bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023‒06‒11
forty-six papers selected by
Viktor Korolchuk, Newcastle University
  1. The mTOR signaling pathway in cardiac aging.
  2. Profiling of purified autophagic vesicle degradome in the maturing and aging brain.
  3. Mitophagy and long-term neuronal homeostasis.
  4. Molecular mechanisms of macroautophagy, microautophagy, and chaperone-mediated autophagy.
  5. Redundant electrostatic interactions between GATOR1 and the Rag GTPase heterodimer drives efficient amino acid sensing in human cells.
  6. An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway.
  7. Targeting neuronal mitophagy in ischemic stroke: an update.
  8. Interaction between mitophagy, cadmium and zinc.
  9. Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases.
  10. Toward a standard model for autophagosome biogenesis.
  11. Unraveling the Link between Class 1A PI3-Kinase, Autophagy, and Myelodysplasia.
  12. mTORC1 inhibition impairs activation of the unfolded protein response and induces cell death during ER stress in cardiomyocytes.
  13. GPX4 in cell death, autophagy, and disease.
  14. Reversal of memory and autism-related phenotypes in Tsc2+/- mice via inhibition of Nlgn1.
  15. Mammalian ATG8 proteins maintain autophagosomal membrane integrity through ESCRTs.
  16. Autophagy-related proteins: Potential diagnostic and prognostic biomarkers of aging-related diseases.
  17. BAX/MLKL signaling contributes to lipotoxicity-induced lysosomal membrane permeabilization in alcohol-associated liver disease.
  18. Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases.
  19. Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies.
  20. Desmin mutations impact the autophagy flux in C2C12 cell in mutation-specific manner.
  21. Autophagosome membrane expansion is mediated by the N-terminus and cis-membrane association of human ATG8s.
  22. Arginine depletion attenuates renal cystogenesis in tuberous sclerosis complex model.
  23. ATF4 regulates mitochondrial content, morphology, and function in differentiating skeletal muscle myotubes.
  24. The Dysregulated MAD in Mad: A Neuro-theranostic Approach Through the Induction of Autophagic Biomarkers LC3B-II and ATG.
  25. Eating your mitochondria-when too much of a good thing turns bad.
  26. Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter anion exchanger 2, SLC4A2.
  27. Tangzhiqing-mediated NRF2 reduces autophagy-dependent ferroptosis to mitigate diabetes-related cognitive impairment neuronal damage.
  28. Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic-Reticulum-Targeted Therapy: Left or Right?
  29. Liposome encapsulated anticancer drugs on autophagy in cancer cells - current and future perspective.
  30. SLC12A9 is a lysosome-detoxifying ammonium - chloride co-transporter.
  31. Upstream Open Reading Frame-encoded MP31 Disrupts the Mitochondrial Quality Control Process and Inhibits Tumorigenesis in Glioblastoma.
  32. Thymoquinone induces apoptosis and protective autophagy in gastric cancer cells by inhibiting the PI3K/Akt/mTOR pathway.
  33. The role of Raptor in lymphocytes differentiation and function.
  34. C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A.
  35. Stress-responsive Gdf15 counteracts renointestinal toxicity via autophagic and microbiota reprogramming.
  36. GPI-anchored Gas1 protein regulates cytosolic proteostasis in yeast.
  37. A systems biology approach to define mechanisms, phenotypes, and drivers in PanNETs with a personalized perspective.
  38. PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis.
  39. Rapamycin reverses ferroptosis by increasing autophagy in MPTP/MPP+-induced models of Parkinson's disease.
  40. Early pheromone perception remodels neurodevelopment and accelerates neurodegeneration in adult C. elegans.
  41. Atg1, a key regulator of autophagy, functions to promote MAPK activation and cell death upon calcium overload in fission yeast.
  42. Sialic acids promote macrophage M1 polarization and atherosclerosis by upregulating ROS and autophagy blockage.
  43. Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition.
  44. Convergent mechanisms of microglia-mediated synaptic dysfunction contribute to diverse neuropathological conditions.
  45. Neratinib is a TFEB and TFE3 activator that potentiates autophagy and unbalances energy metabolism in ERBB2+ breast cancer cells.
  46. Proximity Proteomics and Biochemical Analysis Reveal a Noncanonical Function for UFM1-Specific Protease 1 in the p62 Body Formation.
  1. J Cardiovasc Aging. 2023 ;pii: 24. [Epub ahead of print]3(3):
    The mTOR signaling pathway in cardiac aging.
    Dao-Fu Dai, Ping Kang, Hua Bai.
      The mammalian target of rapamycin (mTOR) is one of the most important signaling pathways that regulate nutrient sensing, cell growth, metabolism, and aging. The mTOR pathway, particularly mTOR complex 1 (mTORC1), has been shown to control aging, lifespan, and healthspan through the regulation of protein synthesis, autophagy, mitochondrial function, and metabolic health. The mTOR pathway also plays critical roles in the heart, from cardiac development, growth and maturation, and maintenance of cardiac homeostasis. Hyperactivation of mTORC1 signaling is well documented in aging and many age-related pathologies, including age-related cardiac dysfunction and heart failure. Suppression of mTORC1 by calorie restriction or rapamycin not only extends lifespan but also restores youthful phenotypes in the heart. In this article, we review model organisms of cardiac aging and highlight recent advances in the impact of the mTORC1 pathway on organismal and cardiac aging, particularly in Drosophila and mice. We focus on the downstream signaling pathways S6 kinase and 4EBP1, which regulates protein synthesis, as well as ULK1 and its related pathway that regulates autophagy. The interaction with mTOR complex 2 (mTORC2) and its potential role in cardiac aging are also discussed.
    Keywords:  aging; caloric restriction; cardiac aging; heart failure; mTOR; rapamycin
    DOI:  https://doi.org/10.20517/jca.2023.10
  2. Neuron. 2023 May 26. pii: S0896-6273(23)00384-7. [Epub ahead of print]
    Profiling of purified autophagic vesicle degradome in the maturing and aging brain.
    Emmanouela Kallergi, Devanarayanan Siva Sankar, Alessandro Matera, Angeliki Kolaxi, Rosa Chiara Paolicelli, Joern Dengjel, Vassiliki Nikoletopoulou.
      Autophagy disorders prominently affect the brain, entailing neurodevelopmental and neurodegenerative phenotypes in adolescence or aging, respectively. Synaptic and behavioral deficits are largely recapitulated in mouse models with ablation of autophagy genes in brain cells. Yet, the nature and temporal dynamics of brain autophagic substrates remain insufficiently characterized. Here, we immunopurified LC3-positive autophagic vesicles (LC3-pAVs) from the mouse brain and proteomically profiled their content. Moreover, we characterized the LC3-pAV content that accumulates after macroautophagy impairment, validating a brain autophagic degradome. We reveal selective pathways for aggrephagy, mitophagy, and ER-phagy via selective autophagy receptors, and the turnover of numerous synaptic substrates, under basal conditions. To gain insight into the temporal dynamics of autophagic protein turnover, we quantitatively compared adolescent, adult, and aged brains, revealing critical periods of enhanced mitophagy or degradation of synaptic substrates. Overall, this resource unbiasedly characterizes the contribution of autophagy to proteostasis in the maturing, adult, and aged brain.
    Keywords:  ER-phagy; aggrephagy; autophagic vesicles; brain; degradome; mitophagy; proteomic profiling; synapse
    DOI:  https://doi.org/10.1016/j.neuron.2023.05.011
  3. J Cell Sci. 2023 Jun 01. pii: jcs260638. [Epub ahead of print]136(11):
    Mitophagy and long-term neuronal homeostasis.
    Maria Markaki, Dikaia Tsagkari, Nektarios Tavernarakis.
      Neurons are highly polarized, post-mitotic cells that are characterized by unique morphological diversity and complexity. As highly differentiated cells that need to survive throughout organismal lifespan, neurons face exceptional energy challenges in time and space. Therefore, neurons are heavily dependent on a healthy mitochondrial network for their proper function and maintenance under both physiological and stress conditions. Multiple quality control systems have evolved to fine-tune mitochondrial number and quality, thus preserving neuronal energy homeostasis. Here, we review the contribution of mitophagy, a selective form of autophagy that targets dysfunctional or superfluous mitochondria for degradation, in maintaining nervous system homeostasis. In addition, we discuss recent evidence implicating defective or dysregulated mitophagy in the pathogenesis of neurodegenerative diseases.
    Keywords:  Autophagy; Energy homeostasis; Mitochondria; Mitophagy; Nervous system; Neurodegeneration; Neurodegenerative diseases; Neuron; Non-neuronal cells
    DOI:  https://doi.org/10.1242/jcs.260638
  4. J Nippon Med Sch. 2023 Jun 02.
    Molecular mechanisms of macroautophagy, microautophagy, and chaperone-mediated autophagy.
    Hayashi Yamamoto, Takahide Matsui.
      Autophagy is a self-digestive process that is conserved in eukaryotic cells and responsible for maintaining cellular homeostasis through proteolysis. By this process, cells break down their own components in lysosomes. Autophagy can be classified into three categories: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy involves membrane elongation and microautophagy involves membrane internalization, and both pathways undergo selective or non-selective processes that transport cytoplasmic components into lysosomes to be degraded. CMA, however, involves selective incorporation of cytosolic materials into lysosomes without membrane deformation. All three categories of autophagy have attracted much attention due to their involvement in various biological phenomena and their relevance to human diseases, such as neurodegenerative diseases and cancer. Clarification of the molecular mechanisms behind these processes is key to understanding autophagy and recent studies have made major progress in this regard, especially for the mechanisms of initiation and membrane elongation in macroautophagy and substrate recognition in microautophagy and CMA. Furthermore, it is becoming evident that the three categories of autophagy are related to each other despite their implementation by different sets of proteins and the involvement of completely different membrane dynamics. In this review, recent progress in macroautophagy, microautophagy, and CMA are summarized.
