bims-auttor 2022-08-07 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2022–08–07
forty papers selected by
Viktor Korolchuk, Newcastle University

Neuronal-specific septin-3 binds Atg8/LC3B, accumulates and localizes to autophagosomes during induced autophagy.
Convergence of Signaling Pathways in Mediating Actions of Leucine and IGF-1 on mTORC1 in L6 Myoblasts.
TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression.
SDC1-dependent TGM2 determines radiosensitivity in glioblastoma by coordinating EPG5-mediated fusion of autophagosomes with lysosomes.
Interactions between mTORC2 core subunits Rictor and mSin1 dictate selective and context-dependent phosphorylation of substrate kinases SGK1 and Akt.
Paradoxical feeding activation of gut lipophagy by FGF15/FGF19-NR0B2/SHP-TFEB.
Regulatory roles of selective autophagy through targeting of native proteins in plant adaptive responses.
Mitophagy initiates retrograde mitochondrial-nuclear signaling to guide retinal pigment cell heterogeneity.
SIRT1 and Autophagy: Implications in Endocrine Disorders.
Proteasomal and autophagy-mediated degradation of mutp53 proteins through mitochondria-targeting aggregation-induced-emission materials.
O-GlcNAcylation stabilizes the autophagy-initiating kinase ULK1 by inhibiting chaperone-mediated autophagy upon HPV infection.
Selective Disruption of Drp1-Independent Mitophagy and Mitolysosome Trafficking by an Alzheimer's Disease Relevant Tau Modification in a Novel C. elegans Model.
Sirolimus relieves seizures and neuropsychiatric symptoms via changes of microglial polarity in tuberous sclerosis complex model mice.
Rapamycin rescues mitochondrial dysfunction in cells carrying the m.8344A > G mutation in the mitochondrial tRNALys.
Vacuolating Cytotoxin A Triggers Mitophagy in Helicobacter pylori-Infected Human Gastric Epithelium Cells.
TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease.
KCTD7 mutations impair the trafficking of lysosomal enzymes through CLN5 accumulation to cause neuronal ceroid lipofuscinoses.
Disaccharide Trehalose in Experimental Therapies for Neurodegenerative Disorders: Molecular Targets and Translational Potential.
PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells.
NBR1 mediates autophagic degradation of IRF3 to negatively regulate type I interferon production.
Deacetylation of ATG4B promotes autophagy initiation under starvation.
High-fat diet affects autophagy and mitochondrial compartment in rat Harderian gland.
Nrf2 as a regulator of mitochondrial function: Energy metabolism and beyond.
Incomplete autophagy promotes the proliferation of Mycoplasma hyopneumoniae through the JNK and Akt pathways in porcine alveolar macrophages.
Roles of phosphatidylserine and phospholipase C in the activation of TOR complex 2 signaling in Saccharomyces cerevisiae.
A Highly Selective GSK-3β Inhibitor CHIR99021 Promotes Osteogenesis by Activating Canonical and Autophagy-Mediated Wnt Signaling.
Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus.
Lysosomal K+ channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's disease.
Decreased expression of GRIM-19 induces autophagy through the AMPK/ULK1 signaling pathway during adenomyosis.
Feeding and lipophagy: it takes guts to deliver.
Mitochondria, mitophagy, and the role of deubiquitinases as novel therapeutic targets in liver pathology.
Neutrophil extracellular traps-mediated Beclin-1 suppression aggravates atherosclerosis by inhibiting macrophage autophagy.
A novel nanoparticle system targeting damaged mitochondria for the treatment of Parkinson's disease.
Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy.
Highly conserved shifts in ubiquitin-proteasome system (UPS) activity drive mitochondrial remodeling during quiescence.
Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells.
Involvement of autophagic protein DEF8 in Lewy bodies.
Bibliometric Insights of Global Research Landscape in Mitophagy.
GSNOR deficiency attenuates MPTP-induced neurotoxicity and autophagy by facilitating CDK5 S-nitrosation in a mouse model of Parkinson's disease.
The IRG1/itaconate/TFEB axis: A new weapon in macrophage antibacterial defense.

Cell Mol Life Sci. 2022 Aug 06. 79(9): 471

Neuronal-specific septin-3 binds Atg8/LC3B, accumulates and localizes to autophagosomes during induced autophagy.

Vilmos Tóth, Henrietta Vadászi, Lilla Ravasz, Dániel Mittli, Dominik Mátyás, Tamás Molnár, András Micsonai, Tamás Szaniszló, Péter Lőrincz, Réka Á Kovács, Tünde Juhász, Tamás Beke-Somfai, Gábor Juhász, Balázs András Györffy, Katalin A Kékesi, József Kardos.

  In synapses that show signs of local apoptosis and mitochondrial stress and undergo neuro-immunological synapse pruning, an increase in the levels of the presynaptic protein, neuronal-specific septin-3 can be observed. Septin-3 is a member of the septin GTPase family with the ability to form multimers and contribute to the cytoskeleton. However, the function of septin-3 remains elusive. Here, we provide evidence that septin-3 is capable of binding the most-studied autophagy protein Atg8 homolog microtubule-associated protein 1 light chain 3B (LC3B), besides another homolog, GABA receptor-associated protein-like 2 (GABARAPL2). Moreover, we demonstrate that colocalization of septin-3 and LC3B increases upon chemical autophagy induction in primary neuronal cells. Septin-3 is accumulated in primary neurons upon autophagy enhancement or blockade, similar to autophagy proteins. Using electron microscopy, we also show that septin-3 localizes to LC3B positive membranes and can be found at mitochondria. However, colocalization results of septin-3 and the early mitophagy marker PTEN-induced kinase 1 (PINK1) do not support that binding of septin-3 to mitochondria is mitophagy related. We conclude that septin-3 correlates with synaptic/neuronal autophagy, binds Atg8 and localizes to autophagic membranes that can be enhanced with chemical autophagy induction. Based on our results, elevated septin-3 levels might indicate enhanced or impeded autophagy in neurons.

Keywords:  Atg8; Autophagy; LIR; Neuronal autophagy; Septin; Synaptic autophagy; Synaptic pruning

DOI:  https://doi.org/10.1007/s00018-022-04488-8
Am J Physiol Cell Physiol. 2022 Aug 01.

Convergence of Signaling Pathways in Mediating Actions of Leucine and IGF-1 on mTORC1 in L6 Myoblasts.

Paul A Roberson, Leonard S Jefferson, Scot R Kimball.

  Leucine and Insulin-like Growth Factor-1 (IGF-1) are important regulators of protein synthesis in skeletal muscle. The mechanistic target of rapamycin complex 1 (mTORC1) is of particular importance in their mechanism of action. In the present study, pathways through which leucine and IGF-1 converge to mediate activation of mTORC1 were examined in L6 myoblasts that were deprived of leucine and serum followed by readdition of either leucine or IGF-1. Compared to leucine- and serum-deprived myoblasts, IGF-1, but not leucine, promoted phosphorylation of Protein Kinase B (AKT), Tuberous Sclerosis Complex 2 (TSC2), and the autophosphorylation site on mTOR (S2481) and also stimulated mTOR kinase activity in mTOR immunoprecipitated samples. Both leucine and IGF-1 promoted phosphorylation of mTOR on S2448. The association of mTOR with the Regulatory Associated Protein of mTOR (Raptor) was altered by IGF-1 treatment and trended (p=0.065) to be altered by leucine treatment. Alterations in the association of mTOR with Raptor were proportional to changes in phosphorylation of the mTOR substrates, eIF4E-Binding Protein 1 (4E-BP1) and Ribosomal Protein S6 Kinase-β1 (p70S6K1). Surprisingly, leucine, but not IGF-1, stimulated protein synthesis suggesting a unique role for nutrients in regulating protein synthesis. Overall, the results are consistent with a model whereby IGF-1 stimulates phosphorylation of 4E-BP1 and p70S6K1 in L6 myoblasts through an AKT-TSC2-mTORC1 signaling pathway that also involves changes in the interaction between mTOR and Raptor. In contrast, leucine signaling to mTOR results in alterations in certain mTOR phosphorylation sites, the interaction between mTOR and Raptor, and stimulates protein synthesis.

Keywords:  Cellular Signaling; Metabolism; Protein Synthesis; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpcell.00183.2022
Autophagy. 2022 Aug 03. 1-17

TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression.

Tai-Mei Zhang, Li Liao, Shao-Ying Yang, Min-Ying Huang, Yin-Ling Zhang, Ling Deng, Shu-Yuan Hu, Fan Yang, Fang-Lin Zhang, Zhi-Min Shao, Da-Qiang Li.

  Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to the lack of effective targeted therapies. Transmembrane (TMEM) proteins represent attractive drug targets for cancer therapy, but biological functions of most members of the TMEM family remain unknown. Here, we report for the first time that TMEM63A (transmembrane protein 63A), a poorly characterized TMEM protein with unknown functions in human cancer, functions as a novel oncogene to promote TNBC cell proliferation, migration, and invasion in vitro and xenograft tumor growth and lung metastasis in vivo. Mechanistic investigations revealed that TMEM63A localizes in endoplasmic reticulum (ER) and lysosome membranes, and interacts with VCP (valosin-containing protein) and its cofactor DERL1 (derlin 1). Furthermore, TMEM63A undergoes autophagy receptor TOLLIP-mediated autophagic degradation and is stabilized by VCP through blocking its lysosomal degradation. Strikingly, TMEM63A in turn stabilizes oncoprotein DERL1 through preventing TOLLIP-mediated autophagic degradation. Notably, pharmacological inhibition of VCP by CB-5083 or knockdown of DERL1 partially abolishes the oncogenic effects of TMEM63A on TNBC progression both in vitro and in vivo. Collectively, these findings uncover a previously unknown functional and mechanistic role for TMEM63A in TNBC progression and provide a new clue for targeting TMEM63A-driven TNBC tumors by using a VCP inhibitor.Abbreviations: ATG16L1, autophagy related 16 like 1; ATG5, autophagy related 5; ATP5F1B/ATP5B, ATP synthase F1 subunit beta; Baf-A1, bafilomycin A1; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CANX, calnexin; DERL1, derlin 1; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; HSPA8, heat shock protein family A (Hsp70) member 8; IP, immunoprecipitation; LAMP2A, lysosomal associated membrane protein 2; NBR1, NBR1 autophagy cargo receptor; OPTN, optineurin; RT-qPCR, reverse transcription-quantitative PCR; SQSTM1/p62, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TMEM63A, transmembrane protein 63A; TNBC, triple-negative breast cancer; TOLLIP, toll interacting protein; VCP, valosin containing protein.

