to-vacuole targeting; Cryo-EM: cryo-electron microscopy; ER: endoplasmic reticulum; GFP: green fluorescent protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCS: membrane contact site; NBD-PE: N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine; PAS: phagophore assembly site; PE: phosphatidylethanolamine; prApe1: precursor Ape1; PtdIns3P: phosphatidylinositol-3-phosphate; SLB: supported lipid bilayer; SUV: small unilamellar vesicle; TMD: transmembrane domain; WT: wild type.
    Keywords:  Autophagosome; lipid transfer; membrane contact site; phagophore; scramblase
    DOI:  https://doi.org/10.1080/15548627.2022.2136340
  11. Apoptosis. 2022 Nov 11.
    Regulation of autophagy of the heart in ischemia and reperfusion.
    Sergey V Popov, Alexander V Mukhomedzyanov, Nikita S Voronkov, Ivan A Derkachev, Alla A Boshchenko, Feng Fu, Galina Z Sufianova, Maria S Khlestkina, Leonid N Maslov.
      Ischemia/reperfusion (I/R) of the heart leads to increased autophagic flux. Preconditioning stimulates autophagic flux by AMPK and PI3-kinase activation and mTOR inhibition. The cardioprotective effect of postconditioning is associated with activation of autophagy and increased activity of NO-synthase and AMPK. Oxidative stress stimulates autophagy in the heart during I/R. Superoxide radicals generated by NADPH-oxidase acts as a trigger for autophagy, possibly due to AMPK activation. There is reason to believe that AMPK, GSK-3β, PINK1, JNK, hexokinase II, MEK, PKCα, and ERK kinases stimulate autophagy, while mTOR, PKCδ, Akt, and PI3-kinase can inhibit autophagy in the heart during I/R. However, there is evidence that PI3-kinase could stimulate autophagy in ischemic preconditioning of the heart. It was found that transcription factors FoxO1, FoxO3, NF-κB, HIF-1α, TFEB, and Nrf-2 enhance autophagy in the heart in I/R. Transcriptional factors STAT1, STAT3, and p53 inhibit autophagy in I/R. MicroRNAs could stimulate and inhibit autophagy in the heart in I/R. Long noncoding RNAs regulate the viability and autophagy of cardiomyocytes in hypoxia/reoxygenation (H/R). Nitric oxide (NO) donors and endogenous NO could activate autophagy of cardiomyocytes. Activation of heme oxygenase-1 promotes cardiomyocyte tolerance to H/R and enhances autophagy. Hydrogen sulfide increases cardiac tolerance to I/R and inhibits apoptosis and autophagy via mTOR and PI3-kinase activation.
    Keywords:  Autophagy; Heart; Ischemia/reperfusion; Kinases; Reactive oxygen species; microRNAs
    DOI:  https://doi.org/10.1007/s10495-022-01786-1
  12. Neuropharmacology. 2022 Nov 02. pii: S0028-3908(22)00384-7. [Epub ahead of print] 109325
    Role of mTOR1 signaling in the antidepressant effects of ketamine and the potential of mTORC1 activators as novel antidepressants.
    Taro Kato.
      Conventional antidepressant medications act on monoaminergic systems and have important limitations, including a therapeutic delay of weeks to months and low rates of efficacy. Recently, clinical findings have indicated that ketamine, a dissociative anesthetic that blocks N-methyl-d-aspartate receptor channel activity, causes rapid and long-lasting antidepressant effects. Although the exact mechanisms underlying the antidepressant effects of ketamine are not fully known, preclinical studies have demonstrated a key role for mechanistic target of rapamycin complex 1 (mTORC1) signaling and a subsequent increase in synapse formation in the medial prefrontal cortex. In this review, we discuss the role of mTORC1 and its subsequent signaling cascade in the antidepressant effects of ketamine and other compounds with glutamatergic mechanisms of action. We also present the possibility that mTORC1 signaling itself is a drug discovery target.
    Keywords:  Antidepressants; Glutamatergic signaling; Ketamine; Major depressive disorder; mTOR; mTORC1
    DOI:  https://doi.org/10.1016/j.neuropharm.2022.109325
  13. Cells. 2022 Oct 22. pii: 3333. [Epub ahead of print]11(21):
    FIP200 Methylation by SETD2 Prevents Trim21-Induced Degradation and Preserves Autophagy Initiation.
    Yuan Dai, Weijia Luo, Wenjiao Li, Zhishi Chen, Xinjie Wang, Jiang Chang.
      FIP200, also known as RB1CC1, is a protein that assembles the autophagy initiation complex. Its post-translational modifications and degradation mechanisms are unclear. Upon autophagy activation, we find that FIP200 is methylated at lysine1133 (K1133) by methyltransferase SETD2. We identify the E3 ligase Trim21 to be responsible for FIP200 ubiquitination by targeting K1133, resulting in FIP200 degradation through the ubiquitin-proteasome system. SETD2-induced methylation blocks Trim21-mediated ubiquitination and degradation, preserving autophagy activity. SETD2 and Trim21 orchestrate FIP200 protein stability to achieve dynamic and precise control of autophagy flux.
    Keywords:  autophagy; post-translational modification
    DOI:  https://doi.org/10.3390/cells11213333
  14. EMBO J. 2022 Nov 10. e110833
    The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner.
    Belén Sanz-Castillo, Begoña Hurtado, Diana Vara-Ciruelos, Aicha El Bakkali, Dario Hermida, Beatriz Salvador-Barbero, Diego Martínez-Alonso, José González-Martínez, Clara Santiveri, Ramón Campos-Olivas, Pilar Ximénez-Embún, Javier Muñoz, Mónica Álvarez-Fernández, Marcos Malumbres.
      The AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here, we show that MASTL/Greatwall, a cell cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K-AKT activity by sustaining mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10. Genetic depletion of MASTL results in an inefficient feedback loop and AKT hyperactivity. These defects are rescued by the expression of phosphomimetic ENSA/ARPP19 or inhibition of PP2A/B55 phosphatases. MASTL is directly phosphorylated by mTORC1, thereby limiting the PP2A/B55-dependent dephosphorylation of IRS1 and GRB10 downstream of mTORC1. Downregulation of MASTL results in increased glucose uptake in vitro and increased glucose tolerance in adult mice, suggesting the relevance of the MASTL-PP2A/B55 kinase-phosphatase module in controlling AKT and maintaining metabolic homeostasis.
    Keywords:  AKT; MASTL; cell cycle; glucose homeostasis; mTOR
    DOI:  https://doi.org/10.15252/embj.2022110833
  15. Toxicol In Vitro. 2022 Nov 03. pii: S0887-2333(22)00211-9. [Epub ahead of print] 105513
    Autophagy induces mTOR-dependent glucose uptake and mTOR-independent lactate utilization in cadmium-treated A549 cells.
    Shibo Bao, Cong Zhang, Shengxiang Luo, Liping Jiang, Qiujuan Li, Ying Kong, Jun Cao.
      Cadmium (Cd) is a non-essential heavy metal with many harmful effects, especially tumorigenesis. Previously we established that autophagy-dependent increasing of glycolysis played an important role in Cd-induced cell growth and migration of A549 and HELF cells. In this study, we found Cd could induce autophagy and mTOR in A549 cells, HELF cells and in lung tissues of BALB/c mice. More interestingly, Cd-induced elevation of mTOR was autophagy-dependent and autophagy-induced cell growth and glycolysis was mTOR-dependent. However, in A549 cells, besides the above mTOR-dependent pathway, Cd-induced autophagy could directly induce PKM2 and LDHA independent of mTOR. Further study showed that only in A549 cells could autophagy other than mTOR enable Cd to increase MCT1 expression and MCT1 was involved in autophagy-induced PKM2 and LDHA. Sodium lactate added in the culture medium promoted Cd-induced cell growth of A549 cells, while had no effect on HELF cells. Finally, the effect of autophagy/MCT1/PKM2 pathway on lactate utilization to facilitate Cd-induced A549 cell growth was determined. Above all, we concluded that in HELF cells, autophagy induced mTOR-dependent glycolysis in which GLUT1 and HKII was elevated to promote glucose intake to accelerate cell growth. Whereas, in A549 cells, besides the above pathway to use glucose, autophagy could induce an mTOR-independent glycolysis pathway in which lactate could be used as fuel through autophagy-MCT1-PKM2 to escape glucose deficiency.
    Keywords:  Autophagy; Cadmium; Cell growth; Glycolysis; Lactate utilization; mTOR
    DOI:  https://doi.org/10.1016/j.tiv.2022.105513
  16. Mol Cell. 2022 Nov 01. pii: S1097-2765(22)01017-6. [Epub ahead of print]
    ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation.