    Keywords:  CMA; autophagy; macroautophagy; microautophagy
    DOI:  https://doi.org/10.1272/jnms.JNMS.2024_91-102
  5. J Biol Chem. 2023 Jun 01. pii: S0021-9258(23)01908-7. [Epub ahead of print] 104880
    Redundant electrostatic interactions between GATOR1 and the Rag GTPase heterodimer drives efficient amino acid sensing in human cells.
    Dylan D Doxsey, Steven D Tettoni, Shawn B Egri, Kuang Shen.
      Cells need to coordinate nutrient availability with their growth and proliferation. In eukaryotic cells, this coordination is mediated by the mechanistic target of rapamycin complex 1 (mTORC1) pathway. mTORC1 activation is regulated by two GTPase units, the Rag GTPase heterodimer and the Rheb GTPase. The RagA-RagC heterodimer controls the subcellular localization of mTORC1, and its nucleotide loading states are strictly controlled by upstream regulators including amino acid sensors. A critical negative regulator of the Rag GTPase heterodimer is GATOR1. In the absence of amino acids, GATOR1 stimulates GTP hydrolysis by the RagA subunit to turn off mTORC1 signaling. Despite the enzymatic specificity of GATOR1 to RagA, a recent cryo-EM structural model of the human GATOR1-Rag-Ragulator complex reveals an unexpected interface between Depdc5, a subunit of GATOR1, and RagC. Currently, there is no functional characterization of this interface, nor do we know its biological relevance. Here, combining structure-function analysis, enzymatic kinetic measurements, and cell-based signaling assays, we identified a critical electrostatic interaction between Depdc5 and RagC. This interaction is mediated by the positively charged Arg-1407 residue on Depdc5, and a patch of negatively charged residues on the lateral side of RagC. Abrogating this interaction impairs the GAP activity of GATOR1 and cellular response to amino acid withdrawal. Our results reveal how GATOR1 coordinates the nucleotide loading states of the Rag GTPase heterodimer, and thus precisely controls cellular behavior in the absence of amino acids.
    Keywords:  GATOR1; GTPase Activating Protein; Metabolism; Rag GTPase; mTOR complex 1 (mTORC1)
    DOI:  https://doi.org/10.1016/j.jbc.2023.104880
  6. bioRxiv. 2023 May 26. pii: 2023.05.25.541239. [Epub ahead of print]
    An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway.
    Grace Y Liu, Patrick Jouandin, Raymond E Bahng, Norbert Perrimon, David M Sabatini.
      Animals must sense and respond to nutrient availability in their local niche. This task is coordinated in part by the mTOR complex 1 (mTORC1) pathway, which regulates growth and metabolism in response to nutrients 1-5 . In mammals, mTORC1 senses specific amino acids through specialized sensors that act through the upstream GATOR1/2 signaling hub 6-8 . To reconcile the conserved architecture of the mTORC1 pathway with the diversity of environments that animals can occupy, we hypothesized that the pathway might maintain plasticity by evolving distinct nutrient sensors in different metazoan phyla 1,9,10 . Whether such customization occurs- and how the mTORC1 pathway might capture new nutrient inputs-is not known. Here, we identify the Drosophila melanogaster protein Unmet expectations (Unmet, formerly CG11596) as a species-restricted nutrient sensor and trace its incorporation into the mTORC1 pathway. Upon methionine starvation, Unmet binds to the fly GATOR2 complex to inhibit dTORC1. S -adenosylmethionine (SAM), a proxy for methionine availability, directly relieves this inhibition. Unmet expression is elevated in the ovary, a methionine-sensitive niche 11 , and flies lacking Unmet fail to maintain the integrity of the female germline under methionine restriction. By monitoring the evolutionary history of the Unmet-GATOR2 interaction, we show that the GATOR2 complex evolved rapidly in Dipterans to recruit and repurpose an independent methyltransferase as a SAM sensor. Thus, the modular architecture of the mTORC1 pathway allows it to co-opt preexisting enzymes and expand its nutrient sensing capabilities, revealing a mechanism for conferring evolvability on an otherwise highly conserved system.
    DOI:  https://doi.org/10.1101/2023.05.25.541239
  7. Burns Trauma. 2023 ;11 tkad018
    Targeting neuronal mitophagy in ischemic stroke: an update.
    Jun Li, Jiaying Wu, Xinyu Zhou, Yangyang Lu, Yuyang Ge, Xiangnan Zhang.
      Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms, including autophagic degradation of neuronal mitochondria, or termed mitophagy, following ischemic events. Despite being well-documented, the cellular and molecular mechanisms underlying the regulation of neuronal mitophagy remain unknown. So far, the evidence suggests neuronal autophagy and mitophagy are separately regulated in ischemic neurons, the latter being more likely activated by reperfusional injury. Specifically, given the polarized morphology of neurons, mitophagy is regulated by different neuronal compartments, with axonal mitochondria being degraded by autophagy in the cell body following ischemia-reperfusion insult. A variety of molecules have been associated with neuronal adaptation to ischemia, including PTEN-induced kinase 1, Parkin, BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3), Bnip3-like (Bnip3l) and FUN14 domain-containing 1. Moreover, it is still controversial whether mitophagy protects against or instead aggravates ischemic brain injury. Here, we review recent studies on this topic and provide an updated overview of the role and regulation of mitophagy during ischemic events.
    Keywords:  BCL2 and adenovirus E1B 19-kDa-interacting protein 3; Bnip3-like; Cerebral ischemia; FUN14 domain-containing 1; Mitophagy; Neuroprotection; PTEN-induced kinase 1; Parkin
    DOI:  https://doi.org/10.1093/burnst/tkad018
  8. J Trace Elem Med Biol. 2023 Jun 01. pii: S0946-672X(23)00106-2. [Epub ahead of print]79 127230
    Interaction between mitophagy, cadmium and zinc.
    Nickolay K Isaev, Elena V Stelmashook, Elizaveta E Genrikhs, Galina E Onishchenko.
      Mitophagy is the selective degradation of mitochondria by autophagy. This process is considered to be one of the stages of mitochondrial quality control, as a result of which damaged depolarized mitochondria are eliminated, thus limiting the formation of reactive oxygen species and the release of apoptogenic factors. Selective degradation of mitochondria by autophagy is one of the main ways to protect cells from cadmium toxicity, which results in dysfunction of the mitochondrial electron transport chain, leading to electron leakage, production of reactive oxygen species and cells death. However, excessive autophagy can be dangerous for cells. Currently, the participation of cadmium ions in normal physiological processes has not been detected. Zn2+, unlike Cd2+, regulate the activity of a large number of functionally important proteins, including transcription factors, enzymes, and adapters. It has been shown that Zn2+ not only participate in autophagy, but are also crucial for basal or induced autophagy. It is likely that zinc drugs can be used to reduce the cadmium toxicity and in the regulation of mithophagy.
    Keywords:  Cadmium ions; Mitochondria; Mitophagy; Zinc ions
    DOI:  https://doi.org/10.1016/j.jtemb.2023.127230
  9. Transl Neurodegener. 2023 Jun 08. 12(1): 29
    Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases.
    Chih Hung Lo, Jialiu Zeng.
      Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have been linked to lysosomal de-acidification through impairing the vacuolar-type ATPase and ion channels on the organelle membrane. Similar lysosomal abnormalities are also present in sporadic forms of neurodegeneration, although the underlying pathogenic mechanisms are unclear and remain to be investigated. Importantly, recent studies have revealed early occurrence of lysosomal acidification impairment before the onset of neurodegeneration and late-stage pathology. However, there is a lack of methods for organelle pH monitoring in vivo and a dearth of lysosome-acidifying therapeutic agents. Here, we summarize and present evidence for the notion of defective lysosomal acidification as an early indicator of neurodegeneration and urge the critical need for technological advancement in developing tools for lysosomal pH monitoring and detection both in vivo and for clinical applications. We further discuss current preclinical pharmacological agents that modulate lysosomal acidification, including small molecules and nanomedicine, and their potential clinical translation into lysosome-targeting therapies. Both timely detection of lysosomal dysfunction and development of therapeutics that restore lysosomal function represent paradigm shifts in targeting neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Autophagy dysfunction; Early detection; Lysosomal de-acidification; Nanomedicine; Nanoparticles; Neurodegenerative diseases; Parkinson’s disease; Prognostic marker; Small molecules
    DOI:  https://doi.org/10.1186/s40035-023-00362-0
  10. J Cell Biol. 2023 Jul 03. pii: e202304011. [Epub ahead of print]222(7):
    Toward a standard model for autophagosome biogenesis.
    Annan S I Cook, James H Hurley.
      Two papers in this issue resolve a long-standing obstacle to a "standard model" for autophagosome biogenesis in mammals. The first, Olivas et al. (2023. J. Cell Biol. https://doi.org/10.1083/jcb.202208088), uses biochemistry to confirm that the lipid scramblase ATG9A is a bona fide autophagosome component, while the second, Broadbent et al. (2023. J. Cell Biol. https://doi.org/10.1083/jcb.202210078), uses particle tracking to show that the dynamics of autophagy proteins are consistent with the concept.
    DOI:  https://doi.org/10.1083/jcb.202304011
  11. Autophagy. 2023 Jun 08.
    Unraveling the Link between Class 1A PI3-Kinase, Autophagy, and Myelodysplasia.