Keywords:  Macroautophagic degradation; proteostasis; selective autophagy receptor; transmembrane protein; triple-negative breast cancer

DOI:  https://doi.org/10.1080/15548627.2022.2103992
Autophagy. 2022 Aug 01. 1-19

SDC1-dependent TGM2 determines radiosensitivity in glioblastoma by coordinating EPG5-mediated fusion of autophagosomes with lysosomes.

Wang Zheng, Qianping Chen, Hongxia Liu, Liang Zeng, Yuchuan Zhou, Xinglong Liu, Yang Bai, Jianghong Zhang, Yan Pan, Chunlin Shao.

  Glioblastoma multiforme (GBM) is the most common brain malignancy insensitive to radiotherapy (RT). Although macroautophagy/autophagy was reported to be a fundamental factor prolonging the survival of tumors under radiotherapeutic stress, the autophagic biomarkers coordinated to radioresistance of GBM are still lacking in clinical practice. Here we established radioresistant GBM cells and identified their protein profiles using tandem mass tag (TMT) quantitative proteomic analysis. It was found that SDC1 and TGM2 proteins were overexpressed in radioresistant GBM cells and tissues and they contributed to the poor prognosis of RT. Knocking down SDC1 and TGM2 inhibited the fusion of autophagosomes with lysosomes and thus enhanced the radiosensitivity of GBM cells. After irradiation, TGM2 bound with SDC1 and transported it from the cell membrane to lysosomes, and then bound to LC3 through its two LC3-interacting regions (LIRs), coordinating the encounter between autophagosomes and lysosomes, which should be a prerequisite for lysosomal EPG5 to recognize LC3 and subsequently stabilize the STX17-SNAP29-VAMP8 QabcR SNARE complex assembly. Moreover, when combined with RT, cystamine dihydrochloride (a TGM2 inhibitor) extended the lifespan of GBM-bearing mice. Overall, our findings demonstrated the EPG5 tethering mode with SDC1 and TGM2 during the fusion of autophagosomes with lysosomes, providing new insights into the molecular mechanism and therapeutic target underlying radioresistant GBM.Abbreviations: BafA1: bafilomycin A1; CQ: chloroquine; Cys-D: cystamine dihydrochloride; EPG5: ectopic P-granules 5 autophagy tethering factor; GBM: glioblastoma multiforme; GFP: green fluorescent protein; LAMP2: lysosomal associated membrane protein 2; LIRs: LC3-interacting regions; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NC: negative control; RFP: red fluorescent protein; RT: radiotherapy; SDC1: syndecan 1; SNAP29: synaptosome associated protein 29; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TGM2: transglutaminase 2; TMT: tandem mass tag; VAMP8: vesicle associated membrane protein 8; WT: wild type.

Keywords:  Autophagosome maturation; EPG5; SDC1; TGM2; glioblastoma; radioresistance biomarkers

DOI:  https://doi.org/10.1080/15548627.2022.2105562
J Biol Chem. 2022 Aug 01. pii: S0021-9258(22)00730-X. [Epub ahead of print] 102288

Interactions between mTORC2 core subunits Rictor and mSin1 dictate selective and context-dependent phosphorylation of substrate kinases SGK1 and Akt.

Zanlin Yu, Junliang Chen, Enzo Takagi, Feng Wang, Bidisha Saha, Xi Liu, Lydia-Marie Joubert, Catherine E Gleason, Mingliang Jin, Chengmin Li, Carlos Nowotny, David Agard, Yifan Cheng, David Pearce.

Mechanistic target of rapamycin complex 2 (mTORC2) is a multi-subunit kinase complex, central to multiple essential signaling pathways. Two core subunits, Rictor and mSin1, distinguish it from the related mTORC1 and support context-dependent phosphorylation of its substrates. mTORC2 structures have been determined previously, however, important questions remain, particularly regarding the structural determinants mediating substrate specificity and context-dependent activity. Here, we used cryo-EM to obtain high-resolution structures of the human mTORC2 apo-complex in the presence of substrates Akt and SGK1. Using functional assays, we then tested predictions suggested by substrate-induced structural changes in mTORC2. For the first time, we visualized in the apo-state the side chain interactions between Rictor and mTOR that sterically occlude recruitment of mTORC1 substrates and confer resistance to the mTORC1 inhibitor rapamycin. Also in the apo-state, we observed that mSin1 formed extensive contacts with Rictor via a pair of short α-helices nestled between two Rictor helical repeat clusters, as well as by an extended strand that makes multiple weak contacts with Rictor helical cluster 1. In co-complex structures, we found that SGK1, but not Akt, markedly altered the conformation of the mSin1 N-terminal extended strand, disrupting multiple weak interactions while inducing a large rotation of mSin1 residue Arg-83, which then interacts with a patch of negatively charged residues within Rictor. Finally, we demonstrate mutation of Arg-83 to Ala selectively disrupts mTORC2-dependent phosphorylation of SGK1, but not of Akt, supporting context-dependent substrate selection. These findings provide new structural and functional insights into mTORC2 specificity and context-dependent activity.

DOI: https://doi.org/10.1016/j.jbc.2022.102288
Autophagy. 2022 Aug 01.

Paradoxical feeding activation of gut lipophagy by FGF15/FGF19-NR0B2/SHP-TFEB.

Sunmi Seok, Jongsook Kim Kemper.

  Macroautophagic/autophagic degradation of lipid droplets, lipophagy, is activated by fasting but repressed by feeding. Surprisingly, our recent study showed that this is not the case in the gut, where feeding activates lipophagy, reducing intestinal lipid levels. Transgenic mouse studies revealed that feeding activation of gut lipophagy requires both FGF15/FGF19 (fibroblast growth factor 15/fibroblast growth factor 19) and an orphan nuclear receptor, NR0B2/SHP (nuclear receptor subfamily 0, group B, member 2). Mechanistically, feeding-induced FGF15/FGF19 activates intestinal PRKC/PKC signaling, which in turn phosphorylates NR0B2 and the autophagic activator TFEB (transcription factor EB), leading to their nuclear localization and transcriptional induction of lipophagy network genes, including Ulk1 and Pnpla2/Atgl. Given that an essential function of the gut is to distribute dietary lipids throughout the body, this study identifies a physiologically important homeostatic mechanism to maintain healthy lipid levels. The intestinal FGF15/FGF19-NR0B2/SHP-TFEB pathway that regulates postprandial lipids by lipophagic activation, thus, may provide novel targets for treating dyslipidemia and obesity.

Keywords:  ATGL; FGF15/FGF19; NR0B2; SHP; SHP CHIP-seq; TFEB; autophagy; intestinal SHP

DOI:  https://doi.org/10.1080/15548627.2022.2108296
Plant Cell Rep. 2022 Aug 03.

Regulatory roles of selective autophagy through targeting of native proteins in plant adaptive responses.

Yan Zhang, Gengshou Xia, Li Sheng, Mingjue Chen, Chenyang Hu, Yule Ye, Xiaoyan Yue, Shaocong Chen, Wenwu OuYang, Zhenkai Xia.

   KEY MESSAGE: Selective autophagy functions as a regulatory mechanism by targeting native and functional proteins to ensure their proper levels and activities in plant adaptive responses. Autophagy is a cellular degradation and recycling pathway with a key role in cellular homeostasis and metabolism. Autophagy is initiated with the biogenesis of autophagosomes, which fuse with the lysosomes or vacuoles to release their contents for degradation. Under nutrient starvation or other adverse environmental conditions, autophagy usually targets unwanted or damaged proteins, organelles and other cellular components for degradation and recycling to promote cell survival. Over the past decade, however, a substantial number of studies have reported that autophagy in plants also functions as a regulatory mechanism by targeting enzymes, structural and regulatory proteins that are not necessarily damaged or dysfunctional to ensure their proper abundance and function to facilitate cellular changes required for response to endogenous and environmental conditions. During plant-pathogen interactions in particular, selective autophagy targets specific pathogen components as a defense mechanism and pathogens also utilize autophagy to target functional host factors to suppress defense mechanisms. Autophagy also targets native and functional protein regulators of plant heat stress memory, hormone signaling, and vesicle trafficking associated with plant responses to abiotic and other conditions. In this review, we discuss advances in the regulatory roles of selective autophagy through targeting of native proteins in plant adaptive responses, what questions remain and how further progress in the analysis of these special regulatory roles of autophagy can help understand biological processes important to plants.

Keywords:  Heat stress memory; Phytohormone signaling; Plant-pathogen interactions; Regulatory roles of autophagy; Selective autophagy; Vesicle trafficking

DOI:  https://doi.org/10.1007/s00299-022-02910-w
Autophagy. 2022 Aug 03.