    Alexander R van Vliet, George N Chiduza, Sarah L Maslen, Valerie E Pye, Dhira Joshi, Stefano De Tito, Harold B J Jefferies, Evangelos Christodoulou, Chloë Roustan, Emma Punch, Javier H Hervás, Nicola O'Reilly, J Mark Skehel, Peter Cherepanov, Sharon A Tooze.
      ATG9A and ATG2A are essential core members of the autophagy machinery. ATG9A is a lipid scramblase that allows equilibration of lipids across a membrane bilayer, whereas ATG2A facilitates lipid flow between tethered membranes. Although both have been functionally linked during the formation of autophagosomes, the molecular details and consequences of their interaction remain unclear. By combining data from peptide arrays, crosslinking, and hydrogen-deuterium exchange mass spectrometry together with cryoelectron microscopy, we propose a molecular model of the ATG9A-2A complex. Using this integrative structure modeling approach, we identify several interfaces mediating ATG9A-2A interaction that would allow a direct transfer of lipids from ATG2A into the lipid-binding perpendicular branch of ATG9A. Mutational analyses combined with functional activity assays demonstrate their importance for autophagy, thereby shedding light on this protein complex at the heart of autophagy.
    Keywords:  AlphaFold; autophagosome; autophagy; integrative structure prediction; lipid scramblase; lipid transfer
    DOI:  https://doi.org/10.1016/j.molcel.2022.10.017
  17. Reprod Biol. 2022 Nov 05. pii: S1642-431X(22)00106-1. [Epub ahead of print]22(4): 100707
    Atg9A-mediated mitophagy is required for decidual differentiation of endometrial stromal cells.
    Jing Li, Songying Zhang, Yanling Zhang, Yangyang Dai, Yi Zhang, Anran Yang, Fang Hong, Yibin Pan.
      Endometrial decidualization is the foundation of a healthy pregnancy. Mitochondrial dysfunction is an independent cause of disease for energy-intensive organs. Mitochondrial homeostasis plays a key role in the differentiation processes of many cell types. We showed increased activation of mitophagy (mitochondrial autophagy) in the decidua compared with proliferative or secretory endometrium. To better comprehend the mechanisms underlying healthy conception, understanding the mechanism of endometrial stromal cell decidualization is of great importance. Here, we artificially induced decidualization of a human endometrial stromal cell line (T HESCs) and characterized subsequent activation of mitophagy using immunofluorescence assay, electron microscopy and Western blot assay. Knockdown of autophagy-related 9A (ATG9A) led to an obvious reduction of mitophagy and deficiencies in decidualization. Our findings demonstrate a key role for proper mitochondrial dynamics in decidual differentiation and identify ATG9A-mediated mitophagy as a novel therapeutic target for repeated implantation failure or recurrent abortion.
    Keywords:  ATG9A; Decidualization; Differentiation; Human endometrial stromal cell line; Mitophagy
    DOI:  https://doi.org/10.1016/j.repbio.2022.100707
  18. Aging (Albany NY). 2022 Nov 04. 14
    Denervation induces mitochondrial decline and exacerbates lysosome dysfunction in middle-aged mice.
    Matthew Triolo, Debasmita Bhattacharya, David A Hood.
      With age, skeletal muscle undergoes a progressive decline in size and quality. Imbalanced mitochondrial turnover and the resultant dysfunction contribute to these phenotypic alterations. Motor neuron denervation (Den) is a contributor to the etiology of muscle atrophy associated with age. Further, aged muscle exhibits reduced plasticity to both enhanced and suppressed contractile activity. It remains unclear when the onset of this blunted response occurs, and how middle-aged muscle adapts to denervation. The purpose of this study was to compare mitochondrial turnover pathways in young (Y, ~5months) and middle-aged (MA, ~15months) mice, and determine the influence of Den. Transgenic mt-Keima mice were subjected to 1,3 or 7 days of Den. Muscle mass, mitochondrial content, and PGC-1α protein were not different between Y and MA mice. However, indications of enhanced mitochondrial fission and mitophagy were evident in MA muscle which were supported by a greater abundance of lysosome proteins. Den resulted in muscle atrophy and reductions in mitochondrial protein content by 7-days. These changes occurred concomitant with modest decreases in PGC-1α protein, but without further elevations in mitophagy. Although both autophagosomal and lysosomal proteins were elevated, evidence of lysosome dysfunction was present following Den in MA mice. These data suggest that increases in fission drive an acceleration of mitophagy in muscle of MA mice to preserve mitochondrial quality. Den exacerbates the aging phenotype by reducing biogenesis in the absence of a change in mitophagy, perhaps limited by lysosomal capacity, leading to an accumulation of dysfunctional mitochondria with an age-related loss of neuromuscular innervation.
    Keywords:  autophagy; lysosomes; mitochondrial biogenesis; mitophagy; muscle
    DOI:  https://doi.org/10.18632/aging.204365
  19. Microbiol Res. 2022 Nov 03. pii: S0944-5013(22)00292-0. [Epub ahead of print]266 127252
    Aoatg11 and Aoatg33 are indispensable for mitophagy, and contribute to conidiation, the stress response, and pathogenicity in the nematode-trapping fungus Arthrobotrys oligospora.
    Xuemei Li, Meichen Zhu, Yankun Liu, Le Yang, Jinkui Yang.
      Mitophagy is one of the most important cellular processes to ensure mitochondrial quality control, which aims to transport damaged, dysfunctional, or excess mitochondria for degradation and reuse. Here, we determined the function of AoAtg11 and AoAtg33, two orthologous autophagy-related proteins involved in yeast mitophagy, in the typical nematode-trapping fungus Arthrobotrys oligospora. Deletion of Aoatg11 and Aoatg33 impairs mitophagy, mitochondrial morphology and activity, autophagy, cell apoptosis, reactive oxygen species levels, lipid droplet accumulation, and endocytosis. These combined effects resulted in slow vegetative growth; reduced conidiation, trap formation, cell nucleus, and extracellular protease activity; increased susceptibility to the stress response; and arthrobotrisin production in the ΔAoatg11 and ΔAoatg33 mutants, compared with the wild-type strain. In addition, the absence of Aoatg11 caused an endoplasmic reticulum stress response. Transcriptome analysis revealed that many differentially expressed genes in the ΔAoatg11 mutants were involved in various important cellular processes, such as lipid metabolism, the TCA cycle, mitophagy, nitrogen metabolism, endocytosis, and the MAPK signaling pathway. In conclusion, our study revealed that Aoatg11 and Aoatg33 mediate autophagy and mitophagy in A. oligospora, and provides a basis for elucidating the links between mitophagy and fungal vegetative growth, conidiation, and pathogenicity.
    Keywords:  Arthrobotrys oligospora; Conidiation; Differentially expressed genes; Mitochondrial activity; Mitophagy; Pathogenicity
    DOI:  https://doi.org/10.1016/j.micres.2022.127252
  20. FEBS Lett. 2022 Nov 11.
    Longin domain GAP complexes in nutrient signaling, membrane traffic, and neurodegeneration.
    Rachel M Jansen, James H Hurley.
      Small GTPases act as molecular switches and control numerous cellular processes by virtue of their binding and hydrolysis of guanosine triphosphate (GTP). The activity of small GTPases is coordinated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Recent structural and functional studies have characterized a subset of GAPs whose catalytic units consist of longin domains. Longin domain containing GAPs regulate small GTPases that facilitate nutrient signaling, autophagy, vesicular trafficking, and lysosome homeostasis. All known examples in this GAP family function as part of larger multiprotein complexes. The three characterized mammalian protein complexes in this class are FLCN:FNIP, GATOR1, and C9orf72:SMCR8. Each complex carries out a unique cellular function by regulating distinct small GTPases. In this article, we explore the roles of longin domain GAPs in nutrient sensing, membrane dynamic, vesicular trafficking, and disease. Through a structural lens, we examine the mechanism of each longin domain GAP and highlight potential therapeutic applications.
    Keywords:  C9orf72; FLCN; GAPs; GATOR1; GTPase activating proteins; autophagy; membrane trafficking; nutrient signaling; small GTPases
    DOI:  https://doi.org/10.1002/1873-3468.14538
  21. J Biol Chem. 2022 Nov 07. pii: S0021-9258(22)01123-1. [Epub ahead of print] 102680
    Differential contributions of the proteasome, autophagy, and chaperones to the clearance of arsenite-induced protein aggregates in yeast.