    Kristina Ames, Kira Gritsman.
      Myelodysplastic syndrome (MDS) is a clonal malignancy that develops from hematopoietic stem cells (HSCs), but the underlying mechanisms of MDS initiation are not well understood. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is often dysregulated in MDS. To investigate how PI3K inactivation affects HSC function, we generated a mouse model in which three Class IA PI3K genes were deleted in hematopoietic cells. Surprisingly, PI3K deficiency caused cytopenias, reduced survival, and multilineage dysplasia with chromosomal abnormalities, consistent with MDS initiation. PI3K-deficient HSCs had impaired autophagy, and pharmacologic treatment with autophagy-inducing reagents improved HSC differentiation. Furthermore, a similar autophagic degradation defect was observed in MDS patient HSCs. Therefore, our study uncovered a crucial protective role for Class IA PI3K in maintaining autophagic flux in HSCs to preserve the balance between self-renewal and differentiation.
    Keywords:  Myelodysplastic syndrome; PI3K/AKT; autophagic flux; autophagosome; autophagy; differentiation; hematopoietic stem cells; lysosome; self-renewal
    DOI:  https://doi.org/10.1080/15548627.2023.2221922
  12. Am J Physiol Heart Circ Physiol. 2023 Jun 09.
    mTORC1 inhibition impairs activation of the unfolded protein response and induces cell death during ER stress in cardiomyocytes.
    Christoph Hofmann, Zoe Löwenthal, Marjan Aghajani, Randal J Kaufman, Hugo A Katus, Norbert Frey, Christopher C Glembotski, Mirko Völkers, Shirin Doroudgar.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of protein synthesis that senses and responds to a variety of stimuli to coordinate cellular metabolism with environmental conditions. To ensure that protein synthesis is inhibited during unfavorable conditions, translation is directly coupled to the sensing of cellular protein homeostasis. Thus, translation is attenuated during endoplasmic reticulum (ER) stress by direct inhibition of the mTORC1 pathway. However, residual mTORC1 activity is maintained during prolonged ER stress which is thought to be involved in translational reprogramming and adaption to ER stress. By analyzing the dynamics of mTORC1 regulation during ER stress, we unexpectedly found that mTORC1 is transiently activated in cardiomyocytes within minutes at the onset of ER stress before being inhibited during chronic ER stress. This dynamic regulation of mTORC1 appears to be mediated, at least in part, by ATF6, as its activation was sufficient to induce the biphasic control of mTORC1. We further showed that protein synthesis remains dependent on mTORC1 throughout the ER stress response and that mTORC1 activity is essential for posttranscriptional induction of several unfolded protein response elements. Pharmacological inhibition of mTORC1 increased cell death during ER stress, indicating that the mTORC1 pathway serves adaptive functions during ER stress in cardiomyocytes potentially by controlling the expression of the protective unfolded protein response.
    Keywords:  ATF6; ER stress; cardiomyocytes; cell death; mTORC1
    DOI:  https://doi.org/10.1152/ajpheart.00682.2022
  13. Autophagy. 2023 Jun 04. 1-18
    GPX4 in cell death, autophagy, and disease.
    Yangchun Xie, Rui Kang, Daniel J Klionsky, Daolin Tang.
      Selenoprotein GPX4 (glutathione peroxidase 4), originally known as PHGPX (phospholipid hydroperoxide glutathione peroxidase), is the main oxidoreductase in the use of glutathione as a reducing agent in scavenging lipid peroxidation products. There are three GPX4 isoforms: cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), with distinct spatiotemporal expression patterns during embryonic development and adult life. In addition to inducing the main phenotype of ferroptosis, the loss of GPX4 can in some cells trigger apoptosis, necroptosis, pyroptosis, or parthanatos, which mediates or accelerates developmental defects, tissue damage, and sterile inflammation. The interaction of GPX4 with the autophagic degradation pathway further modulates cell fate in response to oxidative stress. Impaired GPX4 function is implicated in tumorigenesis, neurodegeneration, infertility, inflammation, immune disorders, and ischemia-reperfusion injury. Additionally, the R152H mutation in GPX4 can promote the development of Sedaghatian-type spinal metaphyseal dysplasia, a rare and fatal disease in newborns. Here, we discuss the roles of classical GPX4 functions as well as emerging GPX4-regulated processes in cell death, autophagy, and disease.Abbreviations: AA: arachidonic acid; cGPX4: cytosolic GPX4; CMA: chaperone-mediated autophagy; DAMPs: danger/damage-associated molecular patterns; mGPX4: mitochondrial GPX4; nGPX4: nuclear GPX4; GSDMD-N: N-terminal fragment of GSDMD; I/R: ischemia-reperfusion; PLOOH: phospholipid hydroperoxide; PUFAs: polyunsaturated fatty acids; RCD: regulated cell death; ROS: reactive oxygen species; Se: selenium; SSMD: Sedaghatian-type spondylometaphyseal dysplasia; UPS: ubiquitin-proteasome system.
    Keywords:  Lipid peroxidation; autophagy; cell death; oxidoreductase
    DOI:  https://doi.org/10.1080/15548627.2023.2218764
  14. Front Cell Dev Biol. 2023 ;11 1205112
    Reversal of memory and autism-related phenotypes in Tsc2+/- mice via inhibition of Nlgn1.
    Kleanthi Chalkiadaki, Elpida Statoulla, Maria Zafeiri, Nabila Haji, Jean-Claude Lacaille, Craig M Powell, Seyed Mehdi Jafarnejad, Arkady Khoutorsky, Christos G Gkogkas.
      Tuberous sclerosis complex (TSC) is a rare monogenic disorder co-diagnosed with high rates of autism and is caused by loss of function mutations in the TSC1 or TSC2 genes. A key pathway hyperactivated in TSC is the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which regulates cap-dependent mRNA translation. We previously demonstrated that exaggerated cap-dependent translation leads to autism-related phenotypes and increased mRNA translation and protein expression of Neuroligin 1 (Nlgn1) in mice. Inhibition of Nlgn1 expression reversed social behavior deficits in mice with increased cap-dependent translation. Herein, we report elevated translation of Nlgn1 mRNA and an increase in its protein expression. Genetic or pharmacological inhibition of Nlgn1 expression in Tsc2 +/- mice rescued impaired hippocampal mGluR-LTD, contextual discrimination and social behavior deficits in Tsc2 +/- mice, without correcting mTORC1 hyperactivation. Thus, we demonstrate that reduction of Nlgn1 expression in Tsc2 +/- mice is a new therapeutic strategy for TSC and potentially other neurodevelopmental disorders.
    Keywords:  autism; mTOR; memory; translational control; tuberous sclerosis
    DOI:  https://doi.org/10.3389/fcell.2023.1205112
  15. EMBO J. 2023 Jun 05. e112845
    Mammalian ATG8 proteins maintain autophagosomal membrane integrity through ESCRTs.
    Ruheena Javed, Ashish Jain, Thabata Duque, Emily Hendrix, Masroor Ahmad Paddar, Sajjad Khan, Aurore Claude-Taupin, Jingyue Jia, Lee Allers, Fulong Wang, Michal Mudd, Graham Timmins, Keith Lidke, Tor Erik Rusten, Prithvi Reddy Akepati, Yi He, Fulvio Reggiori, Eeva-Liisa Eskelinen, Vojo Deretic.
      The canonical autophagy pathway in mammalian cells sequesters diverse cytoplasmic cargo within the double membrane autophagosomes that eventually convert into degradative compartments via fusion with endolysosomal intermediates. Here, we report that autophagosomal membranes show permeability in cells lacking principal ATG8 proteins (mATG8s) and are unable to mature into autolysosomes. Using a combination of methods including a novel in vitro assay to measure membrane sealing, we uncovered a previously unappreciated function of mATG8s to maintain autophagosomal membranes in a sealed state. The mATG8 proteins GABARAP and LC3A bind to key ESCRT-I components contributing, along with other ESCRTs, to the integrity and imperviousness of autophagic membranes. Autophagic organelles in cells lacking mATG8s are permeant, are arrested as amphisomes, and do not progress to functional autolysosomes. Thus, autophagosomal organelles need to be maintained in a sealed state in order to become lytic autolysosomes.
    Keywords:  ATG8; ESCRT; LC3; amphisome; autophagy
    DOI:  https://doi.org/10.15252/embj.2022112845
  16. Ageing Res Rev. 2023 Jun 01. pii: S1568-1637(23)00126-5. [Epub ahead of print]89 101967
    Autophagy-related proteins: Potential diagnostic and prognostic biomarkers of aging-related diseases.
    Caterina Miceli, Manuela Leri, Massimo Stefani, Monica Bucciantini.
      Autophagy plays a key role in cellular, tissue and organismal homeostasis and in the production of the energy load needed at critical times during development and in response to nutrient shortage. Autophagy is generally considered as a pro-survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy efficiency declines with age, thus contributing to many different pathophysiological conditions, such as cancer, cardiomyopathy, diabetes, liver disease, autoimmune diseases, infections, and neurodegeneration. Accordingly, it has been proposed that the maintenance of a proper autophagic activity contributes to the extension of the lifespan in different organisms. A better understanding of the interplay between autophagy and risk of age-related pathologies is important to propose nutritional and life-style habits favouring disease prevention as well as possible clinical applications aimed at promoting long-term health.
    Keywords:  Aging; Aging-diseases; Autophagy; Biomarkers; Clinical practice
    DOI:  https://doi.org/10.1016/j.arr.2023.101967
  17. Autophagy. 2023 Jun 08.
    BAX/MLKL signaling contributes to lipotoxicity-induced lysosomal membrane permeabilization in alcohol-associated liver disease.
