bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023‒08‒06
43 papers selected by
Viktor Korolchuk, Newcastle University
  1. O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.
  2. Characterization and chemical modulation of p62/SQSTM1/Sequestosome-1 as an autophagic N-recognin.
  3. FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.
  4. The beneficial and adverse effects of autophagic response to caloric restriction and fasting.
  5. Genome-wide screening for regulators of degradation of insulin secretory granules with a fluorescent reporter.
  6. Tuberous Sclerosis Complex.
  7. The Involvement of Progranulin for α-Synuclein Reduction through Autolysosome Formation.
  8. ecl family genes: Factors linking starvation and lifespan extension in Schizosaccharomyces pombe.
  9. TMEM175: A lysosomal ion channel associated with neurological diseases.
  10. Sustained oral spermidine supplementation rescues functional and structural defects in COL6-deficient myopathic mice.
  11. A PSD-95 peptidomimetic mitigates neurological deficits in a mouse model of Angelman Syndrome.
  12. Self-Destructive Nanoscavengers Capture and Clear Neurotoxic Soluble β-Amyloid Aggregates.
  13. Three consecutive cytosolic glycolysis enzymes modulate autophagic flux.
  14. Chaperone-mediated autophagy dysregulation during aging impairs hepatic fatty acid oxidation via accumulation of NCoR1.
  15. Hirudin inhibits glioma growth through mTOR-regulated autophagy.
  16. Mitochondrial quality control in hepatic ischemia-reperfusion injury.
  17. Monitoring the interactions between N-degrons and N-recognins of the Arg/N-degron pathway.
  18. Role of sestrins in metabolic and aging-related diseases.
  19. AI-based AlphaFold2 significantly expands the structural space of the autophagy pathway.
  20. Dendritic distribution of autophagosomes underlies pathway-selective induction of LTD.
  21. Mitochondrial quality control in lung diseases: current research and future directions.
  22. Characterization of a novel interaction of the Nup159 nucleoporin with asymmetrically localized spindle pole body proteins and its link with autophagy.
  23. Targeted Protein Degradation: Principles, Strategies, and Applications.
  24. Reactive nitrogen species as therapeutic targets for autophagy/mitophagy modulation to relieve neurodegeneration in multiple sclerosis: Potential application for drug discovery.
  25. Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy.
  26. Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches.
  27. Autophagy increase in Merosin-Deficient Congenital Muscular Dystrophy type 1A.
  28. Kinetics of autophagic activity in nanoparticle-exposed lung adenocarcinoma (A549) cells.
  29. Thrap3 promotes nonalcoholic fatty liver disease by suppressing AMPK-mediated autophagy.
  30. LIRcentral: a manually curated online database of experimentally validated functional LIR motifs.
  31. Kinase-independent role of mTOR and on-/off-target effects of an mTOR kinase inhibitor.
  32. Identification of a small chemical as a lysosomal calcium mobilizer and characterization of its ability to inhibit autophagy and viral infection.
  33. Protective Effect and Mechanism of Autophagy in Endothelial Cell Injury Induced by Hyperoxia.
  34. Intermittent cyclic mechanical compression promotes endplate chondrocytes degeneration by disturbing Nrf2/PINK1 signaling pathway-dependent mitophagy.
  35. Transcription factor EB: A potential integrated network regulator in metabolic-associated cardiac injury.
  36. The Hyperproliferation Mechanism of Cholesteatoma Based on Proteomics: SNCA Promotes Autophagy-Mediated Cell Proliferation through the PI3K/AKT/CyclinD1 Signaling Pathway.
  37. Targeting proteostasis network in osteoporosis: pathological mechanisms and therapeutic implications.
  38. VPS35 and α-Synuclein fail to interact to modulate neurodegeneration in rodent models of Parkinson's disease.
  39. The Contributions of the mTOR Complexes: How Does Regional and Temporal Heterogeneity Affect Myelination and Remyelination?
  40. RNF26 binds perinuclear vimentin filaments to integrate ER and endolysosomal responses to proteotoxic stress.
  41. Inter-tissue communication of mitochondrial stress and metabolic health.
  42. A bioinformatic investigation of proteasome and autophagy expression in the central nervous system.
  43. Autophagy controls the protein composition of hair shafts.
  1. Mol Cell. 2023 Jul 28. pii: S1097-2765(23)00526-9. [Epub ahead of print]
    O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.
    Chenchen Xu, Xiaoqing Pan, Dong Wang, Yuanyuan Guan, Wenyu Yang, Xing Chen, Ying Liu.
      The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.
    Keywords:  O-GlcNAcylation; Raptor; glucose sensing; mTOR
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.011
  2. Methods Enzymol. 2023 ;pii: S0076-6879(23)00061-7. [Epub ahead of print]686 235-265
    Characterization and chemical modulation of p62/SQSTM1/Sequestosome-1 as an autophagic N-recognin.
    Su Jin Lee, Hye Yeon Kim, Min Ju Lee, Su Bin Kim, Yong Tae Kwon, Chang Hoon Ji.
      In the Arg/N-degron pathway, single N-terminal (Nt) residues function as N-degrons recognized by UBR box-containing N-recognins that induce substrate ubiquitination and proteasomal degradation. Recent studies led to the discovery of the autophagic Arg/N-degron pathway, in which the autophagic receptor p62/SQSTM1/Sequestosome-1 acts as an N-recognin that binds the Nt-Arg and other destabilizing residues as N-degrons. Upon binding to Nt-Arg, p62 undergoes self-polymerization associated with its cargoes, accelerating the macroautophagic delivery of p62-cargo complexes to autophagosomes leading to degradation by lysosomal hydrolases. This autophagic mechanism is emerging as an important pathway that modulates the lysosomal degradation of various biomaterial ranging from protein aggregates and subcellular organelles to invading pathogens. Chemical mimics of the physiological N-degrons were developed to exert therapeutic efficacy in pathophysiological processes associated with neurodegeneration and other related diseases. Here, we describe the methods to monitor the activities of p62 in a dual role as an N-recognin and an autophagic receptor. The topic includes self-polymerization (for cargo condensation), its interaction with LC3 on autophagic membranes (for cargo targeting), and the degradation of p62-cargo complexes by lysosomal hydrolases. We also discuss the development and use of small molecule mimics of N-degrons that modulate p62-dependent macroautophagy in biological and pathophysiological processes.
    Keywords:  Autophagy flux assay; Autophagy-targeting ligand (ATL); Colocalization assay; In vitro oligomerization assay; Molecular modeling; N-degron pathway; N-terminal arginylation; Selective autophagy; Targeted protein degradation (TPD); p62/SQSTM1/Sequestosome-1
    DOI:  https://doi.org/10.1016/bs.mie.2023.02.005
  3. PLoS Biol. 2023 Aug 03. 21(8): e3002244
    FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.
    Alvaro Sanchez-Martinez, Aitor Martinez, Alexander J Whitworth.
      Functional analyses of genes linked to heritable forms of Parkinson's disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations in PARK15/FBXO7 cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and its Drosophila orthologue, ntc, share functional homology and explored its role in mitophagy in vivo. We show that ntc mutants partially phenocopy Pink1 and parkin mutants and ntc overexpression supresses parkin phenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation that triggers stress-induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditions in vivo and presents a new avenue for therapeutic approaches.
    DOI:  https://doi.org/10.1371/journal.pbio.3002244
  4. Adv Nutr. 2023 Jul 30. pii: S2161-8313(23)01344-3. [Epub ahead of print]
    The beneficial and adverse effects of autophagic response to caloric restriction and fasting.
    Roya Shabkhizan, Sanya Haiaty, Marziyeh Sadat Moslehian, Ahad Bazmani, Fatemeh Sadeghsoltani, Hesam Saghaei Bagheri, Reza Rahbarghazi, Ebrahim Sakhinia.
      Each cell is equipped with a conserved housekeeping mechanism, known as autophagy, to recycle exhausted materials and dispose of injured organelles via lysosomal degradation. Autophagy is an early-stage cellular response to stress stimuli in both physiological and pathological situations. It is thought that the promotion of autophagy flux prevents the host cells from subsequent injuries by removing damaged organelles and misfolded proteins. As a correlate, the modulation of autophagy is suggested as a therapeutic modality in diverse pathological conditions. Accumulated evidence suggests that intermittent fasting or calorie restriction can lead to the induction of adaptive autophagy and increase longevity in the eukaryotic cells. However, prolonged calorie restriction with excessive autophagy response is harmful and can stimulate a type II autophagic cell death. Despite the existence of a close relationship between calorie deprivation and autophagic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible effects of prolonged and short-term calorie restriction on autophagic response and cell homeostasis.
    Keywords:  Autophagy; Cellular Homeostasis; Short-term and Long-term Calorie Restriction; Therapeutic Effects
    DOI:  https://doi.org/10.1016/j.advnut.2023.07.006
  5. Biochem Biophys Res Commun. 2023 Jul 20. pii: S0006-291X(23)00904-X. [Epub ahead of print]676 132-140
    Genome-wide screening for regulators of degradation of insulin secretory granules with a fluorescent reporter.