    Sansan Hua, Agnieszka Kłosowska, Joana I Rodrigues, Gabriel Petelski, Lidia A Esquembre, Emma Lorentzon, Lars F Olsen, Krzysztof Liberek, Markus J Tamás.
      The poisonous metalloid arsenite induces widespread misfolding and aggregation of nascent proteins in vivo, and this mode of toxic action might underlie its suspected role in the pathology of certain protein misfolding diseases. Evolutionarily conserved protein quality-control systems protect cells against arsenite-mediated proteotoxicity and herein, we systematically assessed the contribution of the ubiquitin-proteasome system, the autophagy-vacuole pathway, and chaperone-mediated disaggregation to the clearance of arsenite-induced protein aggregates in Saccharomyces cerevisiae. We show that the ubiquitin-proteasome system is the main pathway that clears aggregates formed during arsenite stress and that cells depend on this pathway for optimal growth. The autophagy-vacuole pathway and chaperone-mediated disaggregation both contribute to clearance, but their roles appear less prominent than the ubiquitin-proteasome system. Our in vitro assays with purified components of the yeast disaggregating machinery demonstrated that chaperone binding to aggregates formed in the presence of arsenite is impaired. Hsp104 and Hsp70 chaperone activity was unaffected by arsenite, suggesting that this metalloid influences aggregate structure, making them less accessible for chaperone-mediated disaggregation. We further show that the defect in chaperone-mediated refolding of a model protein was abrogated in a cysteine-free version of the substrate, suggesting that arsenite directly modifies cysteines in non-native target proteins. In conclusion, our study sheds novel light on the differential contributions of protein quality-control systems to aggregate clearance and cell proliferation, and extends our understanding of how these systems operate during arsenite stress.
    Keywords:  Hsp104; Hsp70; arsenite; protein aggregation; protein degradation; ubiquitin proteasome pathway
    DOI:  https://doi.org/10.1016/j.jbc.2022.102680
  22. Autophagy. 2022 Nov 07. 1-21
    Tegument protein UL21 of alpha-herpesvirus inhibits the innate immunity by triggering CGAS degradation through TOLLIP-mediated selective autophagy.
    Zicheng Ma, Juan Bai, Chenlong Jiang, Huixin Zhu, Depeng Liu, Mengjiao Pan, Xianwei Wang, Jiang Pi, Ping Jiang, Xing Liu.
      Alpha-herpesvirus causes lifelong infections and serious diseases in a wide range of hosts and has developed multiple strategies to counteract the host defense. Here, we demonstrate that the tegument protein UL21 (unique long region 21) in pseudorabies virus (PRV) dampens type I interferon signaling by triggering the degradation of CGAS (cyclic GMP-AMP synthase) through the macroautophagy/autophagy-lysosome pathway. Mechanistically, the UL21 protein scaffolds the E3 ligase UBE3C (ubiquitin protein ligase E3C) to catalyze the K27-linked ubiquitination of CGAS at Lys384, which is recognized by the cargo receptor TOLLIP (toll interacting protein) and degraded in the lysosome. Additionally, we show that the N terminus of UL21 in PRV is dominant in destabilizing CGAS-mediated innate immunity. Moreover, viral tegument protein UL21 in herpes simplex virus type 1 (HSV-1) also displays the conserved inhibitory mechanisms. Furthermore, by using PRV, we demonstrate the roles of UL21 in degrading CGAS to promote viral infection in vivo. Altogether, these findings describe a distinct pathway where alpha-herpesvirus exploits TOLLIP-mediated selective autophagy to evade host antiviral immunity, highlighting a new interface of interplay between the host and DNA virus.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AHV-1: anatid herpesvirus 1; ATG7: autophagy related 7; ATG13: autophagy related 13; ATG101: autophagy related 101; BHV-1: bovine alphaherpesvirus 1; BNIP3L/Nix: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CCDC50: coiled-coil domain containing 50; CCT2: chaperonin containing TCP1 subunit 2; CGAS: cyclic GMP-AMP synthase; CHV-2: cercopithecine herpesvirus 2; co-IP: co-immunoprecipitation; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; Cas9: CRISPR-associated system 9; CTD: C-terminal domain; Ctrl: control; DAPI: 4',6-diamidino-2-phenylindole; DBD: N-terminal DNA binding domain; DMSO: dimethyl sulfoxide; DYNLRB1: dynein light chain roadblock-type 1; EHV-1: equine herpesvirus 1; gB: glycoprotein B; GFP: green fluorescent protein; H&E: hematoxylin and eosin; HSV-1: herpes simplex virus 1; HSV-2: herpes simplex virus 2; IB: immunoblotting; IRF3: interferon regulatory factor 3; lenti: lentivirus; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARCHF9: membrane associated ring-CH-type finger 9; MG132: cbz-leu-leu-leucinal; NBR1: NBR1 autophagy cargo receptor; NC: negative control; NEDD4L: NEDD4 like E3 ubiquitin protein ligase; NH4Cl: ammonium chloride; OPTN: optineurin; p-: phosphorylated; PFU: plaque-forming unit; Poly(dA:dT): Poly(deoxyadenylic-deoxythymidylic) acid; PPP1: protein phosphatase 1; PRV: pseudorabies virus; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RNF126: ring finger protein 126; RT-PCR: real-time polymerase chain reaction; sgRNA: single guide RNA; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TOLLIP: toll interacting protein; TRIM33: tripartite motif containing 33; UL16: unique long region 16; UL21: unique long region 21; UL54: unique long region 54; Ub: ubiquitin; UBE3C: ubiquitin protein ligase E3C; ULK1: unc-51 like autophagy activating kinase 1; Vec: vector; VSV: vesicular stomatitis virus; VZV: varicella-zoster virus; WCL: whole-cell lysate; WT: wild-type; Z-VAD: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone.
    Keywords:  Alpha-herpesvirus; CGAS; UL21 protein; selective autophagy; type I interferon signaling
    DOI:  https://doi.org/10.1080/15548627.2022.2139921
  23. Front Pharmacol. 2022 ;13 1043344
    Ferritinophagy, a form of autophagic ferroptosis: New insights into cancer treatment.
    Kai Sun, Chenyuan Li, Shichong Liao, Xinrui Yao, Yang Ouyang, Yi Liu, Zhong Wang, Zhiyu Li, Feng Yao.
      Ferritinophagy, a form of autophagy, is also an important part of ferroptosis, a type of regulated cell death resulting from abnormal iron metabolism involving the production of reactive oxygen species. As ferroptosis, autophagy and cancer have been revealed, ferritinophagy has attracted increasing attention in cancer development. In this review, we discuss the latest research progress on ferroptosis, autophagy-associated ferroptosis led by ferritinophagy, the regulators of ferritinophagy and promising cancer treatments that target ferritinophagy. Ferritinophagy is at the intersection of ferroptosis and autophagy and plays a significant role in cancer development. The discussed studies provide new insights into the mechanisms of ferritinophagy and promising related treatments for cancer.
    Keywords:  autophagy; cancer; ferritinophagy; ferroptosis; iron
    DOI:  https://doi.org/10.3389/fphar.2022.1043344
  24. Apoptosis. 2022 Nov 12.
    Augmenter of liver regeneration reduces mitochondria-derived ROS and NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy in ischemia-reperfusion-induced renal tubular injury.
    Dongju Zhu, Jie Zhong, Xuefeng Gong, Xiang Wu.
      Ischemia-reperfusion (IR) injury is one of the main causes of acute kidney disease (AKI). Several studies have shown that mitochondrial damage, which leads to increased production of reactive oxygen species (ROS), plays a vital role in the pathogenesis of IR-induced AKI. Increased ROS production can cause oxidative damage and activate the inflammasome in renal tubular cells, ultimately resulting in apoptosis or necrosis. Mitophagy is a type of selective autophagy that plays a protective role in AKI by regulating the quality of mitochondria and reducing the production of ROS. We previously reported that the augmenter of liver regeneration (ALR) exhibits antiapoptotic and antioxidant functions, although the precise mechanisms of action need to be studied further. In the current study, ALR was overexpressed and an in vitro model of IR injury was constructed. The overexpression of ALR reduced the production of mitochondria-derived ROS (mtROS), the activation of the NLRP3 inflammasome, and the rate of apoptosis. Moreover, this suppression of mtROS production and inflammasome activation was mediated through the PTEN-induced kinase 1 (PINK1)/Parkin pathway of mitophagy. These results suggest that ALR can alleviate IR-induced apoptosis via the PINK1/Parkin mitophagy pathway to reduce the production of mtROS and limit the activation of the NLRP3 inflammasome.