Mitophagy initiates retrograde mitochondrial-nuclear signaling to guide retinal pigment cell heterogeneity.

Sayantan Datta, Marisol Cano, Ganesh Satyanarayana, Tongyun Liu, Lei Wang, Jie Wang, Jie Cheng, Kie Itoh, Anjali Sharma, Imran Bhutto, Kannan Rangaramanujam, Jiang Qian, Debasish Sinha, James T Handa.

  Age-related macular degeneration (AMD), the leading cause of blindness among the elderly, is without treatment for early disease. Degenerative retinal pigment epithelial (RPE) cell heterogeneity is a well-recognized but understudied pathogenic factor. Due to the daily phagocytosis of photoreceptor outer segments, unique photo-oxidative stress, and high metabolism for maintaining vision, the RPE has robust macroautophagy/autophagy, and mitochondrial and antioxidant networks. However, the autophagy subtype, mitophagy, in the RPE and AMD is understudied. Here, we found decreased PINK1 (PTEN induced kinase 1) in perifoveal RPE of early AMD eyes. PINK1-deficient RPE have impaired mitophagy and mitochondrial function that triggers death-resistant epithelial-mesenchymal transition (EMT). This reprogramming is mediated by novel retrograde mitochondrial-nuclear signaling (RMNS) through superoxide, NFE2L2 (NFE2 like bZIP transcription factor 2), TXNRD1 (thioredoxin reductase 1), and phosphoinositide 3-kinase (PI3K)-AKT (AKT serine/threonine kinase) that induced canonical transcription factors ZEB1 (zinc finger E-box binding homeobox 1) and SNAI1 (Snail family transcriptional repressor 1) and an EMT transcriptome. NFE2L2 deficiency disrupted RMNS that paradoxically normalized morphology but decreased function and viability. Thus, RPE heterogeneity is defined by the interaction of two cytoprotective pathways that is triggered by mitophagy function. By neutralizing the consequences of impaired mitophagy, an antioxidant dendrimer tropic for the RPE and mitochondria, EMT (a recognized AMD alteration) was abrogated to offer potential therapy for early AMD, a stage without treatment.

Keywords:  NFE2L2; PINK1; age-related macular degeneration; dendrimer; epithelial mesenchymal transition; heterogeneity; mitophagy; retinal pigment epithelium; retrograde mitochondrial-nuclear signaling

DOI:  https://doi.org/10.1080/15548627.2022.2109286
Front Endocrinol (Lausanne). 2022 ;13 930919

SIRT1 and Autophagy: Implications in Endocrine Disorders.

Ji Yong Kim, David Mondaca-Ruff, Sandeep Singh, Yu Wang.

  Autophagy is a cellular process involved in the selective degradation and recycling of dysfunctional intracellular components. It plays a crucial role in maintaining cellular homeostasis and survival by removing damaged and harmful proteins, lipids, and organelles. SIRT1, an NAD+-dependent multifunctional enzyme, is a key regulator of the autophagy process. Through its deacetylase activity, SIRT1 participates in the regulation of different steps of autophagy, from initiation to degradation. The levels and function of SIRT1 are also regulated by the autophagy process. Dysregulation in SIRT1-mediated autophagy hinders the proper functioning of the endocrine system, contributing to the onset and progression of endocrine disorders. This review provides an overview of the crosstalk between SIRT1 and autophagy and their implications in obesity, type-2 diabetes mellitus, diabetic cardiomyopathy, and hepatic steatosis.

Keywords:  SIRT1; autophagy; cardiovascular disease; diabetes; diabetic cardiomyopathy; obesity

DOI:  https://doi.org/10.3389/fendo.2022.930919
Acta Biomater. 2022 Aug 02. pii: S1742-7061(22)00458-5. [Epub ahead of print]

Proteasomal and autophagy-mediated degradation of mutp53 proteins through mitochondria-targeting aggregation-induced-emission materials.

Meimei Wang, Zhenyu Yang, Yang Song, Pengfei Wei, Nestor Ishiwme, Liansheng Wang, Hao Zhang, Manman Jing, Meng Gao, Longping Wen, Yunjiao Zhang.

  Close to half of human cancers harbor point mutations in the tumor-suppressor p53 gene, giving rise to the cellular accumulation of mutant p53 (mutp53) proteins with novel neomorphic gain-of-function (GOF) properties. The destruction of mutp53 proteins through either autophagic or proteasomal degradation is a viable strategy for the targeted therapy of p53-mutated cancers. Several nanomaterials, including zinc-iron and ZIF-8 nanoparticles (NPs), have been reported to induce the proteasomal degradation of mutp53 proteins. However, how autophagy, the other major cellular degradative pathway, influences NP-induced mutp53 degradation has not been investigated. This article shows that AIE-Mit-TPP, a mitochondria-targeting material with aggregation-induced emission (AIE) characteristics, elicits ubiquitination-dependent proteasomal degradation of a broad range of mutp53 proteins. Meanwhile, AIE-Mit-TPP also induces massive mitochondrial damage and autophagy. The inhibition of autophagy further increases AIE-Mit-TPP-elicited mutp53 degradation, revealing the negative impact of autophagy on AIE-Mit-TPP-induced mutp53 degradation. As expected, the degradation of mutp53 proteins by AIE-Mit-TPP abrogated mutp53-manifested GOF, leading to reductions in cell proliferation and migration and increases in cell cycle arrest and cell death. Consequently, AIE-Mit-TPP inhibited the growth of mutp53 tumors. This paper unravels the interesting interplay between the proteasomal and autophagic degradative pathways and pinpoints the modulation of autophagy as a potential strategy for optimizing NP-induced mutp53 degradation and p53-targeted cancer therapy. STATEMENT OF SIGNIFICANCE: We have designed three different types of AIE materials: non-targeting (AIE-Br), mitochondria-targeting (AIE-Mit-TPP), lysosome-targeting (AIE-Lyso). Our results proved that mitochondria-targeting AIE material induced degradation of mutp53 proteins via the proteasome degradation pathway and abrogated mutp53-conferred GOF phenotypes. Furthermore, we performed in vitro studies on the effect of the tested materials in mutp53-expressing cancer cells and demonstrated our findings via in vivo investigations in a mouse subcutaneous p53R175H TOV112D ovarian cancer model. Our results confirmed the link between the proteasome pathway and autophagy and thus proposed a strategy of combining AIE-Mit-TPP with autophagy inhibitors for the targeted treatment of mutp53-associated tumors. Finally, we found that AIE-Mit-TPP could induce degradation of a wide-spectrum mutp53 proteins, which makes mitochondria-targeting AIE materials an effective therapeutic strategy for p53-mutated cancers.

Keywords:  autophagy; mutant p53 (mutp53); proteasomal degradation; targeted cancer therapy

DOI:  https://doi.org/10.1016/j.actbio.2022.07.057
J Biol Chem. 2022 Aug 02. pii: S0021-9258(22)00783-9. [Epub ahead of print] 102341

O-GlcNAcylation stabilizes the autophagy-initiating kinase ULK1 by inhibiting chaperone-mediated autophagy upon HPV infection.

Yingxin Shi, Sheng Yan, Guang-Can Shao, Jinglong Wang, Yong-Ping Jian, Bo Liu, Yanqiu Yuan, Ke Qin, Shanshan Nai, Xiahe Huang, Yingchun Wang, Zhenghui Chen, Xing Chen, Meng-Qiu Dong, Yiqun Geng, Zhi-Xiang Xu, Jing Li.

  Human papillomaviruses (HPVs) cause a subset of cases of head and neck squamous cell carcinomas (HNSCCs). Previously, we demonstrated that HPV16 oncogene E6 or E6/E7 transduction increases the abundance of O-linked GlcNAcylation (O-GlcNAc) transferase (OGT), but the OGT substrates and cellular pathways affected by this increase are unclear. Here, we focus on the effects of O-GlcNAcylation on HPV-positive HNSCCs. We found that upon HPV infection, ULK1, an autophagy-initiating kinase, is hyper-O-GlcNAcylated, stabilized, and linked with autophagy elevation. Through mass spectrometry, we identified that ULK1 is O-GlcNAcylated at Ser409, which is distinct from the previously reported Thr635/Thr754 sites. It has been demonstrated that PKCαmediates phosphorylation of ULK1 at Ser423, which attenuates its stability by shunting ULK1 to the chaperone-mediated autophagy (CMA) pathway. Using biochemical assays, we demonstrate that ULK1 Ser409Ser410 O-GlcNAcylation antagonizes its phosphorylation at Ser423. Moreover, we found that mutations of Ser409A and its neighboring site Ser410A (2A) render ULK1 less stable by promoting interaction with the CMA chaperone Hsc70. Further, we determined that ULK1-2A mutants attenuate the association of ULK1 with STX17, which is vital for the fusion between autophagosomes and lysosomes. Analysis of The Cancer Genome Atlas (TCGA) database reveals that ULK1 is upregulated in HPV-positive HNSCCs and its level positively correlates with HNSCC patient survival. Overall, our work demonstrates that O-GlcNAcylation of ULK1 is altered in response to environmental changes. O-GlcNAcylation of ULK1 at Ser409 and perhaps at its neighboring Ser410 stabilizes ULK1, and this might underlie the molecular mechanism of HPV-positive HNSCC patient survival.

Keywords:  Chaperone-mediated autophagy; HNSCC; HPV; Macroautophagy; O-GlcNAc; ULK1

DOI:  https://doi.org/10.1016/j.jbc.2022.102341
Genetics. 2022 Aug 02. pii: iyac104. [Epub ahead of print]

Selective Disruption of Drp1-Independent Mitophagy and Mitolysosome Trafficking by an Alzheimer's Disease Relevant Tau Modification in a Novel C. elegans Model.