    Akiko Kanai, Yuya Nishida, Tatsuya Iwamoto, Mutsumi Yokota, Shuhei Aoyama, Kyosei Ueki, Minami Ito, Hirotsugu Uzawa, Hitoshi Iida, Masato Koike, Hirotaka Watada.
      Insulin is essential in controlling blood glucose levels, and its synthesis and secretion have been well investigated. In contrast, how insulin secretory granules (ISGs) are degraded in pancreatic beta cells remains largely unknown. To clarify the mechanism, we constructed a fluorescent reporter detecting ISG degradation, where EGFP and mCherry are tandemly conjugated to a cytoplasmic region of ZnT8, an ISG membrane-localized protein. Depletion of serum and amino acid stimulated lysosomal ISG degradation detected with the reporter. Next, with MIN6 cells expressing Cas9 and the reporter, we investigated the involvement of conventional Atg5/7-dependent autophagy to show that it is dispensable for the ISG degradation process. Finally, we performed genome-wide screening by enriching the cells lacking the ISG degradation and showed that pathways regulating autophagy are not identified. These results suggest that alternative degradation in lysosomes, instead of conventional autophagy, may be involved in ISG degradation.
    Keywords:  Autophagy; Crinophagy; Genome-wide screening; Insulin; Secretory granules
    DOI:  https://doi.org/10.1016/j.bbrc.2023.07.040
  6. Keio J Med. 2023 Aug 02.
    Tuberous Sclerosis Complex.
    Mari Wataya-Kaneda.
      Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease characterized by systemic hamartomas, neuropsychiatric symptoms known as TAND (TSC-associated neuropsychiatric disorders), and vitiligo. These symptoms are attributed to the constant activation of mechanistic target of rapamycin complex 1 (mTORC1) caused by genetic mutations in the causative genes TSC1 or TSC2. The elucidation of the pathogenesis of this disease and advances in diagnostic technologies have led to dramatic changes in the diagnosis and treatment of TSC. Diagnostic criteria have been created at a global level, and mTORC1 inhibitors have emerged as therapeutic agents for this disease. Previously, the treatment strategy was limited to symptomatic treatments such as surgery. Inhibitors of mTORC1 are effective against all symptoms of TSC, but they also have systemic side effects. Therefore, the need for a cross-disciplinary, collaborative medical care system has increased, resulting in the establishment of a practice structure known as the "TSC Board." Furthermore, to reduce the side effects of systemic administration of mTORC1 inhibitors, a topical formulation of mTORC1 inhibitor was developed in Japan for the treatment of skin lesions caused by TSC. This report summarizes the pathogenesis and current status of TSC and the contribution of the Neurocutaneous Syndrome Policy Research Group to the policies of the Ministry of Health, Labor, and Welfare with respect to this rare, intractable disease.
    Keywords:  diagnostic criteria; mTORC1; ministry of health labor and welfare; topical formulation of mTORC1 inhibitor; tuberous sclerosis complex
    DOI:  https://doi.org/10.2302/kjm.2023-0011-IR
  7. Biol Pharm Bull. 2023 ;46(8): 1032-1040
    The Involvement of Progranulin for α-Synuclein Reduction through Autolysosome Formation.
    Honoka Fujimori, Takuya Ohba, Shinsuke Nakamura, Masamitsu Shimazawa, Hideaki Hara.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms and neuropathological features, such as loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of alpha-synuclein (α-Syn). Progranulin (PGRN) is a secreted growth factor that exhibits anti-inflammatory properties and regulates lysosomal function. Although autophagy-lysosome pathway is the main degradative pathway for α-Syn, the molecular mechanistic relationship between PD and PGRN remains unclear. In this study, we investigated the role of PGRN in PD pathology. PGRN protein expression in striatum was increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice. Intracerebroventricular (i.c.v.) administration of PGRN ameliorated the decrease in expression of tyrosine hydroxylase, a dopaminergic neuron marker, in MPTP-treated mice. Furthermore, i.c.v. administration of PGRN ameliorated 6-hydroxydopamine-induced motor deficits. In SH-SY5Y human neuroblastoma cells, 1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of MPTP, increased α-Syn expression. In contrast, PGRN ameliorated MPP+-induced increase in α-Syn expression. Although PGRN decreased the levels of autophagy-related proteins Sequestosome-1 (p62) and MAP1LC3 (LC3)-II, PGRN did not influence the phosphorylation of AMP-activated protein kinase and mechanistic target of rapamycin, which are also proteins that regulate autophagy. Immunostaining analysis showed that PGRN ameliorated MPP+-induced increase of LC3 puncta, indicator of autophagosome, and co-localization of LC3 and α-Syn. The DALGreen assay showed that PGRN ameliorated MPP+-induced decreasing trend of autolysosomes. These results suggest that PGRN participates in α-Syn degradation via acceleration of the autophagy-lysosome pathway and is a potential therapeutic target for PD.
    Keywords:  Parkinson’s disease; autophagy; lysosome; progranulin; α-synuclein
    DOI:  https://doi.org/10.1248/bpb.b22-00711
  8. Mol Microbiol. 2023 Jul 31.
    ecl family genes: Factors linking starvation and lifespan extension in Schizosaccharomyces pombe.
    Hokuto Ohtsuka, Yoko Otsubo, Takafumi Shimasaki, Akira Yamashita, Hirofumi Aiba.
      In the fission yeast Schizosaccharomyces pombe, the duration of survival in the stationary phase, termed the chronological lifespan (CLS), is affected by various environmental factors and the corresponding gene activities. The ecl family genes were identified in the genomic region encoding non-coding RNA as positive regulators of CLS in S. pombe, and subsequently shown to encode relatively short proteins. Several studies revealed that ecl family genes respond to various nutritional starvation conditions via different mechanisms, and they are additionally involved in stress resistance, autophagy, sexual differentiation, and cell cycle control. Recent studies reported that Ecl family proteins strongly suppress target of rapamycin complex 1, which is a conserved eukaryotic nutrient-sensing kinase complex that also regulates longevity in a variety of organisms. In this review, we introduce the regulatory mechanisms of Ecl family proteins and discuss their emerging findings.
    Keywords:   Schizosaccharomyces pombe ; TORC1; fission yeast; lifespan; starvation
    DOI:  https://doi.org/10.1111/mmi.15134
  9. Neurobiol Dis. 2023 Jul 29. pii: S0969-9961(23)00259-0. [Epub ahead of print] 106244
    TMEM175: A lysosomal ion channel associated with neurological diseases.
    Luojia Wu, Yue Lin, Jiali Song, Longshan Li, Xiuqin Rao, Wei Wan, Gen Wei, Fuzhou Hua, Jun Ying.
      Lysosomes are acidic intracellular organelles with autophagic functions that are critical for protein degradation and mitochondrial homeostasis, while abnormalities in lysosomal physiological functions are closely associated with neurological disorders. Transmembrane protein 175 (TMEM175), an ion channel in the lysosomal membrane that is essential for maintaining lysosomal acidity, has been proven to coordinate with V-ATPase to modulate the luminal pH of the lysosome to assist the digestion of abnormal proteins and organelles. However, there is considerable controversy about the characteristics of TMEM175. In this review, we introduce the research progress on the structural, modulatory, and functional properties of TMEM175, followed by evidence of its relevance for neurological disorders. Finally, we discuss the potential value of TMEM175 as a therapeutic target in the hope of providing new directions for the treatment of neurodegenerative diseases.
    Keywords:  Autophagy; Ion channel; Lysosomal membrane protein; Lysosome; Neurological disease; TMEM175
    DOI:  https://doi.org/10.1016/j.nbd.2023.106244
  10. Autophagy. 2023 Aug 01. 1-9
    Sustained oral spermidine supplementation rescues functional and structural defects in COL6-deficient myopathic mice.
    Lisa Gambarotto, Samuele Metti, Matteo Corpetti, Martina Baraldo, Patrizia Sabatelli, Silvia Castagnaro, Matilde Cescon, Bert Blaauw, Paolo Bonaldo.
      COL6 (collagen type VI)-related myopathies (COL6-RM) are a distinct group of inherited muscle disorders caused by mutations of COL6 genes and characterized by early-onset muscle weakness, for which no cure is available yet. Key pathophysiological features of COL6-deficient muscles involve impaired macroautophagy/autophagy, mitochondrial dysfunction, neuromuscular junction fragmentation and myofiber apoptosis. Targeting autophagy by dietary means elicited beneficial effects in both col6a1 null (col6a1-/-) mice and COL6-RM patients. We previously demonstrated that one-month per os administration of the nutraceutical spermidine reactivates autophagy and ameliorates myofiber defects in col6a1-/- mice but does not elicit functional improvement. Here we show that a 100-day-long spermidine regimen is able to rescue muscle strength in col6a1-/- mice, with also a beneficial impact on mitochondria and neuromuscular junction integrity, without any noticeable side effects. Altogether, these data provide a rationale for the application of spermidine in prospective clinical trials for COL6-RM.Abbreviations: AChR: acetylcholine receptor; BTX: bungarotoxin; CNF: centrally nucleated fibers; Colch: colchicine; COL6: collagen type VI; COL6-RM: COL6-related myopathies; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NMJ: neuromuscular junction; Spd: spermidine; SQSTM1/p62: sequestosome 1; TA: tibialis anterior; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling.