    Haibo Dong, Wei Guo, Zhanxiang Zhou.
      Lysosomal membrane permeabilization (LMP) has emerged as a significant component of cellular signaling pathway by which autophagy or cell death is regulated under many pathological situations including alcohol-associated liver disease (ALD). However, the mechanisms involved in the regulation of LMP in ALD remain obscure. Recently, we demonstrated that lipotoxicity serves as a causal factor to trigger LMP in hepatocytes. We identified that the apoptotic protein BAX (BCL2 associated X, apoptosis regulator) could recruit MLKL (mixed lineage kinase domain-like pseudokinase), a necroptotic executive protein, to lysosomes and induce LMP in various ALD models. Importantly, the pharmacological or genetic inhibition of BAX or MLKL protects hepatocytes from lipotoxicity-induced LMP. Thus, our study reveals a novel molecular mechanism that activation of BAX/MLKL signaling contributes to the pathogenesis of ALD through mediating lipotoxicity-induced LMP.
    Keywords:  BAX; LAMP2; MLKL; cell death; liver injury; lysosome
    DOI:  https://doi.org/10.1080/15548627.2023.2221989
  18. Neural Regen Res. 2023 Nov;18(11): 2370-2376
    Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases.
    Wenlong Xue, Jie Zhang, Yang Li.
      Millions of people are suffering from Alzheimer's disease globally, but there is still no effective treatment for this neurodegenerative disease. Thus, novel therapeutic approaches for Alzheimer's disease are needed, which requires further evaluation of the regulatory mechanisms of protein aggregate degradation. Lysosomes are crucial degradative organelles that maintain cellular homeostasis. Transcription factor EB-mediated lysosome biogenesis enhances autolysosome-dependent degradation, which subsequently alleviates neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. In this review, we start by describing the key features of lysosomes, including their roles in nutrient sensing and degradation, and their functional impairments in different neurodegenerative diseases. We also explain the mechanisms - especially the post-translational modifications - which impact transcription factor EB and regulate lysosome biogenesis. Next, we discuss strategies for promoting the degradation of toxic protein aggregates. We describe Proteolysis-Targeting Chimera and related technologies for the targeted degradation of specific proteins. We also introduce a group of LYsosome-Enhancing Compounds, which promote transcription factor EB-mediated lysosome biogenesis and improve learning, memory, and cognitive function in APP-PSEN1 mice. In summary, this review highlights the key aspects of lysosome biology, the mechanisms of transcription factor EB activation and lysosome biogenesis, and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; LYsosome-Enhancing Compounds; degradation; lysosome biogenesis; neurodegenerative diseases; post-translational modifications; protein aggregates; transcription factor EB
    DOI:  https://doi.org/10.4103/1673-5374.371346
  19. Front Neurosci. 2023 ;17 1082047
    Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies.
    Stefania Santarelli, Chiara Londero, Alessia Soldano, Carlotta Candelaresi, Leonardo Todeschini, Luisa Vernizzi, Paola Bellosta.
      Proteinopathies are a large group of neurodegenerative diseases caused by both genetic and sporadic mutations in particular genes which can lead to alterations of the protein structure and to the formation of aggregates, especially toxic for neurons. Autophagy is a key mechanism for clearing those aggregates and its function has been strongly associated with the ubiquitin-proteasome system (UPS), hence mutations in both pathways have been associated with the onset of neurodegenerative diseases, particularly those induced by protein misfolding and accumulation of aggregates. Many crucial discoveries regarding the molecular and cellular events underlying the role of autophagy in these diseases have come from studies using Drosophila models. Indeed, despite the physiological and morphological differences between the fly and the human brain, most of the biochemical and molecular aspects regulating protein homeostasis, including autophagy, are conserved between the two species.In this review, we will provide an overview of the most common neurodegenerative proteinopathies, which include PolyQ diseases (Huntington's disease, Spinocerebellar ataxia 1, 2, and 3), Amyotrophic Lateral Sclerosis (C9orf72, SOD1, TDP-43, FUS), Alzheimer's disease (APP, Tau) Parkinson's disease (a-syn, parkin and PINK1, LRRK2) and prion diseases, highlighting the studies using Drosophila that have contributed to understanding the conserved mechanisms and elucidating the role of autophagy in these diseases.
    Keywords:  Drosophila melanogaster; animal model; autophagy; neurodegeneration; non-autonomous signaling; protein-aggregate; protein-misfolding; proteinopathies
    DOI:  https://doi.org/10.3389/fnins.2023.1082047
  20. Cell Tissue Res. 2023 Jun 06.
    Desmin mutations impact the autophagy flux in C2C12 cell in mutation-specific manner.
    K S Sukhareva, N A Smolina, A I Churkina, K K Kalugina, S V Zhuk, A A Khudiakov, A A Khodot, G Faggian, G B Luciani, T Sejersen, A A Kostareva.
      Desmin is the main intermediate filament of striated and smooth muscle cells and plays a crucial role in maintaining the stability of muscle fiber during contraction and relaxation cycles. Being a component of Z-disk area, desmin integrates autophagic pathways, and the disturbance of Z-disk proteins' structure negatively affects chaperone-assisted selective autophagy (CASA). In the present study, we focused on alteration of autophagy flux in myoblasts expressing various Des mutations. We applied Western blotting, immunocytochemistry, RNA sequencing, and shRNA approach to demonstrate that DesS12F, DesA357P, DesL345P, DesL370P, and DesD399Y mutations. Mutation-specific effect on autophagy flux being most severe in aggregate-prone Des mutations such as DesL345P, DesL370P, and DesD399Y. RNA sequencing data confirmed the most prominent effect of these mutations on expression profile and, in particular, on autophagy-related genes. To verify CASA contribution to desmin aggregate formation, we suppressed CASA by knocking down Bag3 and demonstrated that it promoted aggregate formation and lead to downregulation of Vdac2 and Vps4a and upregulation of Lamp, Pink1, and Prkn. In conclusion, Des mutations showed a mutation-specific effect on autophagy flux in C2C12 cells with either a predominant impact on autophagosome maturation or on degradation and recycling processes. Aggregate-prone desmin mutations lead to the activation of basal autophagy level while suppressing the CASA pathway by knocking down Bag3 can promote desmin aggregate formation.
    Keywords:  Autophagy; BAG3; C2C12; CASA; Desmin mutation; Protein aggregates
    DOI:  https://doi.org/10.1007/s00441-023-03790-6
  21. Elife. 2023 Jun 08. pii: e89185. [Epub ahead of print]12
    Autophagosome membrane expansion is mediated by the N-terminus and cis-membrane association of human ATG8s.
    Wenxin Zhang, Taki Nishimura, Deepanshi Gahlot, Chieko Saito, Colin Davis, Harold B J Jefferies, Anne Schreiber, Lipi Thukral, Sharon A Tooze.
      Autophagy is an essential catabolic pathway which sequesters and engulfs cytosolic substrates via autophagosomes, unique double-membraned structures. ATG8 proteins are ubiquitin-like proteins recruited to autophagosome membranes by lipidation at the C-terminus. ATG8s recruit substrates, such as p62, and play an important role in mediating autophagosome membrane expansion. However, the precise function of lipidated ATG8 in expansion remains obscure. Using a real-time in vitro lipidation assay, we revealed that the N-termini of lipidated human ATG8s (LC3B and GABARAP) are highly dynamic and interact with the membrane. Moreover, atomistic MD simulation and FRET assays indicate that N-termini of LC3B and GABARAP associate in cis on the membrane. By using non-tagged GABARAPs, we show that GABARAP N-terminus and its cis-membrane insertion are crucial to regulate the size of autophagosomes in cells irrespectively of p62 degradation. Our study provides fundamental molecular insights into autophagosome membrane expansion, revealing the critical and unique function of lipidated ATG8.
    Keywords:  biochemistry; cell biology; chemical biology; none
    DOI:  https://doi.org/10.7554/eLife.89185
  22. Cell Rep Med. 2023 Jun 02. pii: S2666-3791(23)00192-1. [Epub ahead of print] 101073
    Arginine depletion attenuates renal cystogenesis in tuberous sclerosis complex model.
    Athar Amleh, Hadass Pri Chen, Lana Watad, Ifat Abramovich, Bella Agranovich, Eyal Gottlieb, Iddo Z Ben-Dov, Morris Nechama, Oded Volovelsky.
      Cystic kidney disease is a leading cause of morbidity in patients with tuberous sclerosis complex (TSC). We characterize the misregulated metabolic pathways using cell lines, a TSC mouse model, and human kidney sections. Our study reveals a substantial perturbation in the arginine biosynthesis pathway in TSC models with overexpression of argininosuccinate synthetase 1 (ASS1). The rise in ASS1 expression is dependent on the mechanistic target of rapamycin complex 1 (mTORC1) activity. Arginine depletion prevents mTORC1 hyperactivation and cell cycle progression and averts cystogenic signaling overexpression of c-Myc and P65. Accordingly, an arginine-depleted diet substantially reduces the TSC cystic load in mice, indicating the potential therapeutic effects of arginine deprivation for the treatment of TSC-associated kidney disease.
    Keywords:  ASS1; PTCs; TSC; arginine metabolism; argininosuccinate synthetase 1; cystogenesis; mTORC1; mechanistic target of rapamycin complex 1; proximal tubule cells; tuberous sclerosis complex
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101073
  23. Am J Physiol Cell Physiol. 2023 Jun 05.
    ATF4 regulates mitochondrial content, morphology, and function in differentiating skeletal muscle myotubes.