Sanjib Guha, Anson Cheng, Trae Carroll, Dennisha King, Shon A Koren, Sierra Swords, Keith Nehrke, Gail V W Johnson.

  Accumulation of inappropriately phosphorylated tau into neurofibrillary tangles (NFT) is a defining feature of Alzheimer's disease (AD), with Tau pT231 being an early harbinger of tau pathology. Previously, we demonstrated that expressing a single genomic copy of human phosphomimetic mutant tau (T231E) in C. elegans drove age-dependent neurodegeneration. A critical finding was that T231E, unlike wild type tau, completely and selectively suppressed oxidative stress-induced mitophagy. Here, we used dynamic imaging approaches to analyze T231E-associated changes in mitochondria and mitolysosome (ML) morphology, abundance, trafficking, and stress-induced mitophagy as a function of mitochondrial fission mediator Drp1, which has been demonstrated to interact with hyper phosphorylated tau and contribute to AD pathogenesis, as well as Pink1, a well-recognized mediator of mitochondrial quality control that works together with Parkin to support stress-induced mitophagy. T231E impacted both mitophagy and ML neurite trafficking with exquisite selectivity, sparing macroautophagy as well as lysosome and autolysosome trafficking. Both oxidative-stress induced mitophagy and the ability of T231E to suppress it were independent of drp-1, but at least partially dependent on pink-1. Organelle trafficking was more complicated, with drp-1 and pink-1 mutants exerting independent effects, but generally supported the idea that the mitophagy phenotype is of greater physiologic impact in T231E. Collectively, our results refine the mechanistic pathway through which T231E causes neurodegeneration, demonstrating pathologic selectivity for mutations that mimic tauopathy-associated post-translational modifications, physiologic selectivity for organelles that contain damaged mitochondria, and molecular selectivity for Drp1-independent, Pink1-dependent, perhaps adaptive, mitophagy.

Keywords:   C. elegans ; Alzheimer’s disease; Drp1; Pink1; mitochondria; mitophagy; tau phosphorylation

DOI:  https://doi.org/10.1093/genetics/iyac104
Neuropharmacology. 2022 Aug 02. pii: S0028-3908(22)00262-3. [Epub ahead of print] 109203

Sirolimus relieves seizures and neuropsychiatric symptoms via changes of microglial polarity in tuberous sclerosis complex model mice.

Makiko Koike-Kumagai, Manabu Fujimoto, Mari Wataya-Kaneda.

  Tuberous sclerosis complex (TSC) is a genetic disorder involving a variety of physical manifestations, and is associated with epilepsy and multiple serious neuropsychiatric symptoms. These symptoms are collectively known as TSC-associated neuropsychiatric disorders (TAND), which is a severe burden for patients and their families. Overactivation of the mechanistic target of rapamycin complex 1 (mTORC1) by mutations in TSC1 or TSC2 is thought to cause TSC, and mTORC1 inhibitors such as sirolimus and everolimus are reported to be effective against various tumor types of TSC. However, there are various reports on the effect of mTORC1 inhibitor therapy on TAND in patients with TSC, which may or may not be effective. In our previous investigations, we generated TSC2 conditional knockout mice (Mitf-Cre, Tsc2 KO; Tsc2 cKO). These mice developed spontaneous epileptic activity. In the current study, we further analyzed the detailed behaviors of Tsc2 cKO mice and confirmed that they exhibited phenotypes of TAND as well as epileptic seizures, indicating that Tsc2 cKO mice are a useful model for TAND. Furthermore, the olfactory bulb and piriform cortex caused epilepsy and TAND in Tsc2 cKO mice, and neurodegeneration was observed. Immunohistology and immunophenotypic analysis of cells, and quantitative RT-PCR suggested that changes in microglial polarity were involved in the onset of TSC epilepsy and neuropsychiatric symptoms. Although the effect of mTORC1 inhibitors on TAND has not been established, the results of this study might help elucidate the mechanism of TAND pathogenesis and suggest that sirolimus may be a valuable therapeutic tool for TAND.

Keywords:  Epilepsy; Microglia polarity; Sirolimus; TSC-Associated neuropsychiatric disorders (TAND); Tuberous sclerosis complex (TSC)

DOI:  https://doi.org/10.1016/j.neuropharm.2022.109203
Mol Med. 2022 Aug 03. 28(1): 90

Rapamycin rescues mitochondrial dysfunction in cells carrying the m.8344A > G mutation in the mitochondrial tRNALys.

Mariantonietta Capristo, Valentina Del Dotto, Concetta Valentina Tropeano, Claudio Fiorini, Leonardo Caporali, Chiara La Morgia, Maria Lucia Valentino, Monica Montopoli, Valerio Carelli, Alessandra Maresca.

   BACKGROUND: Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently affecting the tRNALys gene at position m.8344A > G. Defective tRNALys severely impairs mitochondrial protein synthesis and respiratory chain when a high percentage of mutant heteroplasmy crosses the threshold for full-blown clinical phenotype. Therapy is currently limited to symptomatic management of myoclonic epilepsy, and supportive measures to counteract muscle weakness with co-factors/supplements.
METHODS: We tested two therapeutic strategies to rescue mitochondrial function in cybrids and fibroblasts carrying different loads of the m.8344A > G mutation. The first strategy was aimed at inducing mitochondrial biogenesis directly, over-expressing the master regulator PGC-1α, or indirectly, through the treatment with nicotinic acid, a NAD+ precursor. The second was aimed at stimulating the removal of damaged mitochondria through prolonged rapamycin treatment.
RESULTS: The first approach slightly increased mitochondrial protein expression and respiration in the wild type and intermediate-mutation load cells, but was ineffective in high-mutation load cell lines. This suggests that induction of mitochondrial biogenesis may not be sufficient to rescue mitochondrial dysfunction in MERRF cells with high-mutation load. The second approach, when administered chronically (4 weeks), induced a slight increase of mitochondrial respiration in fibroblasts with high-mutation load, and a significant improvement in fibroblasts with intermediate-mutation load, rescuing completely the bioenergetics defect. This effect was mediated by increased mitochondrial biogenesis, possibly related to the rapamycin-induced inhibition of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and the consequent activation of the Transcription Factor EB (TFEB).
CONCLUSIONS: Overall, our results point to rapamycin-based therapy as a promising therapeutic option for MERRF.

Keywords:  MERRF; Mitochondrial DNA; Mitochondrial biogenesis; Mitochondrial dysfunction; Niacin; PGC-1α; Rapamycin; mTORC1

DOI:  https://doi.org/10.1186/s10020-022-00519-z
Front Oncol. 2022 ;12 881829

Vacuolating Cytotoxin A Triggers Mitophagy in Helicobacter pylori-Infected Human Gastric Epithelium Cells.

Li Wang, Juan Yi, Xiao-Yang Yin, Jin-Xia Hou, Jing Chen, Bei Xie, Gang Chen, Qun-Feng Wang, Li-Na Wang, Xiao-Yuan Wang, Jing Sun, Lei-Ming Huo, Tuan-Jie Che, Hu-Lai Wei.

  Helicobacter pylori (H. pylori)-derived vacuolating cytotoxin A (VacA) causes damage to various organelles, including mitochondria, and induces autophagy and cell death. However, it is unknown whether VacA-induced mitochondrial damage can develop into mitophagy. In this study, we found that H. pylori, H. pylori culture filtrate (HPCF), and VacA could activate autophagy in a gastric epithelial cell line (GES-1). VacA-caused mitochondrial depolarization retards the import of PINK1 into the damaged mitochondria and evokes mitophagy. And, among mass spectrometry (LC-MS/MS) identified 25 mitochondrial proteins bound with VacA, Tom20, Tom40, and Tom70, TOM complexes responsible for PINK1 import, were further identified as having the ability to bind VacA in vitro using pull-down assay, co-immunoprecipitation, and protein-protein docking. Additionally, we found that the cell membrane protein STOM and the mitochondrial inner membrane protein PGAM5 also interacted with VacA. These findings suggest that VacA captured by STOM forms endosomes to enter cells and target mitochondria. Then, VacA is transported into the mitochondrial membrane space through the TOM complexes, and PGAM5 aids in inserting VacA into the inner mitochondrial membrane to destroy the membrane potential, which promotes PINK1 accumulation and Parkin recruitment to induce mitophagy. This study helps us understand VacA entering mitochondria to induce the mitophagy process.

Keywords:  GES-1 cells; Helicobacter pylori; PGAM5; STOM; TOM complex; VacA; autophagy; mitophagy

DOI:  https://doi.org/10.3389/fonc.2022.881829
EMBO Mol Med. 2022 Aug 05. e15377

TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease.

Anna Scotto Rosato, Einar K Krogsaeter, Dawid Jaślan, Carla Abrahamian, Sandro Montefusco, Chiara Soldati, Barbara Spix, Maria Teresa Pizzo, Giuseppina Grieco, Julia Böck, Amanda Wyatt, Daniela Wünkhaus, Marcel Passon, Marc Stieglitz, Marco Keller, Guido Hermey, Sandra Markmann, Doris Gruber-Schoffnegger, Susan Cotman, Ludger Johannes, Dennis Crusius, Ulrich Boehm, Christian Wahl-Schott, Martin Biel, Franz Bracher, Elvira De Leonibus, Elena Polishchuk, Diego L Medina, Dominik Paquet, Christian Grimm.