    Keywords:  Autophagy; collagen VI; nutraceutical; skeletal muscle; spermidine
    DOI:  https://doi.org/10.1080/15548627.2023.2241125
  11. Prog Neurobiol. 2023 Aug 01. pii: S0301-0082(23)00114-4. [Epub ahead of print] 102513
    A PSD-95 peptidomimetic mitigates neurological deficits in a mouse model of Angelman Syndrome.
    Kara A Lau, Xin Yang, Mengia S Rioult-Pedotti, Stephen Tang, Mark Appleman Jianan Zhang, Yuyang Tian, Caitlin Marino, Mudi Yao, Qin Jiang, Ayumi C Tsuda, Yu-Wen Alvin Huang, Cong Cao, John Marshall.
      Angelman Syndrome (AS) is a severe cognitive disorder caused by loss of neuronal expression of the E3 ubiquitin ligase UBE3A. In an AS mouse model, we previously reported a deficit in brain-derived neurotrophic factor (BDNF) signaling, and set out to develop a therapeutic that would restore normal signaling. We demonstrate that CN2097, a peptidomimetic compound that binds postsynaptic density protein-95 (PSD-95), a TrkB associated scaffolding protein, mitigates deficits in PLC-CaMKII and PI3K/mTOR pathways to restore synaptic plasticity and learning. Administration of CN2097 facilitated long-term potentiation (LTP) and corrected paired-pulse ratio. As the BDNF-mTORC1 pathway is critical for inhibition of autophagy, we investigated whether autophagy was disrupted in AS mice. We found aberrantly high autophagic activity attributable to a concomitant decrease in mTORC1 signaling, resulting in decreased levels of synaptic proteins, including Synapsin-1 and Shank3. CN2097 increased mTORC1 activity to normalize autophagy and restore hippocampal synaptic protein levels. Importantly, treatment mitigated cognitive and motor dysfunction. These findings support the use of neurotrophic therapeutics as a valuable approach for treating AS pathology.
    Keywords:  Angelman syndrome; Autophagy, PSD-95; BDNF; LTP
    DOI:  https://doi.org/10.1016/j.pneurobio.2023.102513
  12. Macromol Rapid Commun. 2023 Aug 03. e2300378
    Self-Destructive Nanoscavengers Capture and Clear Neurotoxic Soluble β-Amyloid Aggregates.
    Yu Zhao, Qiushi Li, Qingqing Huang, Yang Liu.
      Cerebral soluble β-amyloid aggregates (sAβs) accumulation is one of the most important causes in Alzheimer's disease (AD) progression. In order to mitigate the neurotoxicity induced by sAβs and achieve enhanced AD therapeutic outcomes, robust sAβs clearance become an emerging task. Herein, we report a self-destructive nanoscavenger (SDNS) based on multifunctional peptide-polymer complexes that can capture extracellular sAβs via hydrogen-bonding interactions and deliver them into microglial lysosomes. The internalized SDNS then occurs self-destruction within lysosomes and upregulates autophagy, thereby promoting the degradation of neurotoxic sAβs. Importantly, the enhanced autophagy also significantly suppresses the secretion of inflammatory factors by microglia, which is induced by internalized sAβs. Given that cerebral persistent inflammatory environment disturbs microglia-mediated phagocytosis and degradation, we believe that this synergistic approach has valuable potential as a therapeutic strategy for AD. This article is protected by copyright. All rights reserved.
    Keywords:  autophagy; lysosomal degradation; microglia; self-destructive nanoscavengers; soluble β-amyloid aggregates
    DOI:  https://doi.org/10.1002/marc.202300378
  13. Plant Physiol. 2023 Aug 04. pii: kiad439. [Epub ahead of print]
    Three consecutive cytosolic glycolysis enzymes modulate autophagic flux.
    Du-Hwa Lee, Ilyeong Choi, Seung Jun Park, Sumin Kim, Min-Soo Choi, Ho-Seok Lee, Hyun-Sook Pai.
      Autophagy serves as an important recycling route for the growth and survival of eukaryotic organisms in nutrient-deficient conditions. Since starvation induces massive changes in metabolic flux that are coordinated by key metabolic enzymes, specific processing steps of autophagy may be linked with metabolic flux-monitoring enzymes. We attempted to identify carbon metabolic genes that modulate autophagy using VIGS screening of 45 glycolysis- and Calvin-Benson cycle-related genes in Arabidopsis (Arabidopsis thaliana). Here, we report that three consecutive triose-phosphate-processing enzymes involved in cytosolic glycolysis, TPI (triose-phosphate-isomerase), GAPC (glyceraldehyde-3-phosphate dehydrogenase), and PGK (phosphoglycerate kinase), designated TGP, negatively regulate autophagy. Depletion of TGP enzymes causes spontaneous autophagy induction and increases AUTOPHAGY-RELATED 1 (ATG1) kinase activity. TGP enzymes interact with ATG101, a regulatory component of the ATG1 kinase complex. Spontaneous autophagy induction and abnormal growth under insufficient sugar in the TGP mutants are suppressed by crossing with the atg101 mutant. Considering that triose-phosphates are photosynthates transported to the cytosol from active chloroplasts, the TGP enzymes would be strategically positioned to monitor the flow of photosynthetic sugars and modulate autophagy accordingly. Collectively, these results suggest that TGP enzymes negatively control autophagy acting upstream of the ATG1 complex, which is critical for seedling development.
    DOI:  https://doi.org/10.1093/plphys/kiad439
  14. Mol Metab. 2023 Jul 29. pii: S2212-8778(23)00118-7. [Epub ahead of print] 101784
    Chaperone-mediated autophagy dysregulation during aging impairs hepatic fatty acid oxidation via accumulation of NCoR1.
    You-Jin Choi, Sung Ho Yun, Jihyeon Yu, Yewon Mun, Wonseok Lee, Cheon Jun Park, Byung Woo Han, Byung-Hoon Lee.
      OBJECTIVE: Alterations in lipid metabolism are associated with aging and age-related diseases. Chaperone-mediated autophagy (CMA) is a lysosome-dependent process involved in specific protein degradation. Heat shock cognate 71 kDa protein (Hsc70) recognizes cytosolic proteins with KFERQ motif and allows them to enter the lysosome via lysosome-associated membrane glycoprotein 2 isoform A (LAMP2A). CMA deficiency is associated with dysregulated lipid metabolism in the liver. In this study, we examined the effect of CMA on lipid metabolism in the aged liver.METHODS: 12-week-old and 88-week-old mice were employed to assess the effect of aging on hepatic CMA activity. We generated CMA-deficient mouse primary hepatocytes using siRNA for Lamp2a and liver-specific LAMP2A knockdown mice via adeno-associated viruses expressing short hairpin RNAs to investigate the influence of CMA on lipid metabolism.
    RESULTS: We noted aging-induced progression toward fatty liver and a decrease in LAMP2A levels in total protein and lysosomes. The expression of genes associated with fatty acid oxidation was markedly downregulated in the aged liver, as verified in CMA-deficient mouse primary hepatocytes. In addition, the aged liver accumulated nuclear receptor corepressor 1 (NCoR1), a negative regulator of peroxisome proliferator-activated receptor α (PPARα). We found that Hsc70 binds to NCoR1 via the KFERQ motif. Lamp2a siRNA treatment accumulated NCoR1 and decreased the fatty acid oxidation rate. Pharmacological activation of CMA by AR7 treatment increased LAMP2A expression, leading to NCoR1 degradation. A liver-specific LAMP2A knockdown via adeno-associated viruses expressing short hairpin RNAs caused NCoR1 accumulation, inactivated PPARα, downregulated the expression of fatty acid oxidation-related genes and significantly increased liver triglyceride levels.
    CONCLUSIONS: Our results elucidated a novel PPARα regulatory mechanism involving CMA-mediated NCoR1 degradation during aging. These findings demonstrate that CMA dysregulation is crucial for the progression of aging-related fatty liver diseases.
    Keywords:  Aging; Chaperone-mediated autophagy; Fatty acid oxidation; NCoR1; PPARα
    DOI:  https://doi.org/10.1016/j.molmet.2023.101784
  15. J Cell Mol Med. 2023 Aug 04.
    Hirudin inhibits glioma growth through mTOR-regulated autophagy.
    Ying Ma, Senbin Wu, Fanyi Zhao, Huifeng Li, Qiaohong Li, Jingzhi Zhang, Hua Li, Zhongmin Yuan.
      Glioma is the most common primary malignant brain tumour, and survival is poor. Hirudin has anticancer pharmacological effects through suppression of glioma cell progression, but the molecular target and mechanism are poorly understood. In this study, we observed that hirudin dose- and time-dependently inhibited glioma invasion, migration and proliferation. Mechanistically, hirudin activated LC3-II but not Caspase-3 to induce the autophagic death of glioma cells by decreasing the phosphorylation of mTOR and its downstream substrates ULK1, P70S6K and 4EBP1. Furthermore, hirudin inhibited glioma growth and induced changes in autophagy in cell-derived xenograft (CDX) nude mice, with a decrease in mTOR activity and activation of LC3-II. Collectively, our results highlight a new anticancer mechanism of hirudin in which hirudin-induced inhibition of glioma progression through autophagy activation is likely achieved by inhibition of the mTOR signalling pathway, thus providing a molecular basis for hirudin as a potential and effective clinical drug for glioma therapy.