    Keywords:  Acute kidney injury; Augmenter of liver regeneration; Inflammation; Ischemia–reperfusion; Mitophagy; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s10495-022-01794-1
  25. Med Sci Monit. 2022 Nov 11. 28 e938519
    Autophagy and Its Association with Genetic Mutations in Parkinson Disease.
    Nour S Erekat.
      Parkinson disease is the second most common neurodegenerative disorder, affecting 0.1-0.2% of the general population. It is a progressive debilitating disorder caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta. It is characterized by motor and non-motor symptoms. Parkinson disease can be caused by mutations in genes that encode proteins involved in the autophagic process, resulting in impaired autophagy. Indeed, autophagy has been implicated in the pathogenesis of Parkinson disease, particularly because its impairment causes the buildup of proteins. Thus, this review aims to provide an overview of Parkinson disease-related genetic mutations and their association with autophagy impairment in Parkinson disease, which can be helpful in improving the understanding of the pathogenesis of Parkinson disease, illustrating the potential therapeutic implications of agents that can enhance autophagy in Parkinson disease. Additionally, we will highlight the essential need for the development of highly sensitive and specific assays for gene-based diagnostic biomarkers. Finally, we will provide an overview on the potential gene-based therapeutic approaches for Parkinson disease, which have been most advanced and are associated with the most common targets being alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2), and glucocerebrosidase (GBA).
    DOI:  https://doi.org/10.12659/MSM.938519
  26. Int J Mol Sci. 2022 Oct 22. pii: 12720. [Epub ahead of print]23(21):
    Quantitative Metabolomic Analysis of Changes in the Rat Blood Serum during Autophagy Modulation: A Focus on Accelerated Senescence.
    Olga Snytnikova, Yuri Tsentalovich, Renad Sagdeev, Nataliya Kolosova, Oyuna Kozhevnikova.
      Autophagy is involved in the maintenance of cellular homeostasis and the removal of damaged proteins and organelles and is necessary to maintain cell metabolism in conditions of energy and nutrient deficiency. A decrease in autophagic activity plays an important role in age-related diseases. However, the metabolic response to autophagy modulation remains poorly understood. Here, we for the first time explored the effects of (1) autophagy activation by 48 h fasting, (2) inhibition by chloroquine (CQ) treatment, and (3) combined effects of fasting and CQ on the quantitative composition of metabolites in the blood serum of senescent-accelerated OXYS and control Wistar rats at the age of 4 months. By means of high-resolution 1H NMR spectroscopy, we identified the quantitative content of 55 serum metabolites, including amino acids, organic acids, antioxidants, osmolytes, glycosides, purine, and pyrimidine derivatives. Groups of 48 h fasting (induction of autophagy), CQ treatment (inhibition of autophagy), and combined effects (CQ + fasting) are clearly separated from control groups by principal component analysis. Fasting for 48 h led to significant changes in the serum metabolomic profile, primarily affecting metabolic pathways related to fatty acid metabolism, and led to metabolism of several amino acids. Under CQ treatment, the most affected metabolites were citrate, betaine, cytidine, proline, tryptophan, glutamate, and mannose. As shown by two-way ANOVA, for many metabolites the effects of autophagy modulation depend on the animal genotype, indicating a dysregulation of metabolome reactivity in OXYS rats. Thus, the metabolic responses to modulation of autophagy in OXYS rats and Wistar rats are different. Altered metabolites in OXYS rats may serve as potential biomarkers of the manifestation of the signs of accelerated aging. Metabolic signatures characteristic to fasting and CQ treatment revealed in this work might provide a better understanding of the connections between metabolism and autophagy.
    Keywords:  NMR spectroscopy; autophagy; blood serum; chloroquine; metabolomics; senescence-accelerated OXYS rats
    DOI:  https://doi.org/10.3390/ijms232112720
  27. Nano Lett. 2022 Nov 07.
    Enhanced Sensitivity of Tumor Cells to Autophagy Inhibitors Using Fasting-Mimicking Diet and Targeted Lysosomal Delivery Nanoplatform.
    Ruihao Qian, Guoliang Cao, Wen Su, Jie Zhang, Yue Jiang, Haohao Song, Fuhao Jia, Hai Wang.
      Autophagy is one of the key pathways for tumor cell survival and proliferation. Therefore, inhibition of autophagy has been extensively studied for cancer therapy. However, current autophagy inhibitors lack specificity and are ineffective in limiting tumor progression. Herein, we report a nanoplatform for tumor-site-targeted delivery of hydroxychloroquine (HCQ) using insulin-like growth factors 2 receptor (IGF2R)-targeted liposomes (iLipo-H). A fasting-mimicking diet (FMD) is used to increase the autophagy levels in tumor cells, thereby increasing the sensitivity of tumor cells to HCQ. In addition, FMD treatment upregulates the expression of IGF2R in tumor cells, but not normal cells. Consequently, iLipo-H nanoparticles efficiently accumulate at the tumor site under FMD condition. In vivo studies demonstrate that iLipo-H nanoparticles efficiently inhibit 4T1 tumor growth without obvious side effects, especially under FMD condition. This study provides a promising strategy to increase the sensitivity of tumor cells to autophagy inhibitors for effective cancer therapy.
    Keywords:  autophagy; hydroxychloroquine; insulin-like growth factors 2 receptor; targeted delivery
    DOI:  https://doi.org/10.1021/acs.nanolett.2c03890
  28. Front Aging Neurosci. 2022 ;14 986849
    Exploring therapeutic potential of mitophagy modulators using Drosophila models of Parkinson's disease.
    Jyotsna Asthana, Bhupendra V Shravage.
      Parkinson's disease (PD) is the second most popular age-associated neurodegenerative disorder after Alzheimer's disease. The degeneration of dopaminergic neurons, aggregation of α-synuclein (α-syn), and locomotor defects are the main characteristic features of PD. The main cause of a familial form of PD is associated with a mutation in genes such as SNCA, PINK1, Parkin, DJ-1, LRKK2, and others. Recent advances have uncovered the different underlying mechanisms of PD but the treatment of PD is still unknown due to the unavailability of effective therapies and preventive medicines in the current scenario. The pathophysiology and genetics of PD have been strongly associated with mitochondria in disease etiology. Several studies have investigated a complex molecular mechanism governing the identification and clearance of dysfunctional mitochondria from the cell, a mitochondrial quality control mechanism called mitophagy. Reduced mitophagy and mitochondrial impairment are found in both sporadic and familial PD. Pharmacologically modulating mitophagy and accelerating the removal of defective mitochondria are of common interest in developing a therapy for PD. However, despite the extensive understanding of the mitochondrial quality control pathway and its underlying mechanism, the therapeutic potential of targeting mitophagy modulation and its role in PD remains to be explored. Thus, targeting mitophagy using chemical agents and naturally occurring phytochemicals could be an emerging therapeutic strategy in PD prevention and treatment. We discuss the current research on understanding the role of mitophagy modulators in PD using Drosophila melanogaster as a model. We further explore the contribution of Drosophila in the pathophysiology of PD, and discuss comprehensive genetic analysis in flies and pharmacological drug screening to develop potential therapeutic molecules for PD.
    Keywords:  Drosophila; Mitophagy; Parkinson’s disease; mitochondria; neurodegenerative disorder
    DOI:  https://doi.org/10.3389/fnagi.2022.986849
  29. Plants (Basel). 2022 Oct 26. pii: 2858. [Epub ahead of print]11(21):
    Identification and Expression Analysis of the Solanum tuberosum StATG8 Family Associated with the WRKY Transcription Factor.
    Injeong Song, Suji Hong, Sung Un Huh.
      Autophagy is an evolutionarily well-conserved cellular catabolic pathway in eukaryotic cells and plays an important role in cellular processes. Autophagy is regulated by autophagy-associated (ATG) proteins. Among these ATG proteins, the ubiquitin-like protein ATG8/LC3 is essential for autophagosome formation and function. In this study, the potato StATG8 family showed clade I and clade II with significantly different sequences. Expression of the StATG8 family was also increased in senescence. Interestingly, the expression of the StATG8 and other core StATG genes decreased in potato tubers as the tubers matured. The StATG8 family also responded to a variety of stresses such as heat, wounding, salicylic acid, and salt stress. We also found that some Arabidopsis WRKY transcription factors interacted with the StATG8 protein in planta. Based on group II-a WRKY, StATG8-WRKY interaction is independent of the ATG8 interacting motif (AIM) or LC3 interacting region (LIR) motif. This study showed that the StATG8 family had diverse functions in tuber maturation and multiple stress responses in potatoes. Additionally, StATG8 may have an unrelated autophagy function in the nucleus with the WRKY transcription factor.