  Lysosomes are cell organelles that degrade macromolecules to recycle their components. If lysosomal degradative function is impaired, e.g., due to mutations in lysosomal enzymes or membrane proteins, lysosomal storage diseases (LSDs) can develop. LSDs manifest often with neurodegenerative symptoms, typically starting in early childhood, and going along with a strongly reduced life expectancy and quality of life. We show here that small molecule activation of the Ca2+ -permeable endolysosomal two-pore channel 2 (TPC2) results in an amelioration of cellular phenotypes associated with LSDs such as cholesterol or lipofuscin accumulation, or the formation of abnormal vacuoles seen by electron microscopy. Rescue effects by TPC2 activation, which promotes lysosomal exocytosis and autophagy, were assessed in mucolipidosis type IV (MLIV), Niemann-Pick type C1, and Batten disease patient fibroblasts, and in neurons derived from newly generated isogenic human iPSC models for MLIV and Batten disease. For in vivo proof of concept, we tested TPC2 activation in the MLIV mouse model. In sum, our data suggest that TPC2 is a promising target for the treatment of different types of LSDs, both in vitro and in-vivo.

Keywords:  Batten; MLIV; NPC1; TPC2; TRPML

DOI:  https://doi.org/10.15252/emmm.202115377
Sci Adv. 2022 Aug 05. 8(31): eabm5578

KCTD7 mutations impair the trafficking of lysosomal enzymes through CLN5 accumulation to cause neuronal ceroid lipofuscinoses.

Yalan Wang, Xiaotong Cao, Pei Liu, Weijia Zeng, Rui Peng, Qing Shi, Kai Feng, Pingzhao Zhang, Huiru Sun, Chenji Wang, Hongyan Wang.

Lysosomes are central organelles for cellular degradation and energy metabolism. Neuronal ceroid lipofuscinoses (NCLs) are a group of the most common neurodegenerative lysosomal storage disorders characterized by intracellular accumulation of ceroid in neurons. Mutations in KCTD7, a gene encoding an adaptor of the CUL3-RING E3 ubiquitin ligase (CRL3) complex, are categorized as a unique NCL subtype. However, the underlying mechanisms remain elusive. Here, we report various lysosomal and autophagic defects in KCTD7-deficient cells. Mechanistically, the CRL3-KCTD7 complex degrades CLN5, whereas patient-derived KCTD7 mutations disrupt the interaction between KCTD7-CUL3 or KCTD7-CLN5 and ultimately lead to excessive accumulation of CLN5. The accumulated CLN5 disrupts the interaction between CLN6/8 and lysosomal enzymes at the endoplasmic reticulum (ER), subsequently impairing ER-to-Golgi trafficking of lysosomal enzymes. Our findings reveal previously unrecognized roles of KCTD7-mediated CLN5 proteolysis in lysosomal homeostasis and demonstrate that KCTD7 and CLN5 are biochemically linked and function in a common neurodegenerative pathway.

DOI: https://doi.org/10.1126/sciadv.abm5578
Pharmacol Res. 2022 Jul 27. pii: S1043-6618(22)00318-8. [Epub ahead of print] 106373

Disaccharide Trehalose in Experimental Therapies for Neurodegenerative Disorders: Molecular Targets and Translational Potential.

Alexander B Pupyshev, Tatyana P Klyushnik, Anna A Akopyan, Sandeep Kumar Singh, Maria A Tikhonova.

  Induction of autophagy is a prospective approach to the treatment of neurodegeneration. In the recent decade, trehalose attracted special attention. It is an autophagy inducer with negligible adverse effects and is approved for use in humans according to FDA requirements. Trehalose has a therapeutic effect in various experimental models of diseases. This glucose disaccharide with a flexible α-1-1'-glycosidic bond has unique properties: induction of mTOR-independent autophagy (with kinase AMPK as the main target) and a chaperone-like effect on proteins imparting them natural spatial structure. Thus, it can reduce the accumulation of neurotoxic aberrant/misfolded proteins. Trehalose has an anti-inflammatory effect and inhibits detrimental oxidative stress partially owing to the enhancement of endogenous antioxidant defense represented by the Nrf2 protein. The disaccharide activates lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1. Here we review various mechanisms of the neuroprotective action of trehalose and touch on the possibility of pleiotropic effects. Current knowledge about specific features of trehalose pharmacodynamics is discussed. The neuroprotective effects of trehalose in animal models of major neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are examined too. Attention is given to translational transition to clinical trials of this drug, especially oral and parenteral routes of administration. Besides, the possibility of enhancing the therapeutic benefit via a combination of mTOR-dependent and mTOR-independent autophagy inducers is analyzed. In general, trehalose appears to be a promising multitarget tool for the inhibition of experimental neurodegeneration and requires thorough investigation of its clinical capabilities.

Keywords:  clinical trial; mTOR-independent autophagy; multitarget therapy; neurodegenerative disorder; neuroprotection; trehalose

DOI:  https://doi.org/10.1016/j.phrs.2022.106373
Sci Rep. 2022 Aug 03. 12(1): 13324

PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells.

Neil Saptarshi, Louise F Porter, Luminita Paraoan.

Retinal pigment epithelium (RPE) performs essential functions for ensuring retinal homeostasis and is a key site for pathogenic changes leading to age-related macular degeneration (AMD). Compromised proteostasis in RPE results in ER stress and ER stress-dependent antioxidant, apoptosis and autophagic responses. ER stress induces the unfolded protein response (UPR) in which EIF2AK3, encoding the protein kinase RNA-like ER kinase (PERK), acts as a key regulator. Downregulated EIF2AK3 gene expression has recently been identified in AMD using human donor RPE, however the molecular mechanisms that integrate the various ER-mediated cellular pathways underpinning progressive RPE dysfunction in AMD have not been fully characterised. This study investigated the downstream effects of PERK downregulation in response to Brefeldin A (BFA)-induced ER stress in ARPE-19 cells. PERK downregulation resulted in increased ER stress and impaired apoptosis induction, antioxidant responses and autophagic flux. ARPE-19 cells were unable to efficiently induce autophagy following PERK downregulation and PERK presented a role in regulating the rate of autophagy induction. The findings support PERK downregulation as an integrative event facilitating dysregulation of RPE processes critical to cell survival known to contribute to AMD development and highlight PERK as a potential future therapeutic target for AMD.

DOI: https://doi.org/10.1038/s41598-022-16909-6
Biochem Biophys Res Commun. 2022 Jul 14. pii: S0006-291X(22)01012-9. [Epub ahead of print]623 140-147

NBR1 mediates autophagic degradation of IRF3 to negatively regulate type I interferon production.

Yiting Cai, Yue Zhu, Jiaqi Zheng, Yuchuan Zhang, Wei Chen.

  In the setting of virus infection, autophagy regulates the synthesis of type I interferon (IFN) via multiple mechanisms to prevent adverse overreaction. Interferon regulatory factor (IRF) 3, the dominant transcriptional factor of type I IFN, can be degraded via autophagy-lysosomal pathway. However, the exact regulatory mechanism is not yet well elucidated. IRF3 was targeted into autophagosome by interacting with cargo receptors including p62, NDP52 and NBR1. The recent studies have reported the mechanism of p62 and NDP52 sequestrating IRF3. This work aims to investigate the role of NBR1 in the process of IRF3 degradation. We found that blocking autophagy via ATG3/ATG7 knockout and chemical inhibitors both resulted in the accumulation of IRF3 protein and increased synthesis of type I IFN, while enhancing autophagy activity led to more obvious clearance of IRF3 in HEK293T cells infected with Sendai virus (SeV). Our data suggested that NBR1 bound both unphosphorylated and phosphorylated IRF3 through its ubiquitin-associated domain. Meanwhile, viral infection elevated the expression of NBR1, which sequentially formed a negative feedback loop to promote IRF3 degradation and hence optimized the type I IFN signaling. This study expands the knowledge of molecular mechanisms regulating the IRF3 stability and function during viral infection.

Keywords:  Autophagy; IRF3; NBR1; Type I interferon

DOI:  https://doi.org/10.1016/j.bbrc.2022.07.043
Sci Adv. 2022 Aug 05. 8(31): eabo0412

Deacetylation of ATG4B promotes autophagy initiation under starvation.

Liangbo Sun, Haojun Xiong, Lingxi Chen, Xufang Dai, Xiaojing Yan, Yaran Wu, Mingzhen Yang, Meihua Shan, Tao Li, Jie Yao, Wenbin Jiang, Haiyan He, Fengtian He, Jiqin Lian.

Eukaryotes initiate autophagy when facing environmental changes such as a lack of external nutrients. However, the mechanisms of autophagy initiation are still not fully elucidated. Here, we showed that deacetylation of ATG4B plays a key role in starvation-induced autophagy initiation. Specifically, we demonstrated that ATG4B is activated during starvation through deacetylation at K39 by the deacetylase SIRT2. Moreover, starvation triggers SIRT2 dephosphorylation and activation in a cyclin E/CDK2 suppression-dependent manner. Meanwhile, starvation down-regulates p300, leading to a decrease in ATG4B acetylation at K39. K39 deacetylation also enhances the interaction of ATG4B with pro-LC3, which promotes LC3-II formation. Furthermore, an in vivo experiment using Sirt2 knockout mice also confirmed that SIRT2-mediated ATG4B deacetylation at K39 promotes starvation-induced autophagy initiation. In summary, this study reveals an acetylation-dependent regulatory mechanism that controls the role of ATG4B in autophagy initiation in response to nutritional deficiency.

DOI: https://doi.org/10.1126/sciadv.abo0412
J Exp Zool A Ecol Integr Physiol. 2022 Aug 04.

High-fat diet affects autophagy and mitochondrial compartment in rat Harderian gland.

Gabriella Chieffi Baccari, Sara Falvo, Maria M Di Fiore, Federica Cioffi, Antonia Giacco, Alessandra Santillo.