    Keywords:  Hirudin; apoptosis; autophagy; glioma; mTOR
    DOI:  https://doi.org/10.1111/jcmm.17851
  16. Heliyon. 2023 Jul;9(7): e17702
    Mitochondrial quality control in hepatic ischemia-reperfusion injury.
    LiuSong Wang, Zan Jie Feng, Xuan Ma, Kai Li, Xin Yao Li, Yi Tang, Cijun Peng.
      Hepatic ischemia-reperfusion injury is a phenomenon in which exacerbating damage of liver cells due to restoration of blood flow following ischemia during liver surgery, especially those involving liver transplantation. Mitochondria, the energy-producing organelles, are crucial for cell survival and apoptosis and have evolved a range of quality control mechanisms to maintain homeostasis in the mitochondrial network in response to various stress conditions. Hepatic ischemia-reperfusion leads to disruption of mitochondrial quality control mechanisms, as evidenced by reduced mitochondrial autophagy, excessive division, reduced fusion, and inhibition of biogenesis. This leads to dysfunction of the mitochondrial network. The accumulation of damaged mitochondria ultimately results in apoptosis of hepatocytes due to the release of apoptotic proteins like cytochrome C. This worsens hepatic ischemia-reperfusion injury. Currently, hepatic ischemia-reperfusion injury protection is being studied using different approaches such as drug pretreatment, stem cells and exosomes, genetic interventions, and mechanical reperfusion, all aimed at targeting mitochondrial quality control mechanisms. This paper aims to provide direction for future research on combating HIRI by reviewing the latest studies that focus on targeting mitochondrial quality control mechanisms.
    Keywords:  Hepatic ischemia-reperfusion injury; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control mechanisms; Mitophagy
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e17702
  17. Methods Enzymol. 2023 ;pii: S0076-6879(23)00194-5. [Epub ahead of print]686 165-203
    Monitoring the interactions between N-degrons and N-recognins of the Arg/N-degron pathway.
    Soon Chul Kwon, Jihoon Lee, Yong Tae Kwon, Ah Jung Heo.
      As defined by the N-degron pathway, single N-terminal (Nt) amino acids can function as N-degrons that induce the degradation of proteins and other biological materials. Central to this pathway is the selective recognition of N-degrons by cognate N-recognins that direct the substrates to either the ubiquitin (Ub)-proteasome system (UPS) or autophagy-lysosome pathway (ALP). Eukaryotic cells have developed diverse pathways to utilize all 20 amino acids in the genetic code as pro-N-degrons or N-degrons which can be generated through endoproteolytic cleavage or post-translational modifications. Amongst these, the arginine (Arg) N-degron plays a key role in both cis- and trans-degradation of a large spectrum of cellular materials by the proteasome or lysosome. In mammals, Arg/N-degrons can be generated through endoproteolytic cleavage or post-translational conjugation of the amino acid L-Arg by ATE1-encoded R-transferases (EC 2.3.2.8), which requires Arg-tRNAArg as a cofactor. Arg/N-degrons of short-lived substrates are recognized by a family of N-recognins characterized by the UBR box for polyubiquitination and proteasomal degradation. Under stresses, however, the same degrons can be recognized for autophagic degradation by the ZZ domain of the N-recognin p62/SQSTSM-1/Sequestosome-1 or KCMF1. Biochemical tools were developed to monitor the interaction of Arg/N-degrons with its cognate N-recognins. These assays were employed to identify new N-recognins and to characterize their biochemical properties and physiological functions. The principles of these assays may be applied for other types of N-degron pathways. Below, we describe the methods that analyze the interaction of Arg/N-degrons and their chemical mimics to N-recognins.
    Keywords:  ATE1 R-transferases; Autophagy-lysosome system; N-terminal arginylation; Pulldown assay; UBR box; Ubiquitin-proteasome system; p62/SQSTSM-1/sequestosome-1
    DOI:  https://doi.org/10.1016/bs.mie.2023.05.009
  18. Biogerontology. 2023 Jul 30.
    Role of sestrins in metabolic and aging-related diseases.
    Huan Fang, Xiaomin Shi, Juyi Wan, Xiaolin Zhong.
      Sestrins are a type of highly conserved stress-inducing protein that has antioxidant and mTORC1 inhibitory functions. Metabolic dysfunction and aging are the main risk factors for development of human diseases, such as diabetes, neurodegenerative diseases, and cancer. Sestrins have important roles in regulating glucose and lipid metabolism, anti-tumor functions, and aging by inhibiting the reactive oxygen species and mechanistic target of rapamycin complex 1 pathways. In this review, the structure and biological functions of sestrins are summarized, and how sestrins are activated and contribute to regulation of the downstream signal pathways of metabolic and aging-related diseases are discussed in detail with the goal of providing new ideas and therapeutic targets for the treatment of related diseases.
    Keywords:  Aging; Metabolism; ROS; Sestrins; mTORC1
    DOI:  https://doi.org/10.1007/s10522-023-10053-y
  19. Autophagy. 2023 Jul 30. 1-20
    AI-based AlphaFold2 significantly expands the structural space of the autophagy pathway.
    Nidhi Malhotra, Shantanu Khatri, Ajit Kumar, Akanksha Arun, Purba Daripa, Saman Fatihi, Sureshkumar Venkadesan, Niyati Jain, Lipi Thukral.
      ABBREVIATIONS: AF2: AlphaFold2; AF2-Mult: AlphaFold2 multimer; ATG: autophagy-related; CTD: C-terminal domain; ECTD: extreme C-terminal domain; FR: flexible region; MD: molecular dynamics; NTD: N-terminal domain; pLDDT: predicted local distance difference test; UBL: ubiquitin-like.
    Keywords:  ATG7-ATG10 complex; AlphaFold2; autophagic interactome; autophagy; molecular dynamics simulations
    DOI:  https://doi.org/10.1080/15548627.2023.2238578
  20. Cell Rep. 2023 Jul 28. pii: S2211-1247(23)00909-9. [Epub ahead of print]42(8): 112898
    Dendritic distribution of autophagosomes underlies pathway-selective induction of LTD.
    Kevin M Keary, Qin-Hua Gu, Jiji Chen, Zheng Li.
      The mechanism of long-term depression (LTD), a cellular substrate for learning, memory, and behavioral flexibility, is extensively studied in Schaffer collateral (SC) synapses, with inhibition of autophagy identified as a key factor. SC inputs terminate at basal and proximal apical dendrites, whereas distal apical dendrites receive inputs from the temporoammonic pathway (TAP). Here, we demonstrate that TAP and SC synapses have a shared LTD mechanism reliant on NMDA receptors, caspase-3, and autophagy inhibition. Despite this shared LTD mechanism, proximal apical dendrites contain more autophagosomes than distal apical dendrites. Additionally, unlike SC LTD, which diminishes with age, TAP LTD persists into adulthood. Our previous study shows that the high autophagy in adulthood disallows SC LTD induction. The reduction of autophagosomes from proximal to distal dendrites, combined with distinct LTD inducibility at SC and TAP synapses, suggests a model where the differential distribution of autophagosomes in dendrites gates LTD inducibility at specific circuits.
    Keywords:  CA1; CP: Neuroscience; LTD; autophagy; caspase-3; dendrites; hippocampus; synaptic plasticity; temporoammonic pathway
    DOI:  https://doi.org/10.1016/j.celrep.2023.112898
  21. Front Physiol. 2023 ;14 1236651
    Mitochondrial quality control in lung diseases: current research and future directions.
    Jiliu Liu, Junyi Wang, Anying Xiong, Lei Zhang, Yi Zhang, Yao Liu, Ying Xiong, Guoping Li, Xiang He.
      Lung diseases are a major global health problem, affecting millions of people worldwide. Recent research has highlighted the critical role that mitochondrial quality control plays in respiratory-related diseases, including chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF). In this review, we summarize recent findings on the involvement of mitochondrial quality control in these diseases and discuss potential therapeutic strategies. Mitochondria are essential organelles for energy production and other cellular processes, and their dysfunction is associated with various diseases. The quality control of mitochondria involves a complex system of pathways, including mitophagy, mitochondrial biogenesis, fusion/fission dynamics, and regulation of gene expression. In COPD and lung cancer, mitochondrial quality control is often involved in disease development by influencing oxidative stress and apoptosis. In IPF, it appears to be involved in the disease process by participating in the cellular senescence process. Mitochondrial quality control is a promising target for therapeutic interventions in lung diseases. However, there are conflicting reports on different pathological processes, such as the role of mitochondrial autophagy in lung cancer, which pose difficulties in the study of targeted mitochondrial quality control drugs. Additionally, there seems to be a delicate balance between the mitochondrial quality control processes in the physiological state. Emerging evidence suggests that molecules such as PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PRKN), dynamin-related protein 1 (DRP1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), as well as the signaling pathways they affect, play an important role in respiratory-related diseases. Targeting these molecules and pathways could contribute to the development of effective treatments for lung diseases. In conclusion, the involvement of mitochondrial quality control in lung diseases presents a promising new avenue for disease treatment. Further research is needed to better understand the complex mechanisms involved in the pathogenesis of respiratory diseases and to develop targeted therapies that could improve clinical outcomes.