    Jonathan M Memme, Victoria C Sanfrancesco, David A Hood.
      Mitochondrial function is widely recognized as a major determinant of health, emphasizing the importance of understanding the mechanisms promoting mitochondrial quality in various tissues. Recently, the mitochondrial unfolded protein response (UPRmt) has come into focus as a modulator of mitochondrial homeostasis, particularly in stress conditions. In muscle, the necessity for ATF4 and its role in regulating mitochondrial quality control (MQC) has yet to be determined. We overexpressed (OE) and knocked down ATF4 in C2C12 myoblasts, differentiated them to myotubes for 5 days, and subjected them to acute (ACA) or chronic (CCA) contractile activity. ATF4 mediated myotube formation through the regulated expression of myogenic factors, mainly Myc and MyoD, and supressed mitochondrial biogenesis basally through PGC-1a. However, our data also show that ATF4 expression levels are directly related to mitochondrial fusion and dynamics, UPRmt activation, as well as lysosomal biogenesis and autophagy. Thus, ATF4 promoted enhanced mitochondrial networking, protein handling, and capacity for clearance of dysfunctional organelles under stress conditions, despite lower levels of mitophagy flux with OE. Indeed, we found that ATF4 promoted the formation of a smaller pool of high functioning mitochondria that are more responsive to contractile activity, have higher oxygen consumption rates and lower reactive oxygen species levels. These data provide evidence that ATF4 is both necessary and sufficient for mitochondrial quality control and adaptation during both differentiation and contractile activity, thus advancing the current understanding of ATF4 beyond its canonical functions, to include the regulation of mitochondrial morphology, lysosomal biogenesis and mitophagy in muscle cells.
    Keywords:  ATF4; mitochondrial quality control; mitochondrial unfolded protein response; mitophagy and lysosomal biogenesis; skeletal muscle C2C12
    DOI:  https://doi.org/10.1152/ajpcell.00080.2023
  24. Mol Neurobiol. 2023 Jun 05.
    The Dysregulated MAD in Mad: A Neuro-theranostic Approach Through the Induction of Autophagic Biomarkers LC3B-II and ATG.
    Siva Prasad Panda, Vikrant Singh.
      The word mad has historically been associated with the psyche, emotions, and abnormal behavior. Dementia is a common symptom among psychiatric disorders or mad (schizophrenia, depression, bipolar disorder) patients. Autophagy/mitophagy is a protective mechanism used by cells to get rid of dysfunctional cellular organelles or mitochondria. Autophagosome/mitophagosome abundance in autophagy depends on microtubule-associated protein light chain 3B (LC3B-II) and autophagy-triggering gene (ATG) which functions as an autophagic biomarker for phagophore production and quick mRNA disintegration. Defects in either LC3B-II or the ATG lead to dysregulated mitophagy-and-autophagy-linked dementia (MAD). The impaired MAD is closely associated with schizophrenia, depression, and bipolar disorder. The pathomechanism of psychosis is not entirely known, which is the severe limitation of today's antipsychotic drugs. However, the reviewed circuit identifies new insights that may be especially helpful in targeting biomarkers of dementia. Neuro-theranostics can also be achieved by manufacturing either bioengineered bacterial and mammalian cells or nanocarriers (liposomes, polymers, and nanogels) loaded with both imaging and therapeutic materials. The nanocarriers must cross the BBB and should release both diagnostic agents and therapeutic agents in a controlled manner to prove their effectiveness against psychiatric disorders. In this review, we highlighted the potential of microRNAs (miRs) as neuro-theranostics in the treatment of dementia by targeting autophagic biomarkers LC3B-II and ATG. Focus was also placed on the potential for neuro-theranostic nanocells/nanocarriers to traverse the BBB and induce action against psychiatric disorders. The neuro-theranostic approach can provide targeted treatment for mental disorders by creating theranostic nanocarriers.
    Keywords:  BBB; LC3B-II; MAD; Nanocarriers; Psychiatric disorders; miRs
    DOI:  https://doi.org/10.1007/s12035-023-03402-y
  25. EMBO J. 2023 Jun 05. e114542
    Eating your mitochondria-when too much of a good thing turns bad.
    Léa P Wilhelm, Ian G Ganley.
      How mitophagy is turned on to remove damaged or excess mitochondria from cells has been well-studied, but less is known about how the pathway is turned off to avoid "over-eating" of mitochondria under basal conditions. Three new studies now reveal the disease-associated FBXL4 protein as an important negative regulator of constitutive mitophagy, controlling the stability of mitophagy receptors BNIP3 and NIX.
    DOI:  https://doi.org/10.15252/embj.2023114542
  26. Cell Rep. 2023 Jun 03. pii: S2211-1247(23)00612-5. [Epub ahead of print]42(6): 112601
    Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter anion exchanger 2, SLC4A2.
    Johanna Michl, Stefania Monterisi, Bobby White, Wiktoria Blaszczak, Alzbeta Hulikova, Gulnar Abdullayeva, Esther Bridges, Zinan Yin, Walter F Bodmer, Pawel Swietach.
      Acidic environments reduce the intracellular pH (pHi) of most cells to levels that are sub-optimal for growth and cellular functions. Yet, cancers maintain an alkaline cytoplasm despite low extracellular pH (pHe). Raised pHi is thought to be beneficial for tumor progression and invasiveness. However, the transport mechanisms underpinning this adaptation have not been studied systematically. Here, we characterize the pHe-pHi relationship in 66 colorectal cancer cell lines and identify the acid-loading anion exchanger 2 (AE2, SLC4A2) as a regulator of resting pHi. Cells adapt to chronic extracellular acidosis by degrading AE2 protein, which raises pHi and reduces acid sensitivity of growth. Acidity inhibits mTOR signaling, which stimulates lysosomal function and AE2 degradation, a process reversed by bafilomycin A1. We identify AE2 degradation as a mechanism for maintaining a conducive pHi in tumors. As an adaptive mechanism, inhibiting lysosomal degradation of AE2 is a potential therapeutic target.
    Keywords:  CP: Cancer; CP: Metabolism; acid adaptation; acid-base; acidosis; chloride/bicarbonate exchanger; colorectal cancer; intracellular pH; lysosomes; tumor acidity; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2023.112601
  27. Rejuvenation Res. 2023 Jun 06.
    Tangzhiqing-mediated NRF2 reduces autophagy-dependent ferroptosis to mitigate diabetes-related cognitive impairment neuronal damage.
    Lingyan Qiu, Kai Chen, Xu Wang, Yun Zhao.
      Diabetes is a chronic condition defined by the body's inability to process glucose. The most common form, diabetes mellitus, reflects the body's insulin resistance, which leads to long-term raised glucose blood levels. These levels can cause oxidative damage, cell stress, and excessive autophagy throughout the body, including the nervous system. Diabetes-related cognitive impairment (DCI) results from chronic elevation of blood glucose, and as diabetes cases continue to rise, so too do comorbidities such as DCI. Although there are medications to address high blood glucose, there are few that can inhibit excessive autophagy and cell death. Therefore, we investigated if the Traditional Chinese Medicine, Tangzhiqing (TZQ), can reduce the impact of DCI in a high-glucose cell model. We used commercially available kits to evaluate cell viability, mitochondrial activity, and oxidative stress. We found that TZQ treatment increased cell viability, ensured continued mitochondrial activity, and reduced reactive oxygen species. We also found that TZQ functions by increasing NRF2 activity, which decreases the ferroptotic-associated pathways that involve p62, HO-1, and GPX4. Therefore, TZQ should be further investigated for its role in reducing DCI.
    DOI:  https://doi.org/10.1089/rej.2023.0013
  28. Adv Sci (Weinh). 2023 Jun 08. e2301434
    Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic-Reticulum-Targeted Therapy: Left or Right?
    Xinran Shen, Yudi Deng, Liqiang Chen, Chendong Liu, Lian Li, Yuan Huang.
      Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of autophagy better suits ER-targeting therapy remains controversial. Here, a targeted nanosystem is constructed, which efficiently escorts anticancer therapeutics into the ER, triggering substantial ER stress and autophagy. Concurrently, an autophagy enhancer or inhibitor is combined into the same nanoparticle, and their impacts on ER-related activities are compared. In the orthotopic breast cancer mouse model, the autophagy enhancer increases the antimetastasis effect of ER-targeting therapy and suppresses over 90% of cancer metastasis, while the autophagy inhibitor has a bare effect. Mechanism studies reveal that further enhancing autophagy accelerates central protein snail family transcriptional repressor 1 (SNAI1) degradation, suppressing downstream epithelial-mesenchymal transition, while inhibiting autophagy does the opposite. With the same trend, ER-targeting therapy combined with an autophagy enhancer provokes stronger immune response and tumor inhibition than the autophagy inhibitor. Mechanism studies reveal that the autophagy enhancer elevates Ca2+ release from the ER and functions as a cascade amplifier of ER dysfunction, which accelerates Ca2+ release, resulting in immunogenic cell death (ICD) induction and eventually triggering immune responses. Together, ER-targeting therapy benefits from the autophagy-enhancing strategy more than the autophagy-inhibiting strategy for antitumor and antimetastasis treatment.
    Keywords:  antimetastasis therapy; autophagy modulation; drug delivery system; endoplasmic reticulum targeting; immunotherapy
    DOI:  https://doi.org/10.1002/advs.202301434
  29. Int J Pharm. 2023 Jun 04. pii: S0378-5173(23)00525-2. [Epub ahead of print] 123105
    Liposome encapsulated anticancer drugs on autophagy in cancer cells - current and future perspective.
    N Bhagya, K R Chandrashekar.