  The Harderian gland (HG) of Rattus norvegicus is an orbital gland secreting lipids that accumulate in excess under condition of increased lipid metabolism. To study the response elicitated by lipid overload in rat HG, we housed the animals in thermoneutral conditions (28-30°C) in association to high fat diet (HFD). In HFD rats alterated blood lipid levels result in lipid accumulation in HG as demonstrated by the increased gland weight and histochemical/ultrastructural analyses. The HFD-caused oxidative stress forces the gland to trigger antioxidant defense mechanisms and autophagic process, such as lipophagy and mitophagy. Induction of mitochondrial DNA (mtDNA) damage and repair was stronger in HFD-rat HGs. An increase in marker expression levels of mitochondrial biogenesis, fission, and fusion occurred to counteract mtDNA copy number reduction and mitophagy. Therefore, the results demonstrate that rat HG activates autophagy as survival strategy under conditions of increased lipid metabolism and suggest a key role for mitophagy and membrane dynamics in the mitochondrial adaptive response to HFD.

Keywords:  Harderian gland; autophagy; high-fat diet; mitochondria

DOI:  https://doi.org/10.1002/jez.2646
Free Radic Biol Med. 2022 Jul 30. pii: S0891-5849(22)00496-8. [Epub ahead of print]

Nrf2 as a regulator of mitochondrial function: Energy metabolism and beyond.

Noemí Esteras, Andrey Y Abramov.

  Mitochondria are unique and essential organelles that mediate many vital cellular processes including energy metabolism and cell death. The transcription factor Nrf2 (NF-E2 p45-related factor 2) has emerged in the last few years as an important modulator of multiple aspects of mitochondrial function. Well-known for controlling cellular redox homeostasis, the cytoprotective effects of Nrf2 extend beyond its ability to regulate a diverse network of antioxidant and detoxification enzymes. Here, we review the role of Nrf2 in the regulation of mitochondrial function and structure. We focus on Nrf2 involvement in promoting mitochondrial quality control and regulation of basic aspects of mitochondrial function, including energy production, reactive oxygen species generation, calcium signalling, and cell death induction. Given the importance of mitochondria in the development of multiple diseases, these findings reinforce the pharmacological activation of Nrf2 as an attractive strategy to counteract mitochondrial dysfunction.

Keywords:  Calcium; Dynamics; Energy; Fission; Fusion; Mitochondria; Mitochondrial biogenesis; Mitophagy; Nrf2; ROS; mPTP

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.07.013
Vet Res. 2022 Aug 04. 53(1): 62

Incomplete autophagy promotes the proliferation of Mycoplasma hyopneumoniae through the JNK and Akt pathways in porcine alveolar macrophages.

Yukang Wen, Zhengkun Chen, Yaqin Tian, Mei Yang, Qingshuang Dong, Yujiao Yang, Honglei Ding.

  Autophagy is an important conserved homeostatic process related to nutrient and energy deficiency and organelle damage in diverse eukaryotic cells and has been reported to play an important role in cellular responses to pathogens and bacterial replication. The respiratory bacterium Mycoplasma hyopneumoniae has been identified to enter porcine alveolar macrophages, which are considered important immune cells. However, little is known about the role of autophagy in the pathogenesis of M. hyopneumoniae infection of porcine alveolar macrophages. Our experiments demonstrated that M. hyopneumoniae infection enhanced the formation of autophagosomes in porcine alveolar macrophages but prevented the fusion of autophagosomes with lysosomes, thereby blocking autophagic flux and preventing the acidification and destruction of M. hyopneumoniae in low-pH surroundings. In addition, using different autophagy regulators to intervene in the autophagy process, we found that incomplete autophagy promoted the intracellular proliferation of M. hyopneumoniae. We also found that blocking the phosphorylation of JNK and Akt downregulated the autophagy induced by M. hyopneumoniae, but pathways related to two mitogen-activated protein kinases (Erk1/2 and p38) did not affect the process. Collectively, M. hyopneumoniae induced incomplete autophagy in porcine alveolar macrophages through the JNK and Akt signalling pathways; conversely, incomplete autophagy prevented M. hyopneumoniae from entering and degrading lysosomes to realize the proliferation of M. hyopneumoniae in porcine alveolar macrophages. These findings raise the possibility that targeting the autophagic pathway may be effective for the prevention or treatment of M. hyopneumoniae infection.

Keywords:  LC3; autophagosome; immunofluorescence assay; pig; porcine alveolar macrophage

DOI:  https://doi.org/10.1186/s13567-022-01074-5
J Cell Sci. 2022 Aug 01. pii: jcs.259988. [Epub ahead of print]

Roles of phosphatidylserine and phospholipase C in the activation of TOR complex 2 signaling in Saccharomyces cerevisiae.

Wataru Nomura, Su-Ping Ng, Terunao Takahara, Tatsuya Maeda, Teruo Kawada, Tsuyoshi Goto, Yoshiharu Inoue.

  The target of rapamycin (TOR) forms two distinct complexes, TORC1 and TORC2, to exert its functions essential for cellular growth and homeostasis. TORC1 signaling is regulated in response to nutrients such as amino acids and glucose; however, the mechanisms underlying the activation of TORC2 signaling are still poorly understood compared to TORC1 signaling. In the budding yeast Saccharomyces cerevisiae, TORC2 targets protein kinases Ypk1, Ypk2, and Pkc1 for phosphorylation. Plasma membrane stress is known to activate the TORC2-Ypk1/2 signaling. We have previously reported that methylglyoxal (MG), a metabolite derived from glycolysis, activates TORC2-Pkc1 signaling. In this study, we found that MG activates the TORC2-Ypk1/2 and TORC2-Pkc1 signaling, and that phosphatidylserine is involved in the activation of both signaling pathways. We also demonstrated that the Rho-family GTPase Cdc42 contributes to the plasma membrane stress-induced activation of TORC2-Ypk1/2 signaling. Furthermore, we revealed that phosphatidylinositol-specific phospholipase C, Plc1, contributes to the activation of both TORC2-Ypk1/2 and TORC2-Pkc1 signaling.

Keywords:  Phosphatidylserine; Phospholipase C; Signaling; TORC2; Yeast

DOI:  https://doi.org/10.1242/jcs.259988
Front Endocrinol (Lausanne). 2022 ;13 926622

A Highly Selective GSK-3β Inhibitor CHIR99021 Promotes Osteogenesis by Activating Canonical and Autophagy-Mediated Wnt Signaling.

Bo Wang, Saima Khan, Pengtao Wang, Xiaofang Wang, Yangxi Liu, Jingjing Chen, Xiaolin Tu.

  The discovery and application of small molecules is one of the practical strategies of safe osteogenic drugs. The small molecule CHIR99021 (C91) is a highly specific, safe, and most effective GSK-3β Inhibitor. This study found that it efficiently activates the canonical Wnt signaling of bone marrow stromal cell ST2 and promotes osteoblast differentiation and mineralization. C91 increases the production and biochemical activity of osteoblast marker alkaline phosphatase, the expression of osteoblast marker genes Alpl, Bglap, Runx2, and Sp7, and the formation of bone nodules. Triptonide is a transcription inhibitor of Wnt target gene, which diminishes C91-induced osteoblast differentiation in a dose-dependent manner. Meanwhile, C91 also induces autophagy through autophagosome formation and conversion of autophagy biomarker LC-3I into LC-3II. Autophagy inhibitor 3MA partially reduces C91-induced osteoblast differentiation and mineralization; autophagy inducer Rapamycin increases the expression of β-catenin to promote osteogenic differentiation, but cannot alleviate the inhibition of Triptonide on C91-induced osteogenic differentiation, indicating the crosstalk of canonical Wnt signaling and autophagy regulates C91-induced osteoblast differentiation. Furthermore, in order to simulate the in vivo detection of C91 in osteogenesis process, we made a C91 slow-release hydrogel with our newly established polycaprolactone and cell-integrated 3D printing system (PCCI3D module). The sustained release C91 promotes the differentiation and mineralization of ST2 cells. C91 can also enhance the proliferative activity of ST2 cells. The release rate of C91 from hydrogel gradually decreases within 7 days. During this period, the C91 is released by 83.0% and the cell viability maintained at 96.4%. Therefore, the small molecule Wnt agonist C91 promotes osteogenesis through caonical and autophagy-mediated Wnt signaling pathway with an option for translational application.

Keywords:  CHIR99021; PCL scaffold; Wnt/β-catenin signaling; autophagy; integrated 3D printing; osteoblast differentiation; osteoporosis; slow-release hydrogel

DOI:  https://doi.org/10.3389/fendo.2022.926622
Neurobiol Dis. 2022 Jul 28. pii: S0969-9961(22)00223-6. [Epub ahead of print] 105831

Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus.

Ozan Baytas, Julie A Kauer, Eric M Morrow.

  Locus coeruleus (LC) is among the first brain areas to degenerate in Alzheimer's disease and. Parkinson's disease; however, the underlying causes for the vulnerability of LC neurons are not well defined. Here we report a novel mechanism of degeneration of LC neurons caused by loss of the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). GPT2 Deficiency is a newly-recognized childhood neurometabolic disorder. The GPT2 enzyme regulates cell growth through replenishment of tricarboxylic acid (TCA) cycle intermediates and modulation of amino acid metabolism. In Gpt2-null mice, we observe an early loss of tyrosine hydroxylase (TH) positive neurons in LC and reduced soma size at postnatal day 18. Gpt2-null LC shows selective positive Fluoro-Jade C staining. Neuron loss is accompanied by selective, prominent microgliosis and astrogliosis in LC. We observe reduced noradrenergic projections to and norepinephrine levels in hippocampus and spinal cord. Whole cell recordings in Gpt2-null LC slices show reduced soma size and abnormal action potentials with altered firing kinetics. Strikingly, we observe early decreases in phosphorylated S6 in Gpt2-null LC, preceding prominent p62 aggregation, increased LC3B-II to LC3B-I ratio, and neuronal loss. These data are consistent with a possible mechanism involving deficiency in protein synthesis and cell growth, associated subsequently with abnormal autophagy and neurodegeneration. As compared to the few genetic animal models with LC degeneration, loss of LC neurons in Gpt2-null mice is developmentally the earliest. Early neuron loss in LC in a model of human neurometabolic disease provides important clues regarding the metabolic vulnerability of LC and may lead to new therapeutic targets.