    Keywords:  chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; lung cancer; mitochondrial quality control; therapeutic approaches
    DOI:  https://doi.org/10.3389/fphys.2023.1236651
  22. PLoS Biol. 2023 Aug 03. 21(8): e3002224
    Characterization of a novel interaction of the Nup159 nucleoporin with asymmetrically localized spindle pole body proteins and its link with autophagy.
    Inés García de Oya, Javier Manzano-López, Alejandra Álvarez-Llamas, María de la Paz Vázquez-Aroca, Cristina Cepeda-García, Fernando Monje-Casas.
      Both the spindle microtubule-organizing centers and the nuclear pore complexes (NPCs) are convoluted structures where many signaling pathways converge to coordinate key events during cell division. Interestingly, despite their distinct molecular conformation and overall functions, these structures share common components and collaborate in the regulation of essential processes. We have established a new link between microtubule-organizing centers and nuclear pores in budding yeast by unveiling an interaction between the Bfa1/Bub2 complex, a mitotic exit inhibitor that localizes on the spindle pole bodies, and the Nup159 nucleoporin. Bfa1/Bub2 association with Nup159 is reduced in metaphase to not interfere with proper spindle positioning. However, their interaction is stimulated in anaphase and assists the Nup159-dependent autophagy pathway. The asymmetric localization of Bfa1/Bub2 during mitosis raises the possibility that its interaction with Nup159 could differentially promote Nup159-mediated autophagic processes, which might be relevant for the maintenance of the replicative lifespan.
    DOI:  https://doi.org/10.1371/journal.pbio.3002224
  23. Adv Biol (Weinh). 2023 Jul 30. e2300083
    Targeted Protein Degradation: Principles, Strategies, and Applications.
    Ting He, Chenxi Wen, Guodong Yang, Xuekang Yang.
      Protein degradation is a general process to maintain cell homeostasis. The intracellular protein quality control system mainly includes the ubiquitin-proteasome system and the lysosome pathway. Inspired by the physiological process, strategies to degrade specific proteins have developed, which emerge as potent and effective tools in biological research and drug discovery. This review focuses on recent advances in targeted protein degradation techniques, summarizing the principles, advantages, and challenges. Moreover, the potential applications and future direction in biological science and clinics are also discussed.
    Keywords:  autophagy-lysosome pathway; clinical application; endosome-lysosome system; targeted protein degradation; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1002/adbi.202300083
  24. Free Radic Biol Med. 2023 Aug 01. pii: S0891-5849(23)00568-3. [Epub ahead of print]208 37-51
    Reactive nitrogen species as therapeutic targets for autophagy/mitophagy modulation to relieve neurodegeneration in multiple sclerosis: Potential application for drug discovery.
    Wenting Li, Meiling Wu, Yuzhen Li, Jiangang Shen.
      Multiple sclerosis (MS) is a neuroinflammatory disease with limited therapeutic effects, eventually developing into handicap. Seeking novel therapeutic strategies for MS is timely important. Active autophagy/mitophagy could mediate neurodegeneration, while its roles in MS remain controversial. To elucidate the exact roles of autophagy/mitophagy and reveal its in-depth regulatory mechanisms, we conduct a systematic literature study and analyze the factors that might be responsible for divergent results obtained. The dynamic change levels of autophagy/mitophagy appear to be a determining factor for final neuron fate during MS pathology. Excessive neuronal autophagy/mitophagy contributes to neurodegeneration after disease onset at the active MS phase. Reactive nitrogen species (RNS) serve as key regulators for redox-related modifications and participate in autophagy/mitophagy modulation in MS. Nitric oxide (•NO) and peroxynitrite (ONOO-), two representative RNS, could nitrate or nitrosate Drp1/parkin/PINK1 pathway, activating excessive mitophagy and aggravating neuronal injury. Targeting RNS-mediated excessive autophagy/mitophagy could be a promising strategy for developing novel anti-MS drugs. In this review, we highlight the important roles of RNS-mediated autophagy/mitophagy in neuronal injury and review the potential therapeutic compounds with the bioactivities of inhibiting RNS-mediated autophagy/mitophagy activation and attenuating MS progression. Overall, we conclude that reactive nitrogen species could be promising therapeutic targets to regulate autophagy/mitophagy for multiple sclerosis treatment.
    Keywords:  Autophagy; Mitophagy; Multiple sclerosis; Reactive nitrogen species; Therapeutic compounds
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.07.032
  25. Nat Commun. 2023 08 01. 14(1): 4622
    Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy.
    Yujiao Zhang, Marie Vandestienne, Jean-Rémi Lavillegrand, Jeremie Joffre, Icia Santos-Zas, Aonghus Lavelle, Xiaodan Zhong, Wilfried Le Goff, Maryse Guérin, Rida Al-Rifai, Ludivine Laurans, Patrick Bruneval, Coralie Guérin, Marc Diedisheim, Melanie Migaud, Anne Puel, Fanny Lanternier, Jean-Laurent Casanova, Clément Cochain, Alma Zernecke, Antoine-Emmanuel Saliba, Michal Mokry, Jean-Sebastien Silvestre, Alain Tedgui, Ziad Mallat, Soraya Taleb, Olivia Lenoir, Cécile Vindis, Stéphane M Camus, Harry Sokol, Hafid Ait-Oufella.
      Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe-/- mice as well as hematopoietic deletion in Ldlr-/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe-/-Rag2-/-Card9-/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1β production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.
    DOI:  https://doi.org/10.1038/s41467-023-40216-x
  26. Naunyn Schmiedebergs Arch Pharmacol. 2023 Aug 03.
    Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches.
    Xiong Yang, Yu Zhang, Jia-Xin Luo, Tao Zhu, Zhao Ran, Ben-Rong Mu, Mei-Hong Lu.
      Mitochondria serve as a vital energy source for nerve cells. The mitochondrial network also acts as a defense mechanism against external stressors that can threaten the stability of the nervous system. However, excessive accumulation of damaged mitochondria can lead to neuronal death. Mitophagy is an essential pathway in the mitochondrial quality control system and can protect neurons by selectively removing damaged mitochondria. In most neurological disorders, dysfunctional mitochondria are a common feature, and drugs that target mitophagy can improve symptoms. Here, we reviewed the role of mitophagy in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, stroke, and traumatic brain injuries. We also summarized drug and non-drug approaches to promote mitophagy and described their therapeutic role in neurological disorders in order to provide valuable insight into the potential therapeutic agents available for neurological disease treatment. However, most studies on mitophagy regulation are based on preclinical research using cell and animal models, which may not accurately reflect the effects in humans. This poses a challenge to the clinical application of drugs targeting mitophagy. Additionally, these drugs may carry the risk of intolerable side effects and toxicity. Future research should focus on the development of safer and more targeted drugs for mitophagy.
    Keywords:  Mitochondrial dysfunction; Mitophagy; Mitophagy pathways; Mitophagy target drug; Neurological diseases
    DOI:  https://doi.org/10.1007/s00210-023-02636-w
  27. Eur J Transl Myol. 2023 Jul 28.
    Autophagy increase in Merosin-Deficient Congenital Muscular Dystrophy type 1A.
    Mariangela Mastrapasqua, Roberta Rossi, Lucrezia De Cosmo, Annalisa Resta, Mariella Errede, Antonella Bizzoca, Stefania Zampatti, Nicoletta Resta, Emiliano Giardina, Maddalena Ruggieri, Daniela Virgintino, Tiziana Annese, Nicola Laforgia, Francesco Girolamo.
      The autophagy process recycles dysfunctional cellular components and protein aggregates by sequestering them in autophagosomes directed to lysosomes for enzymatic degradation. A basal level of autophagy is essential for skeletal muscle maintenance. Increased autophagy occurs in several forms of muscular dystrophy and in the merosin-deficient congenital muscular dystrophy 1A mouse model (dy3k/dy3k) lacking the laminin-α2 chain. This pilot study aimed to compare autophagy marker expression and autophagosomes presence using light and electron microscopes and western blotting in diagnostic muscle biopsies from newborns affected by different congenital muscular myopathies and dystrophies. Morphological examination showed dystrophic muscle features, predominance of type 2A myofibers, accumulation of autophagosomes in the subsarcolemmal areas, increased number of autophagosomes overexpressing LC3b, Beclin-1 and ATG5, in the merosin-deficient newborn suggesting an increased autophagy. In Duchenne muscular dystrophy, nemaline myopathy, and spinal muscular atrophy the predominant accumulation of p62+ puncta rather suggests an autophagy impairment.
    DOI:  https://doi.org/10.4081/ejtm.2023.11501
  28. Autophagy Rep. 2023 ;pii: 2186568. [Epub ahead of print]2(1):
    Kinetics of autophagic activity in nanoparticle-exposed lung adenocarcinoma (A549) cells.
    Arnold Sipos, Kwang-Jin Kim, Constantinos Sioutas, Edward D Crandall.