      Autophagy act as a double-edged sword in cancer with both tumor promoting and inhibiting roles. Under normal conditions of autophagy, the damaged cell organelles and other debris degrade inside the lysosome to provide energy and macromolecular precursors. However, enhanced autophagy can lead to apoptosis and programmed cell death highlighting its significance in cancer therapy. Liposome-based drug delivery systems for treating cancer patients have significant advantages over their non-formulated or free drug counterparts which could be effectively used to manipulate autophagy pathway in cancer patients. In the current review, drug uptake by the cells and its role in autophagy-mediated cancer cell death are discussed. Besides, the challenges and translational difficulties associated with the use of liposome-based chemotherapeutic drugs in clinical trials and in biomedical applications are also discussed.
    Keywords:  Liposomes; autophagy; cancer; drug uptake; multidrug resistance
    DOI:  https://doi.org/10.1016/j.ijpharm.2023.123105
  30. bioRxiv. 2023 May 22. pii: 2023.05.22.541801. [Epub ahead of print]
    SLC12A9 is a lysosome-detoxifying ammonium - chloride co-transporter.
    Roni Levin-Konigsberg, Koushambi Mitra, AkshatKumar Nigam, Kaitlyn Spees, Pravin Hivare, Katherine Liu, Anshul Kundaje, Yamuna Krishnan, Michael C Bassik.
      Ammonia is a ubiquitous, toxic by-product of cell metabolism. Its high membrane permeability and proton affinity causes ammonia to accumulate inside acidic lysosomes in its poorly membrane-permeant form: ammonium (NH 4 + ). Ammonium buildup compromises lysosomal function, suggesting the existence of mechanisms that protect cells from ammonium toxicity. Here, we identified SLC12A9 as a lysosomal ammonium exporter that preserves lysosomal homeostasis. SLC12A9 knockout cells showed grossly enlarged lysosomes and elevated ammonium content. These phenotypes were reversed upon removal of the metabolic source of ammonium or dissipation of the lysosomal pH gradient. Lysosomal chloride increased in SLC12A9 knockout cells and chloride binding by SLC12A9 was required for ammonium transport. Our data indicate that SLC12A9 is a chloride-driven ammonium co-transporter that is central in an unappreciated, fundamental mechanism of lysosomal physiology that may have special relevance in tissues with elevated ammonia, such as tumors.
    DOI:  https://doi.org/10.1101/2023.05.22.541801
  31. Neuro Oncol. 2023 Jun 06. pii: noad099. [Epub ahead of print]
    Upstream Open Reading Frame-encoded MP31 Disrupts the Mitochondrial Quality Control Process and Inhibits Tumorigenesis in Glioblastoma.
    Nunu Huang, Zhipeng Chen, Xuesong Yang, Yixin Gao, Jian Zhong, Yan Li, Feizhe Xiao, Xiuxing Wang, Yu Shi, Nu Zhang.
      BACKGROUND: Mitochondrial hyperpolarization achieved by the elevation of mitochondrial quality control (MQC) activity is a hallmark of glioblastoma (GBM). Therefore, targeting the MQC process to disrupt mitochondrial homeostasis should be a promising approach for GBM therapy.METHOD: We used two-photon fluorescence microscopy, FACS and confocal microscopy with specific fluorescent dyes to detect the mitochondrial membrane potential (MMP) and mitochondrial structures. Mitophagic flux was measured with mKeima.
    RESULTS: MP31, a PTEN uORF-translated and mitochondria-localized micropeptide, disrupted the MQC process and inhibited GBM tumorigenesis. Re-expression of MP31 in patient-derived GBM cells induced MMP loss to trigger mitochondrial fission but blocked mitophagic flux, leading to the accumulation of damaged mitochondria in cells, followed by ROS production and DNA damage. Mechanistically, MP31 inhibited lysosome function and blocked lysosome fusion with mitophagosomes by competing with V-ATPase A1 for LDHB binding to induce lysosomal alkalinization. Furthermore, MP31 enhanced the sensitivity of GBM cells to TMZ by suppressing protective mitophay in vitro and in vivo, but showed no side effects on normal human astrocytes (NHAs) or microglia cells (MG).
    CONCLUSION: MP31 disrupts cancerous mitochondrial homeostasis and sensitizes GBM cells to current chemotherapy, without inducing toxicity in NHA and MG. MP31 is a promising candidate for GBM treatment.
    Keywords:  GBM; MP31; MQC; V-ATPase A1; mitophagy
    DOI:  https://doi.org/10.1093/neuonc/noad099
  32. Phytother Res. 2023 Jun 08.
    Thymoquinone induces apoptosis and protective autophagy in gastric cancer cells by inhibiting the PI3K/Akt/mTOR pathway.
    Pengzhan He, Yang He, Jingjing Ma, Yinghui Liu, Chuan Liu, Yu Baoping, Weiguo Dong.
      Gastric cancer (GC) is often diagnosed in the advanced stages with a poor prognosis. Thymoquinone (TQ) is known for its antitumor activity; however, the specific mechanism in GC remains unknown. In our study, TQ inhibited GC cell proliferation and induced apoptosis and autophagy in a concentration-dependent manner. Transmission electron microscopy showed increased autophagosome formation in GC cells treated with TQ. Meanwhile, the LC3B puncta and LC3BII protein levels were significantly increased in GC cells, while p62 expression was significantly decreased. The autophagy inhibitor, Bafilomycin A1 enhanced TQ-inhibited proliferation and TQ-induced apoptosis, suggesting that TQ-induced autophagy has a protective effect on GC cells. Furthermore, TQ decreased the phosphorylation levels of phosphatidylinositol-4,5-bisphosphate 3 kinase (PI3K), protein kinase B (Akt), and mechanistic target of rapamycin (mTOR). The PI3K agonist partially rescued TQ-induced autophagy and apoptosis. Finally, in vivo experiments showed that TQ could inhibit tumor growth and promote apoptosis and autophagy. This study provides new insights into the specific mechanism for the anti-GC effect of TQ. TQ inhibits the proliferation of GC cells and induces apoptosis and protective autophagy by inhibiting the PI3K/Akt/mTOR pathway. The results suggest that the combination of TQ and autophagy inhibitors might be a potential chemotherapeutic strategy for GC.
    Keywords:  PI3K/Akt/mTOR; apoptosis; autophagy; gastric cancer; thymoquinone
    DOI:  https://doi.org/10.1002/ptr.7820
  33. Front Immunol. 2023 ;14 1146628
    The role of Raptor in lymphocytes differentiation and function.
    Jianing Tang, Lu Yang, Fei Guan, Heather Miller, Niels Olsen Saraiva Camara, Louisa K James, Kamel Benlagha, Masato Kubo, Steffen Heegaard, Pamela Lee, Jiahui Lei, Hu Zeng, Chengwei He, Zhimin Zhai, Chaohong Liu.
      Raptor, a key component of mTORC1, is required for recruiting substrates to mTORC1 and contributing to its subcellular localization. Raptor has a highly conserved N-terminus domain and seven WD40 repeats, which interact with mTOR and other mTORC1-related proteins. mTORC1 participates in various cellular events and mediates differentiation and metabolism. Directly or indirectly, many factors mediate the differentiation and function of lymphocytes that is essential for immunity. In this review, we summarize the role of Raptor in lymphocytes differentiation and function, whereby Raptor mediates the secretion of cytokines to induce early lymphocyte metabolism, development, proliferation and migration. Additionally, Raptor regulates the function of lymphocytes by regulating their steady-state maintenance and activation.
    Keywords:  B cell; Raptor; T cell; immune; mTORC1
    DOI:  https://doi.org/10.3389/fimmu.2023.1146628
  34. Commun Biol. 2023 06 05. 6(1): 606
    C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A.
    Junyang Tan, Wenjun Wang, Xinjie Liu, Jinhong Xu, Yaping Che, Yanyan Liu, Jiaqiao Hu, Liubing Hu, Jianshuang Li, Qinghua Zhou.
      C11orf54 is an ester hydrolase highly conserved across different species. C11orf54 has been identified as a biomarker protein of renal cancers, but its exact function remains poorly understood. Here we demonstrate that C11orf54 knockdown decreases cell proliferation and enhances cisplatin-induced DNA damage and apoptosis. On the one hand, loss of C11orf54 reduces Rad51 expression and nuclear accumulation, which results in suppression of homologous recombination repair. On the other hand, C11orf54 and HIF1A competitively interact with HSC70, knockdown of C11orf54 promotes HSC70 binding to HIF1A to target it for degradation via chaperone-mediated autophagy (CMA). C11orf54 knockdown-mediated HIF1A degradation reduces the transcription of ribonucleotide reductase regulatory subunit M2 (RRM2), which is a rate-limiting RNR enzyme for DNA synthesis and DNA repair by producing dNTPs. Supplement of dNTPs can partially rescue C11orf54 knockdown-mediated DNA damage and cell death. Furthermore, we find that Bafilomycin A1, an inhibitor of both macroautophagy and chaperone-mediated autophagy, shows similar rescue effects as dNTP treatment. In summary, we uncover a role of C11orf54 in regulating DNA damage and repair through CMA-mediated decreasing of HIF1A/RRM2 axis.
    DOI:  https://doi.org/10.1038/s42003-023-04957-1
  35. Commun Biol. 2023 06 03. 6(1): 602
    Stress-responsive Gdf15 counteracts renointestinal toxicity via autophagic and microbiota reprogramming.
    Navin Ray, Seung Jun Park, Hoyung Jung, Juil Kim, Tamas Korcsmaros, Yuseok Moon.