Keywords:  Autophagy; GPT2; Locus coeruleus; Neurodegeneration; Neurogenetics; Neurometabolism; Proteostasis; Selective vulnerability

DOI:  https://doi.org/10.1016/j.nbd.2022.105831
EMBO Rep. 2022 Aug 01. e53234

Lysosomal K+ channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's disease.

Lili Qu, Bingqian Lin, Wenping Zeng, Chunhong Fan, Haotian Wu, Yushu Ge, Qianqian Li, Canjun Li, Yanan Wei, Jing Xin, Xingbing Wang, Dan Liu, Chunlei Cang.

  Lysosomes are degradative organelles and play vital roles in a variety of cellular processes. Ion channels on the lysosomal membrane are key regulators of lysosomal function. TMEM175 has been identified as a lysosomal potassium channel, but its modulation and physiological functions remain unclear. Here, we show that the apoptotic regulator Bcl-2 binds to and inhibits TMEM175 activity. Accordingly, Bcl-2 inhibitors activate the channel in a caspase-independent way. Increased TMEM175 function inhibits mitophagy, disrupts mitochondrial homeostasis, and increases production of reactive oxygen species (ROS). ROS further activates TMEM175 and thus forms a positive feedback loop to augment apoptosis. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), knockout (KO) of TMEM175 mitigated motor impairment and dopaminergic (DA) neuron loss, suggesting that TMEM175-mediated apoptosis plays an important role in Parkinson's disease (PD). Overall, our study reveals that TMEM175 is an important regulatory site in the apoptotic signaling pathway and a potential therapeutic target for Parkinson's disease (PD).

Keywords:  Parkinson's disease; TMEM175; apoptosis; lysosome; potassium channel

DOI:  https://doi.org/10.15252/embr.202153234
Biol Reprod. 2022 Jul 31. pii: ioac151. [Epub ahead of print]

Decreased expression of GRIM-19 induces autophagy through the AMPK/ULK1 signaling pathway during adenomyosis.

YuFei Huang, Yue Zhao, HaoRan Liu, Yang Yang, LaiYang Cheng, XiaoHui Deng, Lan Chao.

  The processes underlying adenomyosis are similar to those of tumor metastasis, and it is defined as progressive invasion by the endometrium and the subsequent creation of ectopic lesions. GRIM-19 regulates cell death via the mitochondrial respiratory chain. Stress following oxygen deprivation can induce tumor cell autophagy, leading to cell invasion and migration. Here, we revealed that GRIM-19 negatively regulates autophagy, and, at least in adenomyosis, decreased expression of GRIM-19 is accompanied by an increased level of autophagy and 5'-adenosine monophosphate-activated protein kinase-Unc-51 like autophagy activating kinase 1 (AMPK-ULK1) activation. Upregulation of GRIM-19 expression in human primary endometrial cells and ISHIKAWA cells inhibits autophagy via the AMPK-ULK1 pathway and helps control cell invasion and migration. In addition, we also identified increased expression of AMPK and ULK1, and higher levels of autophagy in the uterine tissues of GRIM-19+/- mice. Importantly, the function of the GRIM-19-AMPK-ULK1 axis in regulating autophagy in adenomyosis is similar to that of tumor tissues, which may help elucidate the regulation of adenomyosis tumor-like behavior, and is expected to help identify novel targets for the diagnosis and treatment of adenomyosis.

Keywords:  AMPK; Adenomyosis; Autophagy; GRIM-19; GRIM-19+/− mice; ULK1

DOI:  https://doi.org/10.1093/biolre/ioac151
EMBO J. 2022 Aug 03. e112180

Feeding and lipophagy: it takes guts to deliver.

Nuno Raimundo.

Refeeding after a period of starvation is known to suppress autophagy in the liver. Surprising new work by Seok et al (2022) shows that refeeding activates lipophagy in the intestine, which may help fats in our diet to be efficiently processed after a meal.

DOI: https://doi.org/10.15252/embj.2022112180
J Cell Biochem. 2022 Aug 04.

Mitochondria, mitophagy, and the role of deubiquitinases as novel therapeutic targets in liver pathology.

Elham Aryapour, Thomas Kietzmann.

  Liver diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) have increased over the past few decades due to the absence or ineffective therapeutics. Recently, it has been shown that inappropriate regulation of hepatic mitophagy is linked to the pathogenesis of the above-mentioned liver diseases. As mitophagy maintains cellular homeostasis by removing damaged and nonfunctional mitochondria from the cell, the proper function of the molecules involved are of utmost importance. Thereby, mitochondrial E3 ubiquitin ligases as well as several deubiquitinases (DUBs) appear to play a unique role for the degradation of mitochondrial proteins and for proper execution of the mitophagy process by either adding or removing ubiquitin chains from target proteins. Therefore, these enzymes could be considered as valuable liver disease biomarkers and also as novel targets for therapy. In this review, we focus on the role of different DUBs on mitophagy and their contribution to NAFLD, NASH, alcohol-related liver disease, and especially HCC.

Keywords:  DUBs; HIF; NAFLD; NASH; cancer; liver; mitophagy; ubiquitylation

DOI:  https://doi.org/10.1002/jcb.30312
Front Cell Dev Biol. 2022 ;10 876147

Neutrophil extracellular traps-mediated Beclin-1 suppression aggravates atherosclerosis by inhibiting macrophage autophagy.

Masataka Sano, Yasuhiro Maejima, Shun Nakagama, Yuka Shiheido-Watanabe, Natsuko Tamura, Kenzo Hirao, Mitsuaki Isobe, Tetsuo Sasano.

  A growing body of evidence suggests that neutrophil extracellular traps (NETs) critically contribute to the development of atherosclerosis. However, the detailed mechanism of how NETs promote atherogenesis remains unknown. In this study, we explored the role of NETs for promoting atherosclerosis by modulating the activity of autophagy in macrophages. NETs were effectively induced by a nicotine administration to the HL-60 cell-derived neutrophil-like cells. Treatment with NETs markedly suppressed both autophagosome formation and autophagosome-lysosome fusion in 7-ketocholesterol-treated macrophages, which are accompanied by the enhancement of inflammasome activity. NETs upregulate epidermal growth factor receptor (EGFR) activity, which enhances Beclin-1 phosphorylation of the tyrosine residues of Beclin-1 by EGFR, inhibits the PI3 kinase activity of the Beclin1-Vps34 complex, and suppresses autophagosome formation in macrophages. Furthermore, NET-induced activation of EGFR allows Rubicon to increase its expression, thereby suppressing autophagosome-lysosome fusion. In vivo experiments revealed that the suppression of NET formation by ablating peptidyl arginine deiminase-4 in neutrophil leukocytes resulted in the attenuation of atherosclerotic plaques in a nicotine-administered HFD-fed ApoE -/- mice. Taken together, these results suggest that NET-mediated EGFR-Beclin-1 signaling in the macrophages promotes atherogenesis by autophagy inhibition-mediated inflammasome activation.

Keywords:  Beclin 1; atheroscelrosis; autophagy; macrophage; neutrophil extracelluar traps

DOI:  https://doi.org/10.3389/fcell.2022.876147
Biomater Adv. 2022 Jul;pii: S2772-9508(22)00153-4. [Epub ahead of print]138 212876

A novel nanoparticle system targeting damaged mitochondria for the treatment of Parkinson's disease.

Yue Chen, Bosong Zhang, Lina Yu, Jinyu Zhang, Yufang Zhao, Lifen Yao, Hongji Yan, Weiming Tian.

  Mitochondrial damage is one of the primary causes of neuronal cell death in Parkinson's disease (PD). In PD patients, the mitochondrial damage can be repaired or irreversible. Therefore, mitochondrial damage repair becomes a promising strategy for PD treatment. In this research, hyaluronic acid nanoparticles (HA-NPs) of different molecular weights are used to protect the mitochondria and salvage the mild and limited damage in mitochondria. The HA-NPs with 2190 k Dalton (kDa) HA can improve the mitochondrial function of SH-SY5Y cells and PTEN induced putative kinase 1 (PINK1) knockout mouse embryo fibroblast (MEF) cells. In cases of irreversible damage, NPs with ubiquitin specific peptidase 30 (USP30) siRNA are used to promote mitophagy. Meanwhile, by adding PINK1 antibodies, the NPs can selectively target the irreversibly damaged mitochondria, preventing the excessive clearance of healthy mitochondria.

Keywords:  Hyaluronic acid; Nanoparticles; PINK1 antibody; Parkinson's disease; USP30 siRNA

DOI:  https://doi.org/10.1016/j.bioadv.2022.212876
Nat Commun. 2022 Aug 01. 13(1): 4444

Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy.

Annie Lee, Chandana Kondapalli, Daniel M Virga, Tommy L Lewis, So Yeon Koo, Archana Ashok, Georges Mairet-Coello, Sebastien Herzig, Marc Foretz, Benoit Viollet, Reuben Shaw, Andrew Sproul, Franck Polleux.