      Autophagy, a homeostatic mechanism, is crucial in maintaining normal cellular function. Although dysregulation of autophagic processes is recognized in certain diseases, it is unknown how maintenance of cellular homeostasis might be affected by the kinetics of autophagic activity in response to various stimuli. In this study, we assessed those kinetics in lung adenocarcinoma (A549) cells in response to exposure to nanoparticles (NP) and/or Rapamycin. Since NP are known to induce autophagy, we wished to determine if this phenomenon could be a driver of the harmful effects seen in lung tissues exposed to air pollution. A549 cells were loaded with a fluorescent marker (DAPRed) that labels autophagosomes and autolysosomes. Autophagic activity was assessed based on the fluorescence intensity of DAPRed measured over the entire cell volume of live single cells using confocal laser scanning microscopy (CLSM). Autophagic activity over time was determined during exposure of A549 cells to single agents (50 nM Rapamycin; 80 μg/mL, 20 nm carboxylated polystyrene NP (PNP); or, 1 μg/mL ambient ultrafine particles (UFP) (<180 nm)), or double agents (Rapamycin + PNP or Rapamycin + UFP; concomitant and sequential), known to stimulate autophagy. Autophagic activity increased in all experimental modalities, including both single agent and double agent exposures, and reached a steady state in all cases ~2 times control from ~8 to 24 hrs, suggesting the presence of an upper limit to autophagic capacity. These results are consistent with the hypothesis that environmental stressors might exert their harmful effects, at least in part, by limiting available autophagic response to additional stimulation, thereby making nanoparticle-exposed cells more susceptible to secondary injury due to autophagic overload.
    Keywords:  Rapamycin; ambient ultrafine particles; autophagic capacity; autophagy; polystyrene nanoparticles
    DOI:  https://doi.org/10.1080/27694127.2023.2186568
  29. Exp Mol Med. 2023 Aug 01.
    Thrap3 promotes nonalcoholic fatty liver disease by suppressing AMPK-mediated autophagy.
    Hyun-Jun Jang, Yo Han Lee, Tam Dao, Yunju Jo, Keon Woo Khim, Hye-Jin Eom, Ju Eun Lee, Yi Jin Song, Sun Sil Choi, Kieun Park, Haneul Ji, Young Chan Chae, Kyungjae Myung, Hongtae Kim, Dongryeol Ryu, Neung Hwa Park, Sung Ho Park, Jang Hyun Choi.
      Autophagy functions in cellular quality control and metabolic regulation. Dysregulation of autophagy is one of the major pathogenic factors contributing to the progression of nonalcoholic fatty liver disease (NAFLD). Autophagy is involved in the breakdown of intracellular lipids and the maintenance of healthy mitochondria in NAFLD. However, the mechanisms underlying autophagy dysregulation in NAFLD remain unclear. Here, we demonstrate that the hepatic expression level of Thrap3 was significantly increased in NAFLD conditions. Liver-specific Thrap3 knockout improved lipid accumulation and metabolic properties in a high-fat diet (HFD)-induced NAFLD model. Furthermore, Thrap3 deficiency enhanced autophagy and mitochondrial function. Interestingly, Thrap3 knockout increased the cytosolic translocation of AMPK from the nucleus and enhanced its activation through physical interaction. The translocation of AMPK was regulated by direct binding with AMPK and the C-terminal domain of Thrap3. Our results indicate a role for Thrap3 in NAFLD progression and suggest that Thrap3 is a potential target for NAFLD treatment.
    DOI:  https://doi.org/10.1038/s12276-023-01047-4
  30. Autophagy. 2023 Aug 02. 1-12
    LIRcentral: a manually curated online database of experimentally validated functional LIR motifs.
    Agathangelos Chatzichristofi, Vasileios Sagris, Aristos Pallaris, Marios Eftychiou, Ioanna Kalvari, Nicholas Price, Theodosios Theodosiou, Ioannis Iliopoulos, Ioannis P Nezis, Vasilis J Promponas.
      Several selective macroautophagy receptor and adaptor proteins bind members of the Atg8 (autophagy related 8) family using short linear motifs (SLiMs), most often referred to as Atg8-family interacting motifs (AIMs) or LC3-interacting regions (LIRs). AIM/LIR motifs have been extensively studied during the last fifteen years, since they can uncover the underlying biological mechanisms and possible substrates for this key catabolic process of eukaryotic cells. Prompted by the fact that experimental information regarding LIR motifs can be found scattered across heterogeneous literature resources, we have developed LIRcentral (https://lircentral.eu), a freely available online repository for user-friendly access to comprehensive, high-quality information regarding LIR motifs from manually curated publications. Herein, we describe the development of LIRcentral and showcase currently available data and features, along with our plans for the expansion of this resource. Information incorporated in LIRcentral is useful for accomplishing a variety of research tasks, including: (i) guiding wet biology researchers for the characterization of novel instances of LIR motifs, (ii) giving bioinformaticians/computational biologists access to high-quality LIR motifs for building novel prediction methods for LIR motifs and LIR containing proteins (LIRCPs) and (iii) performing analyses to better understand the biological importance/features of functional LIR motifs. We welcome feedback on the LIRcentral content and functionality by all interested researchers and anticipate this work to spearhead a community effort for sustaining this resource which will further promote progress in studying LIR motifs/LIRCPs.Abbreviations: AIM, Atg8-family interacting motif; Atg8, autophagy related 8; GABARAP, GABA type A receptor-associated protein; LIR, LC3-interacting region; LIRCP, LIR-containing protein; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; PMID, PubMed identifier; PPI, protein-protein interaction; SLiM, short linear motif.
    Keywords:  Atg8 family; database; manual literature curation/annotation; online resource; peptide-protein interaction; selective macroautophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2235851
  31. Leukemia. 2023 Aug 02.
    Kinase-independent role of mTOR and on-/off-target effects of an mTOR kinase inhibitor.
    Cuiqing Fan, Mark Wunderlich, Xiongwei Cai, Zijun Yan, Feng Zhang, Ashley Kuenzi Davis, Lingli Xu, Fukun Guo, Q Richard Lu, Mohammad Azam, Weidong Tian, Yi Zheng.
      mTOR, as a serine/threonine kinase, is a widely pursued anticancer target. Multiple clinical trials of mTOR kinase inhibitors are ongoing, but their specificity and safety features remain lacking. Here, we have employed an inducible kinase-inactive D2338A mTOR knock-in mouse model (mTOR-/KI) together with a mTOR conditional knockout model (mTOR-/-) to assess the kinase-dependent/-independent function of mTOR in hematopoiesis and the on-/off-target effects of mTOR kinase inhibitor AZD2014. Despite exhibiting many similar phenotypes to mTOR-/- mice in hematopoiesis, the mTOR-/KI mice survived longer and showed differences in hematopoietic progenitor cells compared to mTOR-/- mice, suggesting a kinase-independent function of mTOR in hematopoiesis. Gene expression signatures in hematopoietic stem cells (HSCs) further revealed both kinase-dependent and independent effects of mTOR. AZD2014, a lead mTOR kinase inhibitor, appeared to work mostly on-target in suppressing mTOR kinase activity, mimicking that of mTOR-/KI HSCs in transcriptome analysis, but it also induced a small set of off-target responses in mTOR-/KI HSCs. In murine and human myeloid leukemia, besides kinase-inhibitory on-target effects, AZD2014 displayed similar off-target and growth-inhibitory cytostatic effects. These studies provide new insights into kinase-dependent/-independent effects of mTOR in hematopoiesis and present a genetic means for precisely assessing the specificity of mTOR kinase inhibitors.
    DOI:  https://doi.org/10.1038/s41375-023-01987-w
  32. FEBS J. 2023 Aug 01.
    Identification of a small chemical as a lysosomal calcium mobilizer and characterization of its ability to inhibit autophagy and viral infection.
    Kehui Zhang, Lihong Huang, Yang Cai, Yi Zhong, Nanjun Chen, Fei Gao, Liang Zhang, Qi Li, Zhenming Liu, Rongxin Zhang, Liangren Zhang, Jianbo Yue.
      We previously identified GAPDH as one of the cyclic adenosine diphosphoribose (cADPR)'s binding proteins and found that GAPDH participates in cADPR-mediated Ca2+ release from ER via ryanodine receptors (RyRs). Here we aimed to chemically synthesize and pharmacologically characterize novel cADPR analogues. Based on the simulated cADPR-GAPDH complex structure, we performed the structure-based drug screening, identified several small chemicals with high docking scores to cADPR's binding pocket in GAPDH, and showed that two of these compounds, C244 and C346, are potential cADPR antagonists. We further synthesized several analogs of C346, and found that its analog, G42, also mobilized Ca2+ release from lysosomes. G42 alkalized lysosomal pH, and inhibited autophagosome-lysosome fusion. Moreover, G42 markedly inhibited Zika virus (ZIKV, a flavivirus) or murine hepatitis virus (MHV, a β-coronavirus) infections of host cells. These results suggest that G42 inhibits virus infection, likely by triggering lysosomal Ca2+ mobilization and inhibiting autophagy.
    Keywords:  Antiviral infection; Autophagy; Ca2+; lysosome
    DOI:  https://doi.org/10.1111/febs.16920
  33. Am J Perinatol. 2023 Jul 29.
    Protective Effect and Mechanism of Autophagy in Endothelial Cell Injury Induced by Hyperoxia.
    Xiaodan Zhu, Shasha He, Rong Zhang, Lan Kang, Xiaoping Lei, Wenbin Dong.