    Keywords:  ATG8; ATG8-interacting motif (AIM); WRKY transcription factor; autophagy; autophagy-related (ATG) protein
    DOI:  https://doi.org/10.3390/plants11212858
  30. Cells. 2022 Nov 04. pii: 3502. [Epub ahead of print]11(21):
    Palmitate Inhibits Mouse Macrophage Efferocytosis by Activating an mTORC1-Regulated Rho Kinase 1 Pathway: Therapeutic Implications for the Treatment of Obesity.
    László Sós, Éva Garabuczi, Tibor Sághy, Gábor Mocsár, Zsuzsa Szondy.
      Every day, billions of our cells die and get cleared without inducing inflammation. When, clearance is improper, uncleared cells undergo secondary necrosis and trigger inflammation. In addition, proper efferocytosis would be required for inducing resolution of inflammation, thus clearance deficiencies in the long term lead to development of various chronic inflammatory diseases. Increasing evidence indicates that obesity, itself being a low-grade inflammatory disease, predisposes to a variety of other chronic inflammatory diseases. Previous studies indicated that this later might be partially related to an impaired efferocytosis induced by increased uptake of circulating saturated fatty acids by macrophages in obese people. Here, we show that palmitate inhibits efferocytosis by bone marrow-derived macrophages in a dose-dependent manner. Palmitate triggers autophagy but also activates an energy-sensing mTORC1/ROCK1 signaling pathway, which interferes with the autophagosome-lysosome fusion, resulting in accumulation of the cellular membranes in autophagosomes. We propose that lack of sufficient plasma membrane supply attenuates efferocytosis of palmitate-exposed macrophages. AMP-activated protein kinase activators lead to mTORC1 inhibition and, consequently, released the palmitate-induced efferocytosis block in macrophages. Thus, they might be useful in the treatment of obesity not only by affecting metabolism thought so far. ROCK1 inhibitors could also be considered.
    Keywords:  AMPK; ROCK1; autophagy; chronic inflammation; efferocytosis; mTORC1; macrophage; obesity; palmitate
    DOI:  https://doi.org/10.3390/cells11213502
  31. Front Cell Dev Biol. 2022 ;10 1058861
    Editorial: Beclin 1 and autophagy---in memory of Beth Levine (1960-2020).
    Haidong Xu, Zheng-Hong Qin, Yongjie Wei, Junchao Wu.
      
    Keywords:  Beclin 1; Beth Levine; autophagy; cell survival and death; memoriam
    DOI:  https://doi.org/10.3389/fcell.2022.1058861
  32. Eur J Pharmacol. 2022 Nov 04. pii: S0014-2999(22)00624-0. [Epub ahead of print] 175363
    Anesthetic sevoflurane simultaneously regulates autophagic flux and pyroptotic cell death-associated cellular inflammation in the hypoxic/re-oxygenated cardiomyocytes: Identification of sevoflurane as putative drug for the treatment of myocardial ischemia-reperfusion injury.
    Lin Deng, Lihua Jiang, Na Wei, Jiahang Zhang, Xiaohong Wu.
      PRE: and post-conditioning of sevoflurane attenuate cardiomyocyte death and protects against myocardial ischemia/reperfusion (I/R) injury, and this process is considered to be associated with cell autophagy and pyroptosis, but the detailed molecular mechanisms regarding to this issue have not been fully studied. In this study, we verified that sevoflurane exerted its protective effects in myocardial I/R injury by synergistically regulating the AMPK/ULK1 pathway-mediated autophagy and NLRP3-mediated pyroptotic cell death, and the interplays between cell autophagy and pyroptosis were also preliminarily investigated. Specifically, sevoflurane conditioning suppressed NLRP3 and cleaved caspase-1 expressions to inactivate cell pyroptosis, upregulated LC3B-II/I ratio, facilitated autophagosome formation and accelerated p62 degradation to trigger autophagy, and promoted the expressions of CDK2, CDK6 and Cyclin D1 to recover cell cycle in I/R mouse myocardial tissues in vivo and hypoxic/re-oxygenated (H/R) cardiomyocytes in vitro. Further experiments validated that sevoflurane promoted the phosphorylation of both AMPK (p-AMPK) and ULK1 (p-ULK1) to activate the AMPK/ULK1 pathway, and the promoting effects of sevoflurane on cell autophagy in H/R cardiomyocytes were abrogated by co-treating cells with AMPK inhibitor (compound C) and ULK1 inhibitor (SBI-0206965). Moreover, it was verified that compound C, SBI-0206965 and autophagy blocker chloroquine reversed H/R-induced cell death and pyroptosis in cardiomyocytes. Taken together, we concluded that sevoflurane activated the AMPK/ULK1 pathway to trigger autophagic flux and suppress NLRP3-mediated pyroptotic cell death in I/R or H/R-treated cardiomyocytes, which further ameliorated myocardial I/R injury.
    Keywords:  AMPK/ULK1 pathway; Autophagic flux; Ischemia-reperfusion injury; NLRP3 inflammasome; Pyroptotic cell death
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175363
  33. Int J Mol Sci. 2022 Oct 28. pii: 13073. [Epub ahead of print]23(21):
    Apelin-13 Increases Functional Connexin-43 through Autophagy Inhibition via AKT/mTOR Pathway in the Non-Myocytic Cell Population of the Heart.
    Emanuela Vitale, Rachele Rosso, Marco Lo Iacono, Caterina Cristallini, Claudia Giachino, Raffaella Rastaldo.
      Studies have shown a link between the downregulation of connexin 43 (Cx43), the predominant isoform in cardiac gap junctions, and high susceptibility to cardiac arrhythmias and cardiomyocyte death. Non-myocytic cells (NMCs), the most abundant component of the heart, exert multiple cardiac functions and represent an important therapeutic target for diseased cardiac tissue. A few studies have investigated the effect of Apelin-13, an endogenous peptide with a key role in various cardiovascular functions, on Cx43 expression in cardiomyocytes. However, it remained unknown whether Apelin-13 influences Cx43 expression in NMCs. Here, we found that in NMCs, Cx43 protein expression increased after Apelin-13 treatment (100 nM for 48 h). Furthermore, dye transfer assays proved that Apelin-13-treated NMCs had a greater ability to communicate with surrounding cardiomyocytes, and this effect was abrogated by carbenoxolone, a gap junction inhibitor. Interestingly, we showed that Apelin-13 increased Cx43 through autophagy inhibition, as proved by the upregulation of p62 and LC3I, acting as 3-MA, a well-known autophagy inhibitor. In addition, Apelin-13-induced AKT and mTOR phosphorylation was abolished by LY294002 and rapamycin inhibitors resulting in Cx43 increased suppression. These results open the possibility of targeting gap junctions in NMCs with Apelin-13 as an exciting therapeutic approach with great potential.
    Keywords:  AKT/mTOR pathway; H9C2 cells; LC3; apelin-13; autophagy; connexin-43; gap junction; non-myocytic cells; p62
    DOI:  https://doi.org/10.3390/ijms232113073
  34. J Cardiovasc Aging. 2022 Oct;pii: 45. [Epub ahead of print]2(4):
    Small molecules that enhance mitophagy to delay aging and neurodegeneration.
    Gerald W Dorn.
      
    DOI:  https://doi.org/10.20517/jca.2022.36
  35. Med Oncol. 2022 Nov 09. 40(1): 12
    Redox balance and autophagy regulation in cancer progression and their therapeutic perspective.
    Sameer Ullah Khan, Kaneez Fatima, Shariqa Aisha, Baseerat Hamza, Fayaz Malik.
      Cellular ROS production participates in various cellular functions but its accumulation decides the cell fate. Malignant cells have higher levels of ROS and active antioxidant machinery, a characteristic hallmark of cancer with an outcome of activation of stress-induced pathways like autophagy. Autophagy is an intracellular catabolic process that produces alternative raw materials to meet the energy demand of cells and is influenced by the cellular redox state thus playing a definite role in cancer cell fate. Since damaged mitochondria are the main source of ROS in the cell, however, cancer cells remove them by upregulating the process of mitophagy which is known to play a decisive role in tumorigenesis and tumor progression. Chemotherapy exploits cell machinery which results in the accumulation of toxic levels of ROS in cells resulting in cell death by activating either of the pathways like apoptosis, necrosis, ferroptosis or autophagy in them. So understanding these redox and autophagy regulations offers a promising method to design and develop new cancer therapies that can be very effective and durable for years. This review will give a summary of the current therapeutic molecules targeting redox regulation and autophagy for the treatment of cancer. Further, it will highlight various challenges in developing anticancer agents due to autophagy and ROS regulation in the cell and insights into the development of future therapies.