During the early stages of Alzheimer's disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β 1-42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble amyloid plaques. In a transgenic AD mouse model, we observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites corresponding to the dendritic domain where the earliest synaptic loss is detected in vivo. We also observed AMPK over-activation as well as increased fragmentation and loss of mitochondrial biomass in Ngn2-induced neurons derived from a new APPSwe/Swe knockin human ES cell line. We demonstrate that Aβ42o-dependent over-activation of the CAMKK2-AMPK kinase dyad mediates synaptic loss through coordinated phosphorylation of MFF-dependent mitochondrial fission and ULK2-dependent mitophagy. Our results uncover a unifying stress-response pathway causally linking Aβ42o-dependent structural remodeling of dendritic mitochondria to synaptic loss.

DOI: https://doi.org/10.1038/s41467-022-32130-5
Nat Commun. 2022 Aug 01. 13(1): 4462

Highly conserved shifts in ubiquitin-proteasome system (UPS) activity drive mitochondrial remodeling during quiescence.

Sibiao Yue, Lei Wang, George N DeMartino, FangZhou Zhao, Yi Liu, Matthew H Sieber.

Defects in cellular proteostasis and mitochondrial function drive many aspects of infertility, cancer, and other age-related diseases. All of these conditions rely on quiescent cells, such as oocytes and adult stem cells, that reduce their activity and remain dormant as part of their roles in tissue homeostasis, reproduction, and even cancer recurrence. Using a multi-organism approach, we show that dynamic shifts in the ubiquitin proteasome system drive mitochondrial remodeling during cellular quiescence. In contrast to the commonly held view that the ubiquitin-proteasome system (UPS) is primarily regulated by substrate ubiquitination, we find that increasing proteasome number and their recruitment to mitochondria support mitochondrial respiratory quiescence (MRQ). GSK3 triggers proteasome recruitment to the mitochondria by phosphorylating outer membrane proteins, such as VDAC, and suppressing mitochondrial fatty acid oxidation. This work defines a process that couples dynamic regulation of UPS activity to coordinated shifts in mitochondrial metabolism in fungi, Drosophila, and mammals during quiescence.

DOI: https://doi.org/10.1038/s41467-022-32206-2
Diabetes Metab J. 2022 Jul;46(4): 533-542

Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells.

Seoil Moon, Hye Seung Jung.

  Pancreatic beta cell homeostasis is crucial for the synthesis and secretion of insulin; disruption of homeostasis causes diabetes, and is a treatment target. Adaptation to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR) and adequate regulation of autophagy, which are closely linked, play essential roles in this homeostasis. In diabetes, the UPR and autophagy are dysregulated, which leads to beta cell failure and death. Various studies have explored methods to preserve pancreatic beta cell function and mass by relieving ER stress and regulating autophagic activity. To promote clinical translation of these research results to potential therapeutics for diabetes, we summarize the current knowledge on ER stress and autophagy in human insulin-secreting cells.

Keywords:  Autophagy; Diabetes mellitus; Endoplasmic reticulum stress; Humans; Insulin secretion; Insulin-secreting cells; Unfolded protein response

DOI:  https://doi.org/10.4093/dmj.2022.0070
Biochem Biophys Res Commun. 2022 Jul 20. pii: S0006-291X(22)01046-4. [Epub ahead of print]623 170-175

Involvement of autophagic protein DEF8 in Lewy bodies.

Makoto Timon Tanaka, Yasuo Miki, Conceição Bettencourt, Taku Ozaki, Kunikazu Tanji, Fumiaki Mori, Akiyoshi Kakita, Koichi Wakabayashi.

  Dysregulation of autophagy, one of the major processes through which abnormal proteins are degraded, is a cardinal feature of synucleinopathies, including Lewy body diseases [Parkinson's disease (PD) and dementia with Lewy bodies (DLB)] and multiple system atrophy (MSA), which are characterized by the presence of abnormal α-synuclein in neurons and glial cells. Although several research groups have reported that Rubicon family proteins can regulate autophagosome-lysosome fusion or positioning, little is known about their involvement in synucleinopathies. In the present study, by studying patients with PD (N = 8), DLB (N = 13), and MSA (N = 5) and controls (N = 16), we explored the involvement of Rubicon family proteins [Rubicon, Pacer and differentially expressed in FDCP8 (DEF8)] in synucleinopathies. Immunohistochemical analysis showed that not only brainstem-type Lewy bodies but also cortical Lewy bodies were immunoreactive for DEF8 in Lewy body diseases, whereas Rubicon and Pacer were detectable in only a few brainstem-type Lewy bodies in PD. Glial cytoplasmic inclusions in patients with MSA were not immunoreactive for Rubicon, Pacer or DEF8. Immunoblotting showed significantly increased protein levels of DEF8 in the substantia nigra and putamen of patients with PD and the temporal cortex of patients with DLB. In addition, the smear band of DEF8 appeared in the insoluble fraction where that of phosphorylated α-synuclein was detected. These findings indicate the involvement of DEF8 in the formation of Lewy bodies. Quantitative and qualitative alterations in DEF8 may reflect the dysregulation of autophagy in Lewy body diseases.

Keywords:  Autophagy; DEF8; Dementia with Lewy bodies; Parkinson's disease; Synucleinopathy; α-synuclein

DOI:  https://doi.org/10.1016/j.bbrc.2022.07.069
Front Mol Biosci. 2022 ;9 851966

Bibliometric Insights of Global Research Landscape in Mitophagy.

Guoli Li, Wei Yin, Yiya Yang, Hongyu Yang, Yinyin Chen, Yumei Liang, Weiru Zhang, Tingting Xie.

  Background: Autophagy is a highly regulated and evolutionarily conserved process in eukaryotes which is responsible for protein and organelle degradation. Although this process was described over 60 years ago, the selective autophagy of mitochondria (mitophagy) was recently coined in 2005. Research on the topic of mitophagy has made rapid progress in the past decade, which proposed to play critical roles in human health and disease. This study aimed to visualize the scientific outputs and research trends of mitophagy. Methods: Articles and reviews related to the topic of mitophagy were retrieved from the Web of Science Core Collection on 30 November 2021. Two kinds of software (CiteSpace and VOSviewer) were used to perform a visualized analysis of countries/regions, institutions, authors, journals, references, and keywords. Results: From 2005 to 2021, total 5844 publications on mitophagy were identified for final analysis. The annual number of publications grew yearly over the past 17 years. United States (N = 2025) and Chinese Academy of Sciences is the leading country and institute (N = 112) ranked by the number of publications, respectively. The most productive author was Jun Ren (N = 38) and Derek P. Narendra obtained the most co-cited times (2693 times). The journals with the highest output and the highest co-citation frequency were Autophagy (N = 208) and Journal of Biological Chemistry (co-citation: 17226), respectively. Analyses of references and keywords suggested that "mechanism of mitochondrial quality control", "molecule and signaling pathway in mitophagy", and "mitophagy related diseases" were research hotspots, and parkin-mediated mitophagy and its roles in skeletal muscle and inflammation-related diseases may be the frontiers of future research. Conclusion: Although mitophagy research has flourished and attracted attention from all over the world, the regional imbalance in the development of mitophagy research was observed. Our results provided a comprehensive global research landscape of mitophagy from 2005- 2021 from a perspective of bibliometrics, which may serve as a reference for future mitophagy studies.

Keywords:  CiteSpace; VOSviewer; bibliometric analysis; mitophagy; visualization

DOI:  https://doi.org/10.3389/fmolb.2022.851966
Free Radic Biol Med. 2022 Jul 30. pii: S0891-5849(22)00499-3. [Epub ahead of print]

GSNOR deficiency attenuates MPTP-induced neurotoxicity and autophagy by facilitating CDK5 S-nitrosation in a mouse model of Parkinson's disease.

Lijin Jiao, Ling-Yan Su, Qianjin Liu, Rongcan Luo, Xinhua Qiao, Ting Xie, Lu-Xiu Yang, Chang Chen, Yong-Gang Yao.

  The S-nitrosoglutathione reductase (GSNOR) is a key denitrosylating enzyme that regulates protein S-nitrosation, a process which has been found to be involved in the pathogenesis of Parkinson's disease (PD). However, the physiological function of GSNOR in PD remains unknown. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, we found that GSNOR expression was significantly increased and accompanied by autophagy mediated by MPTP-induced cyclin dependent kinase 5 (CDK5), behavioral dyskinesias and dopaminergic neuron loss. Whereas, knockout of GSNOR, or treatment with the GSNOR inhibitor N6022, alleviated MPTP-induced PD-like pathology and neurotoxicity. Mechanistically, deficiency of GSNOR inhibited MPTP-induced CDK5 kinase activity and CDK5-mediated autophagy by increasing S-nitrosation of CDK5 at Cys83. Our study indicated that GSNOR is a key regulator of CDK5 S-nitrosation and is actively involved in CDK5-mediated autophagy induced by MPTP.

Keywords:  Autophagy; CDK5; GSNOR; Parkinson's disease; S-nitrosation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.07.016
Mol Cell. 2022 Aug 04. pii: S1097-2765(22)00545-7. [Epub ahead of print]82(15): 2732-2734

The IRG1/itaconate/TFEB axis: A new weapon in macrophage antibacterial defense.

José A Martina, Rosa Puertollano.

Zhang et al. (2022) report that itaconate, a mitochondrial metabolite produced by macrophages upon inflammatory stimuli, activates the master regulator of lysosomal biogenesis TFEB to facilitate clearance of invading bacteria and efficient immune response.

DOI: https://doi.org/10.1016/j.molcel.2022.06.009