      The integrated stress response (ISR) plays a pivotal role in the cellular stress response, primarily through global translational arrest and the upregulation of cellular adaptation-linked molecules. Growth differentiation factor 15 (Gdf15) is a potent stress-responsive biomarker of clinical inflammatory and metabolic distress in various types of diseases. Herein, we assess whether ISR-driven cellular stress contributes to pathophysiological outcomes by modulating Gdf15. Clinical transcriptome analysis demonstrates that PKR is positively associated with Gdf15 expression in patients with renal injury. Gdf15 expression is dependent on protein kinase R (PKR)-linked ISR during acute renointestinal distress in mice and genetic ablation of Gdf15 aggravates chemical-induced lesions in renal tissues and the gut barrier. An in-depth evaluation of the gut microbiota indicates that Gdf15 is associated with the abundance of mucin metabolism-linked bacteria and their enzymes. Moreover, stress-responsive Gdf15 facilitates mucin production and cellular survival via the reorganization of the autophagy regulatory network. Collectively, ISR-activated Gdf15 counteracts pathological processes via the protective reprogramming of the autophagic network and microbial community, thereby providing robust predictive biomarkers and interventions against renointestinal distress.
    DOI:  https://doi.org/10.1038/s42003-023-04965-1
  36. bioRxiv. 2023 May 26. pii: 2023.05.26.542479. [Epub ahead of print]
    GPI-anchored Gas1 protein regulates cytosolic proteostasis in yeast.
    Yuhao Wang, Linhao Ruan, Rong Li.
      Decline in protein homeostasis (proteostasis) is a hallmark of cellular aging and aging-related diseases. Maintaining a balanced proteostasis requires a complex network of molecular machineries that govern protein synthesis, folding, localization, and degradation. Under proteotoxic stress, misfolded proteins that accumulate in cytosol can be imported into mitochondria for degradation via 'mitochondrial as guardian in cytosol' (MAGIC) pathway. Here we report an unexpected role of yeast Gas1, a cell wall-bound glycosylphosphatidylinositol (GPI)-anchored β-1,3-glucanosyltransferase, in differentially regulating MAGIC and ubiquitin-proteasome system (UPS). Deletion of Gas1 inhibits MAGIC but elevates polyubiquitination and UPS-mediated protein degradation. Interestingly, we found that Gas1 exhibits mitochondrial localization attributed to its C-terminal GPI anchor signal. But this mitochondria-associated GPI anchor signal is not required for mitochondrial import and degradation of misfolded proteins via MAGIC. By contrast, catalytic inactivation of Gas1 via the gas1 E161Q mutation inhibits MAGIC but not its mitochondrial localization. These data suggest that the glucanosyltransferase activity of Gas1 is important for regulating cytosolic proteostasis.
    DOI:  https://doi.org/10.1101/2023.05.26.542479
  37. NPJ Syst Biol Appl. 2023 06 03. 9(1): 22
    A systems biology approach to define mechanisms, phenotypes, and drivers in PanNETs with a personalized perspective.
    Silke D Werle, Nensi Ikonomi, Ludwig Lausser, Annika M T U Kestler, Felix M Weidner, Julian D Schwab, Julia Maier, Malte Buchholz, Thomas M Gress, Angelika M R Kestler, Hans A Kestler.
      Pancreatic neuroendocrine tumors (PanNETs) are a rare tumor entity with largely unpredictable progression and increasing incidence in developed countries. Molecular pathways involved in PanNETs development are still not elucidated, and specific biomarkers are missing. Moreover, the heterogeneity of PanNETs makes their treatment challenging and most approved targeted therapeutic options for PanNETs lack objective responses. Here, we applied a systems biology approach integrating dynamic modeling strategies, foreign classifier tailored approaches, and patient expression profiles to predict PanNETs progression as well as resistance mechanisms to clinically approved treatments such as the mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We set up a model able to represent frequently reported PanNETs drivers in patient cohorts, such as Menin-1 (MEN1), Death domain associated protein (DAXX), Tuberous Sclerosis (TSC), as well as wild-type tumors. Model-based simulations suggested drivers of cancer progression as both first and second hits after MEN1 loss. In addition, we could predict the benefit of mTORC1 inhibitors on differentially mutated cohorts and hypothesize resistance mechanisms. Our approach sheds light on a more personalized prediction and treatment of PanNET mutant phenotypes.
    DOI:  https://doi.org/10.1038/s41540-023-00283-8
  38. Autophagy. 2023 Jun 08.
    PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis.
    Hao Liu, Wenxia Shao, Wei Liu, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.
      Inter-organelle contacts enable crosstalk among organelles, facilitating the exchange of materials and coordination of cellular events. In this study, we demonstrated that, upon starvation, autolysosomes recruit Pi4KIIα (Phosphatidylinositol 4-kinase II α) to generate phosphatidylinositol-4-phosphate (PtdIns4P) on their surface and establish endoplasmic reticulum (ER)-autolysosome contacts through PtdIns4P binding proteins Osbp (Oxysterol binding protein) and cert (ceramide transfer protein). We found that the Sac1 (Sac1 phosphatase), Osbp, and cert proteins are required for the reduction of PtdIns4P on autolysosomes. Loss of any of these proteins leads to defective macroautophagy/autophagy and neurodegeneration. Osbp, cert, and Sac1 are required for ER-Golgi contacts in fed cells. Our data establishes a new mode of organelle contact formation-the ER-Golgi contact machinery can be reused by ER-autolysosome contacts by re-locating PtdIns4P from the Golgi apparatus to autolysosomes when faced with starvation.
    Keywords:  Drosophila; Golgi apparatus; PtdIns4P; endoplasmic reticulum-autolysosome contacts
    DOI:  https://doi.org/10.1080/15548627.2023.2222556
  39. Neural Regen Res. 2023 Nov;18(11): 2514-2519
    Rapamycin reverses ferroptosis by increasing autophagy in MPTP/MPP+-induced models of Parkinson's disease.
    Tongyu Liu, Peihan Wang, Huan Yin, Xiangfei Wang, Jing Lv, Jiang Yuan, Jing Zhu, Yunfu Wang.
      Parkinson's disease is a neurodegenerative disorder, and ferroptosis plays a significant role in the pathological mechanism underlying Parkinson's disease. Rapamycin, an autophagy inducer, has been shown to have neuroprotective effects in Parkinson's disease. However, the link between rapamycin and ferroptosis in Parkinson's disease is not entirely clear. In this study, rapamycin was administered to a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease mouse model and a 1-methyl-4-phenylpyridinium-induced Parkinson's disease PC12 cell model. The results showed that rapamycin improved the behavioral symptoms of Parkinson's disease model mice, reduced the loss of dopamine neurons in the substantia nigra pars compacta, and reduced the expression of ferroptosis-related indicators (glutathione peroxidase 4, recombinant solute carrier family 7, member 11, glutathione, malondialdehyde, and reactive oxygen species). In the Parkinson's disease cell model, rapamycin improved cell viability and reduced ferroptosis. The neuroprotective effect of rapamycin was attenuated by a ferroptosis inducer (methyl (1S,3R)-2-(2-chloroacetyl)-1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahyyridoindole-3-carboxylate) and an autophagy inhibitor (3-methyladenine). Inhibiting ferroptosis by activating autophagy may be an important mechanism by which rapamycin exerts its neuroprotective effects. Therefore, the regulation of ferroptosis and autophagy may provide a therapeutic target for drug treatments in Parkinson's disease.
    Keywords:  MPTP; PC12 cell; Parkinson’s disease; autophagy; behavior; ferroptosis; rapamycin; tyrosine hydroxylase
    DOI:  https://doi.org/10.4103/1673-5374.371381
  40. Cell Rep. 2023 Jun 07. pii: S2211-1247(23)00609-5. [Epub ahead of print]42(6): 112598
    Early pheromone perception remodels neurodevelopment and accelerates neurodegeneration in adult C. elegans.
    Jing-Yi Peng, Xuqing Liu, Xian-Ting Zeng, Yue Hao, Jia-Hui Zhang, Qian Li, Xia-Jing Tong.
      Age-associated neurodegenerative disorders such as Parkinson's and Alzheimer's diseases are mainly caused by protein aggregation. The etiologies of these neurodegenerative diseases share a chemical environment. However, how chemical cues modulate neurodegeneration remains unclear. Here, we found that in Caenorhabditis elegans, exposure to pheromones in the L1 stage accelerates neurodegeneration in adults. Perception of pheromones ascr#3 and ascr#10 is mediated by chemosensory neurons ASK and ASI. ascr#3 perceived by G protein-coupled receptor (GPCR) DAF-38 in ASK activates glutamatergic transmission into AIA interneurons. ascr#10 perceived by GPCR STR-2 in ASI activates the secretion of neuropeptide NLP-1, which binds to the NPR-11 receptor in AIA. Activation of both ASI and ASK is required and sufficient to remodel neurodevelopment via AIA, which triggers insulin-like signaling and inhibits autophagy in adult neurons non-cell-autonomously. Our work reveals how pheromone perception at the early developmental stage modulates neurodegeneration in adults and provides insights into how the external environment impacts neurodegenerative diseases.
    Keywords:  CP: Neuroscience; autophagy; early development; insulin signaling; neurodegeneration; pheromones
    DOI:  https://doi.org/10.1016/j.celrep.2023.112598
  41. Microb Cell. 2023 Jun 05. 10(6): 133-140
    Atg1, a key regulator of autophagy, functions to promote MAPK activation and cell death upon calcium overload in fission yeast.
    Teruaki Takasaki, Ryosuke Utsumi, Erika Shimada, Asuka Bamba, Kanako Hagihara, Ryosuke Satoh, Reiko Sugiura.