    Keywords:  Apoptosis; Autophagy; Glutathione; Mitophagy; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s12032-022-01871-0
  36. Front Pharmacol. 2022 ;13 862324
    Platelet derived growth factor promotes the recovery of traumatic brain injury by inhibiting endoplasmic reticulum stress and autophagy-mediated pyroptosis.
    Fangfang Wu, Renkan Zhang, Weiyang Meng, Lei Liu, Yingdan Tang, Leilei Lu, Leilei Xia, Hongyu Zhang, Zhiguo Feng, Daqing Chen.
      Autophagy and endoplasmic reticulum stress (ER stress) are important in numerous pathological processes in traumatic brain injury (TBI). Growing evidence has indicated that pyroptosis-associated inflammasome is involved in the pathogenesis of TBI. Platelet derived growth factor (PDGF) has been reported to be as a potential therapeutic drug for neurological diseases. However, the roles of PDGF, autophagy and ER stress in pyroptosis have not been elucidated in the TBI. This study investigated the roles of ER stress and autophagy after TBI at different time points. We found that the ER stress and autophagy after TBI were inhibited, and the expressions of pyroptosis-related proteins induced by TBI, including NLRP3, Pro-Caspase1, Caspase1, GSDMD, GSDMD P30, and IL-18, were decreased upon PDGF treatment. Moreover, the rapamycin (RAPA, an autophagy activator) and tunicamycin (TM, an ER stress activator) eliminated the PDGF effect on the pyroptosis after TBI. Interestingly, the sodium 4-phenylbutyrate (4-PBA, an ER stress inhibitor) suppressed autophagy but 3-methyladenine (3-MA, an autophagy inhibitor) not for ER stress. The results revealed that PDGF improved the functional recovery after TBI, and the effects were markedly reversed by TM and RAPA. Taken together, this study provides a new insight that PDGF is a potential therapeutic strategy for enhancing the recovery of TBI.
    Keywords:  PDGF; PDGF ameliorates traumatic brain injury; autophagy; er stress; pyroptosis; traumatic brain injury
    DOI:  https://doi.org/10.3389/fphar.2022.862324
  37. New Phytol. 2022 Nov 08.
    A key virulence effector from cyst nematodes targets host autophagy to promote nematode parasitism.
    Jiansong Chen, Shiyan Chen, Chunling Xu, Huijun Yang, Mingkee Achom, Xiaohong Wang.
      Autophagy, an intracellular degradation system conserved in eukaryotes, has been increasingly recognized as a key battlefield in plant-pathogen interactions. However, a role of plant autophagy in nematode parasitism is mostly unknown. We report here the identification of a novel and conserved effector, NMAS1 (Nematode Manipulator of Autophagy System 1), from plant-parasitic cyst nematodes (Heterodera and Globodera spp.). We used molecular and genetic analyses to demonstrate that NMAS1 is required for nematode parasitism. NMAS1 effectors are potent suppressors of ROS induced by flg22 and cell-death mediated by immune receptors in Nicotiana benthamiana, suggesting a key role of NMAS1 effectors in nematode virulence. Arabidopsis atg mutants defective in autophagy showed reduced susceptibility to nematode infection. NMAS1 effectors contain predicted ATG8 (AuTophaGy-related protein 8)-interacting motif (AIM) sequences. In planta protein-protein interaction assays further demonstrated that NMAS1 effectors specifically interact with host plant ATG8 proteins. Interestingly, mutation in AIM2 of GrNMAS1 from the potato cyst nematode G. rostochiensis abolishes its interaction with potato StATG8 proteins and its activity in ROS suppression. Collectively, our results reveal for the first time that cyst nematodes employ a conserved AIM-containing virulence effector capable of targeting a key component of host autophagy to promote disease.
    Keywords:  ATG8 protein; ATG8-interacting motif; Globodera; Heterodera; autophagy; effector; plant immunity; plant-parasitic cyst nematode
    DOI:  https://doi.org/10.1111/nph.18609
  38. Nutrients. 2022 Oct 22. pii: 4440. [Epub ahead of print]14(21):
    The Genetic Variability of Members of the SLC38 Family of Amino Acid Transporters (SLC38A3, SLC38A7 and SLC38A9) Affects Susceptibility to Type 2 Diabetes and Vascular Complications.
    Paolina Crocco, Serena Dato, Alberto Montesanto, Anna Rita Bonfigli, Roberto Testa, Fabiola Olivieri, Giuseppe Passarino, Giuseppina Rose.
      Type 2 Diabetes (T2D) is a metabolic disease associated with long-term complications, with a multifactorial pathogenesis related to the interplay between genetic and modifiable risk factors, of which nutrition is the most relevant. In particular, the importance of proteins and constitutive amino acids (AAs) in disease susceptibility is emerging. The ability to sense and respond to changes in AA supplies is mediated by complex networks, of which AA transporters (AATs) are crucial components acting also as sensors of AA availability. This study explored the associations between polymorphisms in selected AATs genes and T2D and vascular complications in 433 patients and 506 healthy controls. Analyses revealed significant association of SLC38A3-rs1858828 with disease risk. Stratification of patients based on presence/absence of vascular complications highlighted significant associations of SLC7A8-rs3783436 and SLC38A7-rs9806843 with diabetic retinopathy. Additionally, the SLC38A9-rs4865615 resulted associated with chronic kidney disease. Notably, these genes function as AAs sensors, specifically glutamine, leucine, and arginine, linked to the main nutrient signaling pathway mammalian target of rapamycin complex 1 (mTORC1). Thus, their genetic variability may contribute to T2D by influencing the ability to properly transduce a signal activating mTORC1 in response to AA availability. In this scenario, the contribution of dietary AAs supply to disease risk may be relevant.
    Keywords:  SLC38 family; Type 2 Diabetes; amino acid availability; amino acid sensing; amino acid transporters; diabetes complications; genetic variability; mTORC1 pathway
    DOI:  https://doi.org/10.3390/nu14214440
  39. Biomolecules. 2022 Oct 26. pii: 1565. [Epub ahead of print]12(11):
    Focusing on the Role of Natural Products in Overcoming Cancer Drug Resistance: An Autophagy-Based Perspective.
    Jiaqi Yao, Chi Ma, Kaixuan Feng, Guang Tan, Qingping Wen.
      Autophagy is a critical cellular adaptive response in tumor formation. Nutritional deficiency and hypoxia exacerbate autophagic flux in established malignancies, promoting tumor cell proliferation, migration, metastasis, and resistance to therapeutic interventions. Pro-survival autophagy inhibition may be a promising treatment option for advanced cancer. Furthermore, excessive or persistent autophagy is cytotoxic, resulting in tumor cell death. Targeted autophagy activation has also shown significant promise in the fight against tumor drug resistance. Several research groups have examined the ability of natural products (NPs) such as alkaloids, terpenoids, polyphenols, and anthraquinones to serve as autophagy inhibitors or activators. The data support the capacity of NPs that promote lethal autophagy or inhibit pro-survival autophagy from being employed against tumor drug resistance. This paper discusses the potential applications of NPs that regulate autophagy in the fight against tumor drug resistance, some limitations of the current studies, and future research needs and priorities.
    Keywords:  autophagy; natural products; resistance; therapy; tumors
    DOI:  https://doi.org/10.3390/biom12111565
  40. Vaccines (Basel). 2022 Nov 09. pii: 1892. [Epub ahead of print]10(11):
    Mycobacterium tuberculosis: Implications of Ageing on Infection and Maintaining Protection in the Elderly.
    Victor Bonavida, Mitchell Frame, Kevin H Nguyen, Shlok Rajurkar, Vishwanath Venketaraman.
      Several reports have suggested that ageing negatively affects the human body resulting in the alteration of various parameters important for sufficient immune health. Although, the breakdown of innate and adaptive immunity has been hypothesized to increase an individual's susceptibility to infections including Mycobacteria tuberculosis (M. tb), little research has been done to bridge this gap and understand the pathophysiology underlying how ageing increases the pathogenesis of M. tb infection. Our objective was to study research from a plethora of resources to better understand the pathogenesis of ageing and its link to the human immune system. To achieve this goal, this article explores how ageing decreases the collective T-cell immune response, reduces glutathione (GSH) production, over activates the mammalian target of rapamycin (mTORC1) pathway, inhibits autophagy and mitophagy, and alters various protective genes/transcription factors. Specifically highlighting how each of these pathways cripple an individual's immune system and increases their susceptibility from M. tb infection. Furthermore, research summarized in this article gives rise to an additional mechanism of susceptibility to M. tb infection which includes a potential defect in antigen presenting by dendritic cells rather than the T-cells response. Inflammaging has also been shown to play a role in the ageing of the immune system and can also potentially be a driving factor for increased susceptibility to M. tb infection in the elderly. In addition, this article features possible preventative strategies that could decrease infections like M. tb in this population. These strategies would need to be further explored and range from immunomodulators, like Everolimus to antioxidant supplementation through GSH intake. We have also proposed the need to research these therapies in conjunction with the administration of the BCG vaccine, especially in endemic populations, to better understand the risk contracting M. tb infection as well as ways to prevent infection in the first place.