      OBJECTIVE:  Bronchopulmonary dysplasia is a chronic lung disease in premature infants with alveolar simplification and pulmonary vascular development disorder as the main pathological feature and hyperoxia as the main etiology. Autophagy is a highly conserved cytological behavior of self-degrading cellular components and is accompanied by oxidative stress. Studies have reported that autophagy is regulated by FOXO1 posttranslational modification. However, whether autophagy can be involved in the regulation of endothelial cell injury induced by hyperoxia and its mechanism are still unclear.STUDY DESIGN:  We have activated and inhibited autophagy in human umbilical vein endothelial cells under hyperoxia and verified the role of autophagy in endothelial cell-related functions from both positive and negative aspects.
    RESULTS:  Our research showed that the expression level of autophagy-related proteins decreased, accompanied by decreased cell migration ability and tube formation ability and increased cell reactive oxygen species level and cell permeability under hyperoxia conditions. Using an autophagy agonist alleviated hyperoxia-induced changes and played a protective role. However, inhibition of autophagy aggravated the cell damage induced by hyperoxia. Moreover, the decrease in autophagy proteins was accompanied by the upregulation of FOXO1 phosphorylation and acetylation.
    CONCLUSION:  We concluded that autophagy was a protective mechanism against endothelial cell injury caused by hyperoxia. Autophagy might participate in this process by coregulating posttranslational modifications of FOXO1.
    KEY POINTS: · Hyperoxia induces vascular endothelial cell injury.. · Autophagy may has a protective role under hyperoxia conditions.. · FOXO1 posttranslational modification may be involved in the regulation of autophagy..
    DOI:  https://doi.org/10.1055/s-0043-1771258
  34. Hum Cell. 2023 Aug 03.
    Intermittent cyclic mechanical compression promotes endplate chondrocytes degeneration by disturbing Nrf2/PINK1 signaling pathway-dependent mitophagy.
    Quan Zheng, Chuan-Dong Wang, Song Shao, Ming-Fan Wu, Qiang-Bing Dou, Qi-Wei Wang, Liang-Ye Sun.
      An abnormal mechanical load is a pivotal inducer of endplate cartilage degeneration, which subsequently promotes intervertebral disc degeneration. Our previous study indicated that intermittent cyclic mechanical compression (ICMC) promotes endplate chondrocyte degeneration, but the mechanism underlying this effect is unclear. In this study, we investigated PTEN-induced kinase 1(PINK1) dependent mitophagy during ICMC-induced endplate chondrocyte degeneration. Furthermore, we determined whether NF-E2-related factor 2 (Nrf2) activation correlated with PINK1-dependent mitophagy regulation and increased oxidation resistance of endplate chondrocytes under ICMC application. First, we generated a mechanical compression-induced endplate chondrocyte degeneration model in vitro and in vivo. ICMC was found to promote endplate chondrocyte extracellular matrix degradation. PINK1-mediated mitophagy was suppressed in the ICMC-stimulated endplate chondrocytes, while increased mitochondrial reactive oxygen species generation suggested that mitophagy is involved in the protective effect of mechanical strain on endplate chondrocytes. Moreover, Nrf2 expression, interaction with Kelch-like ECH-associated protein (Keap1), and nuclear translocation were inhibited by ICMC. Nrf2 overexpression inhibited reactive oxygen species production and reversed ICMC-induced endplate chondrocyte degeneration. Transfection with PINK1 shRNA abolished this effect and partially blocked Nrf2-induced mitophagy. Our findings suggested that ICMC could inhibit the Nrf2/PINK1 signaling pathway to reduce the mitophagy levels which significantly promote oxidative stress and thereby endplate chondrocyte degeneration. Therapeutic regulation of the Nrf2/PINK1 signaling pathway may be an efficient anabolic strategy for inhibiting this process.
    Keywords:  Endplate chondrocyte; Mechanical compression; Mitophagy; Nrf2/PINK1 signaling; Oxidative stress
    DOI:  https://doi.org/10.1007/s13577-023-00959-7
  35. Metabolism. 2023 Jul 28. pii: S0026-0495(23)00266-4. [Epub ahead of print] 155662
    Transcription factor EB: A potential integrated network regulator in metabolic-associated cardiac injury.
    Weixing Wen, Haoxiao Zheng, Weiwen Li, Guolin Huang, Peng Chen, Xiaolin Zhu, Yue Cao, Jiahuan Li, Xiaohui Huang, Yuli Huang.
      With the worldwide pandemic of metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD), cardiometabolic disease (CMD) has become a significant cause of death in humans. However, the pathophysiology of metabolic-associated cardiac injury is complex and not completely clear, and it is important to explore new strategies and targets for the treatment of CMD. A series of pathophysiological disturbances caused by metabolic disorders, such as insulin resistance (IR), hyperglycemia, hyperlipidemia, mitochondrial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress (ERS), autophagy dysfunction, calcium homeostasis imbalance, and endothelial dysfunction, may be related to the incidence and development of CMD. Transcription Factor EB (TFEB), as a transcription factor, has been extensively studied for its role in regulating lysosomal biogenesis and autophagy. Recently, the regulatory role of TFEB in other biological processes, including the regulation of glucose homeostasis, lipid metabolism, etc. has been gradually revealed. In this review, we will focus on the relationship between TFEB and IR, lipid metabolism, endothelial dysfunction, oxidative stress, inflammation, ERS, calcium homeostasis, autophagy, and mitochondrial quality control (MQC) and the potential regulatory mechanisms among them, to provide a comprehensive summary for TFEB as a potential new therapeutic target for CMD. The integrated regulatory role of TFEB in metabolic-associated cardiac injury. When the body encounters metabolic disorders, it causes a series of pathophysiological reactions including insulin resistance, hyperglycemia, hyperlipidemia, endothelial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress, impaired calcium handling, autophagy dysregulation, mitochondrial dysfunction, ultimately leading to metabolic-associated cardiac injury. TFEB not only plays an important regulatory role in autophagy but also shows great potential in regulating insulin resistance, oxidative stress, inflammation, endoplasmic reticulum stress, calcium homeostasis, lipid metabolism, endothelial function, and mitochondrial quality control.
    Keywords:  Autophagy; Calcium homeostasis; Cardiometabolic disease; Endoplasmic reticulum stress; Endothelial dysfunction; Inflammation; Insulin resistance; Lipid metabolism; Metabolic-associated cardiac injury; Mitochondrial quality control; Oxidative stress; Transcription factor EB
    DOI:  https://doi.org/10.1016/j.metabol.2023.155662
  36. Mol Cell Proteomics. 2023 Jul 31. pii: S1535-9476(23)00139-1. [Epub ahead of print] 100628
    The Hyperproliferation Mechanism of Cholesteatoma Based on Proteomics: SNCA Promotes Autophagy-Mediated Cell Proliferation through the PI3K/AKT/CyclinD1 Signaling Pathway.
    Miao Gao, Heng Xiao, Yonglan Liang, Huimin Cai, Xiaojing Guo, Jianwei Lin, Suling Zhuang, Jianhua Xu, Shengnan Ye.
      Cholesteatoma is a chronic inflammatory ear disease with abnormal keratinized epithelium proliferation and tissue damage. However, the mechanism of keratinized epithelium hyperproliferation in cholesteatoma remains unknown. Hence, our study sought to shed light on mechanisms affecting the pathology and development of cholesteatoma, which could help develop adjunctive treatments. To investigate molecular changes in cholesteatoma pathogenesis, we analyzed clinical cholesteatoma specimens and paired ear canal skin with MS-based proteomics and bioinformatics. From our screen, alpha-synuclein (SNCA) was overexpressed in middle ear cholesteatoma (MEC) and might be a key hub protein associated with inflammation, proliferation, and autophagy in cholesteatoma. SNCA was more sensitive to lipopolysaccharide (LPS)-induced inflammation, and autophagy marker increase was accompanied by autophagy activation in middle ear cholesteatoma tissues. Overexpression of SNCA activated autophagy and promoted cell proliferation and migration, especially under LPS inflammatory stimulation. Moreover, inhibiting autophagy impaired SNCA-mediated keratinocyte proliferation and corresponded with inhibition of the PI3K/AKT/CyclinD1 pathways. Also, 740Y-P, a PI3K activator reversed the suppression of autophagy and PI3K signaling by siATG5 in SNCA overexpressing cells, which restored proliferative activity. Besides, knockdown of SNCA in RHEK-1 and HaCaT cells or knockdown of PI3K in RHEK-1 and HaCaT cells overexpressing SNCA both resulted in attenuated cell proliferation. Our studies indicated that SNCA overexpression in cholesteatoma might maintain the proliferative ability of cholesteatoma keratinocytes by promoting autophagy under inflammatory conditions. This suggests that dual inhibition of SNCA and autophagy may be a promising new target for treating cholesteatoma.
    DOI:  https://doi.org/10.1016/j.mcpro.2023.100628
  37. Ageing Res Rev. 2023 Jul 31. pii: S1568-1637(23)00183-6. [Epub ahead of print] 102024
    Targeting proteostasis network in osteoporosis: pathological mechanisms and therapeutic implications.
    Cong Ma, Ronghui Yu, Junhong Li, Jiashuo Chao, Ping Liu.