      Autophagy promotes or inhibits cell death depending on the environment and cell type. Our previous findings suggested that Atg1 is genetically involved in the regulation of Pmk1 MAPK in fission yeast. Here, we showed that Δatg1 displays lower levels of Pmk1 MAPK phosphorylation than did the wild-type (WT) cells upon treatment with a 1,3-β-D-glucan synthase inhibitor micafungin or CaCl2, both of which activate Pmk1. Moreover, the overproduction of Atg1, but not that of the kinase inactivating Atg1D193A activates Pmk1 without any extracellular stimuli, suggesting that Atg1 may promote Pmk1 MAPK signaling activation. Notably, the overproduction of Atg1 induces a toxic effect on the growth of WT cells and the deletion of Pmk1 failed to suppress the cell death induced by Atg1, indicating that the Atg1-mediated cell death requires additional mechanism(s) other than Pmk1 activation. Moreover, atg1 gene deletion induces tolerance to micafungin and CaCl2, whereas pmk1 deletion induces severe sensitivities to these compounds. The Δatg1Δpmk1 double mutants display intermediate sensitivities to these compounds, showing that atg1 deletion partly suppressed growth inhibition induced by Δpmk1. Thus, Atg1 may act to promote cell death upon micafungin and CaCl2 stimuli regardless of Pmk1 MAPK activity. Since micafungin and CaCl2 are intracellular calcium inducers, our data reveal a novel role of the autophagy regulator Atg1 to induce cell death upon calcium overload independent of its role in Pmk1 MAPK activation.
    Keywords:  Autophagy; Calcium tolerance; Cell death; Fission yeast; Pmk1 MAPK
    DOI:  https://doi.org/10.15698/mic2023.06.798
  42. Int Immunopharmacol. 2023 Jun 02. pii: S1567-5769(23)00733-6. [Epub ahead of print]120 110410
    Sialic acids promote macrophage M1 polarization and atherosclerosis by upregulating ROS and autophagy blockage.
    Xuemei Hu, Yueyue Li, Qingyang Chen, Tingting Wang, Limei Ma, Wanping Zhang, Ruihong Yu, Jun Zhang, Jingyuan Wan, Chao Yu, Zhiyi Yuan.
      Accumulating evidence suggests that sialic acids is closely related to atherosclerosis. However, the effects and underlying mechanisms of sialic acids in atherosclerosis have been not defined. Macrophages are one of the most important cells during plaque progression. In this study, we investigated the role of sialic acids in the M1 macrophage polarization and pathogenesis of atherosclerosis. Here we found that sialic acids can promote the polarization of RAW264.7 cells to the M1 phenotype, thereby promoting the expression of proinflammatory cytokines in vitro. The proinflammatory effect of sialic acids may result from the inhibition of LKB1-AMPK-Sirt3 signaling pathway to upregulate intracellular ROS and impairing autophagy-lysosome system to block autophagic flux. In the APOE-/- mice, sialic acids in plasma increased during the development of atherosclerosis. Moreover, exogenous supplement of sialic acids can promote plaque progression in aortic arch and aortic sinus being accompanied by the differentiation of macrophages into M1 type in peripheral tissues. These studies demonstrated that sialic acids can promote macrophage polarization toward the M1 phenotype to accentuate atherosclerosis via inducing mitochondrial ROS and blocking autophagy, thus providing clue to a novel therapeutic strategy for atherosclerosis.
    Keywords:  Atherosclerosis; Autophagy; Macrophage polarization; ROS; Sialic acids
    DOI:  https://doi.org/10.1016/j.intimp.2023.110410
  43. Cell Rep. 2023 Jun 07. pii: S2211-1247(23)00627-7. [Epub ahead of print]42(6): 112616
    Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition.
    Riccardo Cazzoli, Francesco Romeo, Isabella Pallavicini, Sebastiano Peri, Mauro Romanenghi, Juan Alberto Pérez-Valencia, Eman Hagag, Filippo Ferrucci, Mohamed Elgendy, Orazio Vittorio, Salvatore Pece, Marco Foiani, Jukka Westermarck, Saverio Minucci.
      Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.
    Keywords:  CIP2A; CP: Cancer; CP: Molecular biology; OXPHOS; PP2A; cancer; chaperone-mediated autophagy; fasting; glycolysis; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.112616
  44. Ann N Y Acad Sci. 2023 Jun 05.
    Convergent mechanisms of microglia-mediated synaptic dysfunction contribute to diverse neuropathological conditions.
    Nicole Scott-Hewitt, Youtong Huang, Beth Stevens.
      Changes in synaptic function are an early hallmark of neuropathological conditions that often precede symptom onset, with mounting genetic, transcriptional, and epidemiological evidence implicating microglia in this process. The correlation between infection and neurocognitive sequelae further suggests that environmental exposures modulate neuroimmune interactions and contribute to synaptic alterations. Recent studies investigating functional roles of microglia across broad neuropathological contexts including neurodegeneration, aging, neuropsychiatric and neurodevelopmental disorders, and neurotropic infections reveal convergent mechanisms underlying microglial-mediated synaptic dysfunction. We propose that early microglial changes, driven by genetic alterations coupled with environmental neuroimmune modulation, may be a common denominator that contributes to early synaptic pathologies. Here we review the evidence and discuss how microglia respond, and contribute, to synaptopathies across diverse neurological conditions, spotlighting their importance as broadly relevant therapeutic targets within neurological diseases.
    Keywords:  infection; microglia; neurodegeneration; neuroinflammation; neuropsychiatric disorders; neurotropic; pruning; synaptic dysfunction
    DOI:  https://doi.org/10.1111/nyas.15010
  45. Biochem Pharmacol. 2023 Jun 01. pii: S0006-2952(23)00224-1. [Epub ahead of print]213 115633
    Neratinib is a TFEB and TFE3 activator that potentiates autophagy and unbalances energy metabolism in ERBB2+ breast cancer cells.
    Grazia Bellese, Erica Tagliatti, Maria Cristina Gagliani, Sara Santamaria, Pietro Arnaldi, Paola Falletta, Paola Rusmini, Michela Matteoli, Patrizio Castagnola, Katia Cortese.
      Neratinib (NE) is an irreversible pan-ERBB tyrosine kinase inhibitor used to treat breast cancers (BCa) with amplification of the ERBB2/HER2/Neu gene or overexpression of the ERBB2 receptor. However, the mechanisms behind this process are not fully understood. Here we investigated the effects of NE on critical cell survival processes in ERBB2+ cancer cells. By kinome array analysis, we showed that NE time-dependently inhibited the phosphorylation of two distinct sets of kinases. The first set, including ERBB2 downstream signaling kinases such as ERK1/2, ATK, and AKT substrates, showed inhibition after 2 h of NE treatment. The second set, which comprised kinases involved in DNA damage response, displayed inhibition after 72 h. Flow cytometry analyses showed that NE induced G0/G1 cell cycle arrest and early apoptosis. By immunoblot, light and electron microscopy, we revealed that NE also transiently induced autophagy, mediated by increased expression levels and nuclear localization of TFEB and TFE3. Altered TFEB/TFE3 expression was accompanied by dysregulation of mitochondrial energy metabolism and dynamics, leading to a decrease in ATP production, glycolytic activity, and a transient downregulation of fission proteins. Increased TFEB and TFE3 expression was also observed in ERBB2-/ERBB1 + BCa cells, supporting that NE may act through other ERBB family members and/or other kinases. Overall, this study highlights NE as a potent activator of TFEB and TFE3, leading to the suppression of cancer cell survival through autophagy induction, cell cycle arrest, apoptosis, mitochondrial dysfunction and inhibition of DNA damage response.
    Keywords:  Autophagy; Epidermal growth factor receptor 2; Mitochondrial bioenergetics; Neratinib; TFEB; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.bcp.2023.115633
  46. J Proteome Res. 2023 Jun 07.
    Proximity Proteomics and Biochemical Analysis Reveal a Noncanonical Function for UFM1-Specific Protease 1 in the p62 Body Formation.
    Xiaohui Wang, Lindong Cao, Honglv Jiang, Liang Zhou, Zhanhong Hu, Guoqiang Xu.
      Protein aggregates play crucial roles in the development of neurodegenerative diseases and p62 is one of the key proteins regulating the formation of protein aggregates. Recently, it has been discovered that depletion of several key enzymes including UFM1-activating enzyme UBA5, UFM1-conjugating enzyme UFC1, UFM1-protein ligase UFL1, and UFM1-specific protease UfSP2 in the UFM1-conjugation system induces p62 accumulation to form p62 bodies in the cytosol. However, it is unknown whether UfSP1 participates in the formation of p62 bodies and whether its enzymatic activity is required for this process. Here, the proximity labeling technique and quantitative proteomics identify SQSTM1/p62 as a UfSP1-interacting protein. Coimmunoprecipitation reveals that p62 indeed interacts with UfSP1 and the immunofluorescence experiment discloses that UfSP1 colocalizes with p62 and promotes the formation of p62-mediated protein aggregates. Mechanistic studies unveil that UfSP1 binds to the ubiquitin-associated domain of p62 and promotes the interaction between p62 and ubiquitinated proteins, thereby increasing the formation of p62 bodies. Interestingly, we further demonstrate that both the catalytic active and inactive UfSP1 promote the formation of p62 bodies through the same mechanism. Taken together, this work discovers that UfSP1 exhibits a noncanonical function independent of its protease activity in the p62 body formation.
    Keywords:  TurboID; UFM1; UfSP1; noncanonical function; p62; p62 bodies; quantitative proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.3c00107
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