    Keywords:  ageing; autophagy; immune; infection; mTOR; mitophagy; mycobacterium tuberculosis; susceptibility; tuberculosis
    DOI:  https://doi.org/10.3390/vaccines10111892
  41. Front Oncol. 2022 ;12 947332
    Regulation of autophagy by non-coding RNAs in gastric cancer.
    Zijian Wang, Jiarui Liu, Jingri Xie, Xingxing Yuan, Bingyu Wang, Wenjuan Shen, Yang Zhang.
      Autophagy is a conserved cellular self-digesting process that degrades obsoleting proteins and cellular components and plays a crucial role in the tumorigenesis, metastasis, and drug resistance of various tumors such as gastric cancer (GC). As a hotspot in molecular biology, non-coding RNAs (ncRNAs) are involved in the regulation of multiple biological processes, such as autophagy. Increasing evidence indicate that various ncRNAs exert double roles in the initiation and progression of GC, either serve as oncogenes or tumor suppressors. Recent studies have shown that some ncRNAs could modulate autophagy activity in GC cells, which would affect the malignant transformation and drug resistance. Whether the function of ncRNAs in GC is dependent on autophagy is undefined. Therefore, identifying the underlying moleculr targets of ncRNAs in autophagy pathways and the role of ncRNA-regulated autophagy in GC could develop new treatment interventions for this disease. This review summarizes the autophagy process and its role in GC, and the regulatory mechanisms of ncRNAs, as well as focuses on the dual role of ncRNAs-mediated autophagy in GC, for the development of potential therapeutic strategies in GC patients.
    Keywords:  autophagy; chemoresistance; gastric cancer; non-coding RNA; tumorigenesis
    DOI:  https://doi.org/10.3389/fonc.2022.947332
  42. Blood Cancer J. 2022 Nov 09. 12(11): 151
    The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy.
    Keli Lima, Diego Antonio Pereira-Martins, Lívia Bassani Lins de Miranda, Juan Luiz Coelho-Silva, Giovana da Silva Leandro, Isabel Weinhäuser, Rita de Cássia Cavaglieri, Aline de Medeiros Leal, Wellington Fernandes da Silva, Ana Paula Alencar de Lima Lange, Elvira Deolinda Rodrigues Pereira Velloso, Emmanuel Griessinger, Jacobien R Hilberink, Emanuele Ammatuna, Gerwin Huls, Jan Jacob Schuringa, Eduardo Magalhães Rego, João Agostinho Machado-Neto.
      The treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34+ cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia.
    DOI:  https://doi.org/10.1038/s41408-022-00747-w
  43. Cell Death Dis. 2022 Nov 08. 13(11): 939
    Myo1b promotes tumor progression and angiogenesis by inhibiting autophagic degradation of HIF-1α in colorectal cancer.
    Yi-Hong Chen, Nan-Zhu Xu, Chang Hong, Wen-Qi Li, Yi-Qiong Zhang, Xin-Yi Yu, Yue-Le Huang, Jue-Yu Zhou.
      Myosin 1b (Myo1b) is an important single-headed membrane-associated motor of class I myosins that participate in many critical physiological and pathological processes. Mounting evidence suggests that the dysregulation of Myo1b expression has been extensively investigated in the development and progression of several tumors. However, the functional mechanism of Myo1b in CRC angiogenesis and autophagy progression remains unclear. Herein, we found that the expression of Myo1b was upregulated in CRC tissues and its high expression was correlated with worse survival. The overexpression of Myo1b promoted the proliferation, migration and invasion of CRC cells. Conversely, silencing of Myo1b suppressed tumor progression both in vitro and in vivo. Further studies indicated that Myo1b inhibited the autophagosome-lysosome fusion and potentiated the VEGF secretion of CRC cells to promote angiogenesis. Mechanistically, Myo1b blocked the autophagic degradation of HIF-1α and then led to the accumulation of HIF-1α, thus enhancing VEGF secretion and then promoting tumor angiogenesis in CRC. Together, our study provided novel insights into the role of Myo1b in CRC progression and revealed that it might be a feasible predictive biomarker and promising therapeutic target for CRC patients.
    DOI:  https://doi.org/10.1038/s41419-022-05397-1
  44. Int J Mol Sci. 2022 Oct 28. pii: 13078. [Epub ahead of print]23(21):
    Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease.
    Zohra Rahmani, Satya Surabhi, Francisca Rojo-Cortés, Amina Dulac, Andreas Jenny, Serge Birman.
      Parkinson disease (PD) is a common neurodegenerative condition affecting people predominantly at old age that is characterized by a progressive loss of midbrain dopaminergic neurons and by the accumulation of α-synuclein-containing intraneuronal inclusions known as Lewy bodies. Defects in cellular degradation processes such as the autophagy-lysosomal pathway are suspected to be involved in PD progression. The mammalian Lysosomal-associated membrane proteins LAMP1 and LAMP2 are transmembrane glycoproteins localized in lysosomes and late endosomes that are involved in autophagosome/lysosome maturation and function. Here, we show that the lack of Drosophila Lamp1, the homolog of LAMP1 and LAMP2, severely increased fly susceptibility to paraquat, a pro-oxidant compound known as a potential PD inducer in humans. Moreover, the loss of Lamp1 also exacerbated the progressive locomotor defects induced by the expression of PD-associated mutant α-synuclein A30P (α-synA30P) in dopaminergic neurons. Remarkably, the ubiquitous re-expression of Lamp1 in a mutant context fully suppressed all these defects and conferred significant resistance towards both PD factors above that of wild-type flies. Immunostaining analysis showed that the brain levels of α-synA30P were unexpectedly decreased in young adult Lamp1-deficient flies expressing this protein in comparison to non-mutant controls. This suggests that Lamp1 could neutralize α-synuclein toxicity by promoting the formation of non-pathogenic aggregates in neurons. Overall, our findings reveal a novel role for Drosophila Lamp1 in protecting against oxidative stress and α-synuclein neurotoxicity in PD models, thus furthering our understanding of the function of its mammalian homologs.
    Keywords:  Drosophila; Lamp1; Parkinson disease; paraquat; α-synuclein
    DOI:  https://doi.org/10.3390/ijms232113078
  45. J Clin Invest. 2022 Nov 08. pii: e163584. [Epub ahead of print]
    Integration of ER protein quality control mechanisms defines β-cell function and ER architecture.
    Neha Shrestha, Mauricio Torres, Jason Zhang, You Lu, Leena Haataja, Rachel B Reinert, Jeffrey Knupp, Yu-Jie Chen, Gunes Parlakgul, Ana Paula Arruda, Billy Tsai, Peter Arvan, Ling Qi.
      Three principal ER quality-control mechanisms, namely, unfolded protein response (UPR), ER-associated degradation (ERAD) and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the three pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β-cells. SEL1L-HRD1 ERAD deficiency in β-cells triggers activation of autophagy via IRE1α [an endogenous ERAD substrate]. In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and autophagy in β-cells leads to diabetes in mice shortly after weaning, with premature death by ~11 weeks of age, associated with marked ER retention of proinsulin and β-cell loss. Using focus-ion beam scanning electron microscopy (FIB-SEM) powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in β-cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate crosstalk among the three ER quality-control mechanisms in the dynamic regulation of organellar architecture and β-cell function.
    Keywords:  Autophagy; Cell Biology; Diabetes; Metabolism; Protein misfolding
    DOI:  https://doi.org/10.1172/JCI163584
  46. Biophys Rev. 2022 Oct;14(5): 1105-1107
    Nuclear factor erythroid 2-related factor 2 and autophagy regulation in cancer development.
    Waleska Dornas.
      Nuclear factor erythroid 2-related factor 2 (Nrf2) mitigates cell damage due to stress, environmental xenobiotics, and toxic chemicals. Nrf2 is present in the cytoplasm bound to its cysteine-rich Kelch domain-containing partner, Kelch-like ECH-associated protein 1 (Keap1), where is ubiquitinated and degraded. In addition to inducers that disrupt the Keap1-Nrf2 complex, defective autophagy has recently been shown to upregulate endogenous p62, which interacts with Keap1 triggering transcriptional activation of Nrf2 in several cancers. This regulation by Nrf2-dependent transactivation of cytoprotective genes needs to be validated by clinical trials in view of its persistent activation in a p62-dependent manner when there is deregulation of autophagy.