      As the most common bone disease, osteoporosis (OP) increases bone fragility and makes patients more vulnerable to the threat of osteoporotic fractures. With the ageing population in today's society, OP has become a huge and growing public health problem. Unfortunately, the clear pathogenesis of OP is still under exploration, and effective interventions are still scarce. Therefore, exploring new targets for pharmacological interventions to develop promising therapeutic drugs for OP is of great clinical value. Previous studies have shown that normal bone remodeling depends on proteostasis, whereas loss of proteostasis during ageing leads to the dysfunctional proteostasis network (PN) that fails to maintain bone homeostasis. Nevertheless, only a few studies have revealed the pathophysiological relationship between bone metabolism and a single component of PN, yet the role of PN as a whole in the pathogenesis of OP is still under investigation. This review comprehensively summarized the role of PN in the pathogenesis of OP and further discussed the potential of PN as innovative drug targets for the therapy of OP.
    Keywords:  Autophagy; Molecular chaperones; Osteoporosis; Proteostasis network; Ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.arr.2023.102024
  38. Mol Neurodegener. 2023 Aug 04. 18(1): 51
    VPS35 and α-Synuclein fail to interact to modulate neurodegeneration in rodent models of Parkinson's disease.
    Xi Chen, Elpida Tsika, Nathan Levine, Darren J Moore.
      BACKGROUND: Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene cause late-onset, autosomal dominant Parkinson's disease (PD), with a single missense mutation (Asp620Asn, D620N) known to segregate with disease in families with PD. The VPS35 gene encodes a core component of the retromer complex, involved in the endosomal sorting and recycling of transmembrane cargo proteins. VPS35-linked PD is clinically indistinguishable from sporadic PD, although it is not yet known whether VPS35-PD brains exhibit α-synuclein-positive brainstem Lewy pathology that is characteristic of sporadic cases. Prior studies have suggested a functional interaction between VPS35 and the PD-linked gene product α-synuclein in lower organisms, where VPS35 deletion enhances α-synuclein-induced toxicity. In mice, VPS35 overexpression is reported to rescue hippocampal neuronal loss in human α-synuclein transgenic mice, potentially suggesting a retromer deficiency in these mice.METHODS: Here, we employ multiple well-established genetic rodent models to explore a functional or pathological interaction between VPS35 and α-synuclein in vivo.
    RESULTS: We find that endogenous α-synuclein is dispensable for nigrostriatal pathway dopaminergic neurodegeneration induced by the viral-mediated delivery of human D620N VPS35 in mice, suggesting that α-synuclein does not operate downstream of VPS35. We next evaluated retromer levels in affected brain regions from human A53T-α-synuclein transgenic mice, but find normal levels of the core subunits VPS35, VPS26 or VPS29. We further find that heterozygous VPS35 deletion fails to alter the lethal neurodegenerative phenotype of these A53T-α-synuclein transgenic mice, suggesting the absence of retromer deficiency in this PD model. Finally, we explored the neuroprotective capacity of increasing VPS35 expression in a viral-based human wild-type α-synuclein rat model of PD. However, we find that the overexpression of wild-type VPS35 is not sufficient for protection against α-synuclein-induced nigral dopaminergic neurodegeneration, α-synuclein pathology and reactive gliosis.
    CONCLUSION: Collectively, our data suggest a limited interaction of VPS35 and α-synuclein in neurodegenerative models of PD, and do not provide support for their interaction within a common pathophysiological pathway.
    Keywords:  Alpha-synuclein; Dopaminergic; Lewy pathology; Parkinson’s disease; Retromer; VPS35
    DOI:  https://doi.org/10.1186/s13024-023-00641-4
  39. J Neurosci. 2023 Aug 02. 43(31): 5590-5592
    The Contributions of the mTOR Complexes: How Does Regional and Temporal Heterogeneity Affect Myelination and Remyelination?
    Saina Nemati, Bethany R Kondiles, Sarah Wheeler.
      
    DOI:  https://doi.org/10.1523/JNEUROSCI.0545-23.2023
  40. EMBO J. 2023 Jul 31. e111252
    RNF26 binds perinuclear vimentin filaments to integrate ER and endolysosomal responses to proteotoxic stress.
    Tom Cremer, Lenard M Voortman, Erik Bos, Marlieke Lm Jongsma, Laurens R Ter Haar, Jimmy Jll Akkermans, Cami Mp Talavera Ormeño, Ruud Hm Wijdeven, Jelle de Vries, Robbert Q Kim, George Mc Janssen, Peter A van Veelen, Roman I Koning, Jacques Neefjes, Ilana Berlin.
      Proteotoxic stress causes profound endoplasmic reticulum (ER) membrane remodeling into a perinuclear quality control compartment (ERQC) for the degradation of misfolded proteins. Subsequent return to homeostasis involves clearance of the ERQC by endolysosomes. However, the factors that control perinuclear ER integrity and dynamics remain unclear. Here, we identify vimentin intermediate filaments as perinuclear anchors for the ER and endolysosomes. We show that perinuclear vimentin filaments engage the ER-embedded RING finger protein 26 (RNF26) at the C-terminus of its RING domain. This restricts RNF26 to perinuclear ER subdomains and enables the corresponding spatial retention of endolysosomes through RNF26-mediated membrane contact sites (MCS). We find that both RNF26 and vimentin are required for the perinuclear coalescence of the ERQC and its juxtaposition with proteolytic compartments, which facilitates efficient recovery from ER stress via the Sec62-mediated ER-phagy pathway. Collectively, our findings reveal a scaffolding mechanism that underpins the spatiotemporal integration of organelles during cellular proteostasis.
    Keywords:  ER stress; ERphagy; RNF26; endolysosomes; intermediate filaments
    DOI:  https://doi.org/10.15252/embj.2022111252
  41. Life Metab. 2023 Feb;pii: load001. [Epub ahead of print]2(1):
    Inter-tissue communication of mitochondrial stress and metabolic health.
    Hanlin Zhang, Xinyu Li, Wudi Fan, Sentibel Pandovski, Ye Tian, Andrew Dillin.
      Mitochondria function as a hub of the cellular metabolic network. Mitochondrial stress is closely associated with aging and a variety of diseases, including neurodegeneration and cancer. Cells autonomously elicit specific stress responses to cope with mitochondrial stress to maintain mitochondrial homeostasis. Interestingly, mitochondrial stress responses may also be induced in a non-autonomous manner in cells or tissues that are not directly experiencing such stress. Such non-autonomous mitochondrial stress responses are mediated by secreted molecules called mitokines. Due to their significant translational potential in improving human metabolic health, there has been a surge in mitokine-focused research. In this review, we summarize the findings regarding inter-tissue communication of mitochondrial stress in animal models. In addition, we discuss the possibility of mitokine-mediated intercellular mitochondrial communication originating from bacterial quorum sensing.
    Keywords:  inter-tissue communication; metabolic health; mitochondria; mitokine; quorum sensing
    DOI:  https://doi.org/10.1093/lifemeta/load001
  42. Heliyon. 2023 Jul;9(7): e18188
    A bioinformatic investigation of proteasome and autophagy expression in the central nervous system.
    Yasuhiro Watanabe, Haruka Takeda, Naoto Honda, Ritsuko Hanajima.
      The ubiquitin proteasome system (UPS) and autophagy lysosome pathway (ALP) are crucial in the control of protein quality. However, data regarding the relative significance of UPS and ALP in the central nervous system (CNS) are limited. In the present study, using publicly available data, we computed the quantitative expression status of UPS- and ALP-related genes and their products in the CNS as compared with that in other tissues and cells. We obtained human and mouse gene expression datasets from the reference expression dataset (RefEx) and Genevestigator (a tool for handling curated transcriptomic data from public repositories) as well as human proteomics data from the proteomics database (ProteomicsDB). The expression levels of genes and proteins in four categories-ubiquitin, proteasome, autophagy, and lysosome--in the cells and tissues were assessed. Perturbation of the gene expression by drugs was also analyzed for the four categories. Compared with that for ubiquitin, autophagy, and lysosome, gene expression for proteasome was consistently lower in the CNS of mice but was more pronounced in humans. Neural stem cells and neurons showed low proteasome gene expression as compared with embryonic stem cells. Proteomic analyses, however, did not show trends similar to those observed in the gene expression analyses. Perturbation analyses revealed that azithromycin and vitamin D3 upregulated the expression of both UPS and ALP. Gene and proteomic expression data could offer a fresh perspective on CNS pathophysiology. Our results indicate that disproportional expression of UPS and ALP might affect CNS disorders and that this imbalance might be redressed by several therapeutic candidates.
    Keywords:  Microarray; Neurodegeneration; Protein quality control; Proteomics; Spinal cord
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e18188
  43. J Invest Dermatol. 2023 Jul 28. pii: S0022-202X(23)02420-X. [Epub ahead of print]
    Autophagy controls the protein composition of hair shafts.
    Supawadee Sukseree, Noreen Karim, Karin Jaeger, Shaomin Zhong, Heidemarie Rossiter, Ionela Mariana Nagelreiter, Florian Gruber, Erwin Tschachler, Robert H Rice, Leopold Eckhart.
      
    DOI:  https://doi.org/10.1016/j.jid.2023.06.199
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