    DOI:  https://doi.org/10.1007/s12551-022-00992-0
  47. Hypertension. 2022 Nov 08.
    The Novel Lysosomal Autophagy Inhibitor (ROC-325) Ameliorates Experimental Pulmonary Hypertension.
    Changlei Bao, Shuxin Liang, Ying Han, Zi Yang, Shiyun Liu, Yanan Sun, Shichuang Zheng, Yuzhu Li, Ting Wang, Yali Gu, Kang Wu, Stephen M Black, Jian Wang, Steffan T Nawrocki, Jennifer S Carew, Jason X-J Yuan, Haiyang Tang.
      BACKGROUND: Autophagy plays an important role in the pathogenesis of pulmonary hypertension (PH). ROC-325 is a novel small molecule lysosomal autophagy inhibitor that has more potent anticancer activity than the antimalarial drug hydroxychloroquine, the latter has been prevalently used to inhibit autophagy. Here, we sought to determine the therapeutic benefit and mechanism of action of ROC-325 in experimental PH models.METHODS AND RESULTS: Hemodynamics, echocardiography, and histology measurement showed that ROC-325 treatment prevented the development of PH, right ventricular hypertrophy, fibrosis, dysfunction, and vascular remodeling after monocrotaline and Sugen5416/hypoxia administration. ROC-325 attenuated high K+ or alveolar hypoxia-induced pulmonary vasoconstriction and enhanced endothelial-dependent relaxation in isolated pulmonary artery rings. ROC-325 treatment inhibited autophagy and enhanced endothelial nitric oxide synthase activity in lung tissues of monocrotaline-PH rats. In cultured human and rat pulmonary arterial smooth muscle cell and pulmonary arterial endothelial cell under hypoxia exposure, ROC-325 increased LC3B and p62 accumulation, endothelial cell nitric oxide production via phosphorylation of endothelial nitric oxide synthase (Ser1177) and dephosphorylation of endothelial nitric oxide synthase (Thr495) as well as decreased HIF (hypoxia-inducible factor)-1α and HIF-2α stabilization.
    CONCLUSIONS: These data indicate that ROC-325 is a promising novel agent for the treatment of PH that inhibits autophagy, downregulates HIF levels, and increases nitric oxide production.
    Keywords:  ROC-325; autophagy; heart failure; lung; pulmonary hypertension
    DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.122.19397
  48. Brain. 2022 Nov 10. pii: awac412. [Epub ahead of print]
    Transthyretin attenuates TDP-43 proteinopathy by autophagy activation via ATF4 in FTLD-TDP.
    Yuan-Ping Chu, Lee-Way Jin, Liang-Chao Wang, Pei-Chuan Ho, Wei-Yen Wei, Kuen-Jer Tsai.
      TAR DNA binding protein-43 (TDP-43) proteinopathies are accompanied by the pathological hallmark of cytoplasmic inclusions in the neurodegenerative diseases, including frontal temporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). We found that TTR accumulates with TDP-43 cytoplasmic inclusions in FTLD-TDP human patients and transgenic mice, in which TTR exhibits dramatic expression decline in elderly mice. The upregulation of TTR expression was demonstrated to facilitate the clearance of cytoplasmic TDP-43 inclusions through autophagy, whereof TTR induces autophagy upregulation via ATF4. Of interest, TTR upregulated ATF4 expression and promoted ATF4 nuclear import, presenting physical interaction. Neuronal expression of TTR in FTLD-TDP mice restored autophagy function and facilitated early soluble TDP-43 aggregates for autophagosome targeting, ameliorating neuropathology and behavioral deficits. Thus, TTR conducted two-way regulations by either inducing autophagy activation or escorting TDP-43 aggregates targeted autophagosomes, suggesting that TTR is a potential modulator therapy for neurological disorders caused by TDP-43 proteinopathy.
    Keywords:  ATF4; FTLD; TDP-43; TTR; proteinopathy
    DOI:  https://doi.org/10.1093/brain/awac412
  49. Adv Drug Deliv Rev. 2022 Nov 07. pii: S0169-409X(22)00507-5. [Epub ahead of print] 114617
    Cyclodextrins applied to the treatment of lysosomal disorders.
    Yoichi Ishitsuka, Tetsumi Irie, Muneaki Matsuo.
      Cyclodextrin (CD), a cyclic oligosaccharide, is a pharmaceutical additive that improves the solubility of hydrophobic compounds. Recent research has focused on the potential active pharmaceutical abilities of CD. Lysosomal storage diseases are inherited metabolic diseases characterized by lysosomal dysfunction and abnormal lipid storge. Niemann-Pick disease type C (NPC) is caused by mutations in cholesterol transporter genes (NPC1, NPC2) and is characterized by cholesterol accumulation in lysosomes. A biocompatible cholesterol solubilizer 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was recently used in NPC patients for compassionate use and in clinical trials. HP-β-CD is an attractive drug candidate for NPC; however, its adverse effects, such as ototoxicity, should be solved. In this review, we discuss the current use of HP-β-CD in basic and clinical research and discuss alternative CD derivatives that may outperform HP-β-CD, which should be considered for clinical use. The potential of CD therapy for the treatment of other lysosomal storage diseases is also discussed.
    Keywords:  Niemann-Pick disease type C; cholesterol; cyclodextrin; lipid trafficking; lysosomal storage disease; ototoxicity
    DOI:  https://doi.org/10.1016/j.addr.2022.114617
  50. Sci Adv. 2022 Nov 11. 8(45): eabo7956
    AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
    Lisa Tilokani, Fiona M Russell, Stevie Hamilton, Daniel M Virga, Mayuko Segawa, Vincent Paupe, Anja V Gruszczyk, Margherita Protasoni, Luis-Carlos Tabara, Mark Johnson, Hanish Anand, Michael P Murphy, D Grahame Hardie, Franck Polleux, Julien Prudent.
      Mitochondria are dynamic organelles that undergo membrane remodeling events in response to metabolic alterations to generate an adequate mitochondrial network. Here, we investigated the function of mitochondrial fission regulator 1-like protein (MTFR1L), an uncharacterized protein that has been identified in phosphoproteomic screens as a potential AMP-activated protein kinase (AMPK) substrate. We showed that MTFR1L is an outer mitochondrial membrane-localized protein modulating mitochondrial morphology. Loss of MTFR1L led to mitochondrial elongation associated with increased mitochondrial fusion events and levels of the mitochondrial fusion protein, optic atrophy 1. Mechanistically, we show that MTFR1L is phosphorylated by AMPK, which thereby controls the function of MTFR1L in regulating mitochondrial morphology both in mammalian cell lines and in murine cortical neurons in vivo. Furthermore, we demonstrate that MTFR1L is required for stress-induced AMPK-dependent mitochondrial fragmentation. Together, these findings identify MTFR1L as a critical mitochondrial protein transducing AMPK-dependent metabolic changes through regulation of mitochondrial dynamics.
    DOI:  https://doi.org/10.1126/sciadv.abo7956
  51. Autophagy. 2022 Nov 11. 1-4
    Diversity, equity and inclusion in autophagy research.
    Daniel J Klionsky.
      Over the past several years, I have been interacting with an increasing number of Iranian scientists, including those currently living in Iran as well as others who are being educated elsewhere or have independent positions outside of that country. In all circumstances, the resulting collaborations have extended my own knowledge and allowed me to contribute to papers on a variety of topics that are outside my specific area of expertise, including xenophagy, nanoparticles, cardiac disease and cancer. As the editor-in-chief of this journal, one of my goals is to be as inclusive as possible, encouraging scientists from around the world to engage in autophagy-related research, and to heighten awareness of this work with an aim toward a more complete understanding of the basic process, and to aid in progress toward the modulation of autophagy for medical applications. For this reason, I have been extremely dismayed by the actions of the current government in Iran, which have led to attacks on scientists and students, and in particular to policies that encourage the repression of women. Although we still have not achieved full equality for women in the United States of America, I think we are slowly moving in a positive direction. It is my sincere hope that the lives and aspirations of women around the world can continue to improve so that this half of our population can fully contribute to the scientific enterprise.
    Keywords:  Colleagues; Iran; Mahsa Amini; diversity; respect; rights; women
    DOI:  https://doi.org/10.1080/15548627.2022.2140551
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