bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2022‒03‒13
forty-five papers selected by
Viktor Korolchuk, Newcastle University
  1. Celastrol, a TFEB (transcription factor EB) agonist, is a promising drug candidate for Alzheimer disease.
  2. The V-ATPase complex regulates non-canonical Atg8-family protein lipidation through ATG16L1 recruitment.
  3. Lamp1 mediates lipid transport, but is dispensable for autophagy in Drosophila.
  4. KAT7-mediated CANX (calnexin) crotonylation regulates leucine-stimulated MTORC1 activity.
  5. Autophagy-mediated plasma membrane removal promotes the formation of epithelial syncytia.
  6. Iron chelation promotes mitophagy through SENP3-mediated deSUMOylation of FIS1.
  7. ULK1 Signaling in the Liver: Autophagy Dependent and Independent Actions.
  8. The Interplay between Autophagy and Virus Pathogenesis-The Significance of Autophagy in Viral Hepatitis and Viral Hemorrhagic Fevers.
  9. Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease).
  10. BAG family proteins contributes to autophagy-mediated multidrug resistance of tumor.
  11. OSBPL2 mutations impair autophagy and lead to hearing loss, potentially remedied by rapamycin.
  12. Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson's Disease.
  13. Golgi quality control and autophagy.
  14. The emerging roles of ATG1/ATG13 kinase complex in plants.
  15. Role of autophagy and transcriptome regulation in acute brain injury.
  16. Peroxiredoxin 3 deficiency induces cardiac hypertrophy and dysfunction by impaired mitochondrial quality control.
  17. Incomplete autophagy: Trouble is a friend.
  18. Substrate-specific presentation of MHC class I-restricted antigens via autophagy pathway.
  19. Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism.
  20. Targeting autophagy, oxidative stress, and ER stress for neurodegenerative diseases treatment.
  21. The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis-Frontotemporal Dementia.
  22. α-synuclein and phosphoinositide-binding proteins: α-synuclein inhibits the association of PX- but not FYVE-containing proteins with vesicles in vivo.
  23. Mitochondria-lysosome contact site dynamics and misregulation in neurodegenerative diseases.
  24. Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.
  25. Therapeutic targeting of the USP2-E2F4 axis inhibits autophagic machinery essential for zinc homeostasis in cancer progression.
  26. TRAF6 autophagic degradation by avibirnavirus VP3 inhibits antiviral innate immunity via blocking NFKB/NF-κB activation.
  27. Dysregulation of mTOR Signaling after Brain Ischemia.
  28. FAM134B-mediated ER-phagy alleviates endoplasmic reticulum stress of rat soleus muscle in response to acute exercise.
  29. RTN4/Nogo-A-S1PR2 negatively regulates angiogenesis and secondary neural repair through enhancing vascular autophagy in the thalamus after cerebral cortical infarction.
  30. Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress.
  31. Maintaining Golgi Homeostasis: A Balancing Act of Two Proteolytic Pathways.
  32. Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.
  33. Autophagy-Inflammation Interplay During Infection: Balancing Pathogen Clearance and Host Inflammation.
  34. Energy deprivation-induced AMPK activation inhibits milk synthesis by targeting PrlR and PGC-1α.
  35. GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage.
  36. The Mitochondrial Deubiquitinase USP30 Regulates AKT/mTOR Signaling.
  37. Annexins A1 and A2 are recruited to larger lysosomal injuries independently of ESCRTs to promote repair.
  38. SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation.
  39. Chaperone-mediated Autophagy Regulates Cell Growth by Targeting SMAD3 in Glioma.
  40. Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.
  41. Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy.
  42. Modulation of Intestinal Epithelial Permeability via Protease-Activated Receptor-2-Induced Autophagy.
  43. Lipophagy at a glance.
  44. A light-inducible protein clustering system for in vivo analysis of α-synuclein aggregation in Parkinson disease.
  45. Tsc2 knockout counteracts ubiquitin-proteasome system insufficiency and delays photoreceptor loss in retinitis pigmentosa.
  1. Autophagy. 2022 Mar 06. 1-3
    Celastrol, a TFEB (transcription factor EB) agonist, is a promising drug candidate for Alzheimer disease.
    Wei Zhang, Jigang Wang, Chuanbin Yang.
      Alzheimer disease (AD) is the most common neurodegenerative disease. Unfortunately, current effective therapeutics for AD are limited and thus the discovery of novel anti-AD agents is urgently needed. A key pathological hallmark of AD is the accumulation of phosphorylated MAPT/tau (microtubule associated protein tau) aggregates to form neurofibrillary tangles. Autophagy is a conserved catabolic process that degrades protein aggregates or organelles via lysosomes. TFEB (transcription factor EB), a master regulator of autophagy, transcriptionally regulates multiple autophagy, and lysosomal-related genes. A compromised autophagy-lysosomal pathway (ALP) has been implicated in AD progression, and enhancing TFEB-mediated ALP to degrade MAPT/tau aggregates is a promising anti-AD strategy. In a recent study, we showed that celastrol, a natural small molecule with an anti-obesity effect, is a novel TFEB activator, which enhances autophagy and lysosomal biogenesis both in vitro and in animal brains. Consequently, celastrol promotes the degradation of phosphorylated MAPT/tau aggregates both in cells and in the brain of P301S MAPT/tau and 3XTg mice, two commonly used AD animal models. Interestingly, celastrol also alleviates memory deficits in these mice. Altogether, celastrol enhances TFEB-mediated autophagy and lysosomal biogenesis to ameliorate MAPT/tau pathology, suggesting that celastrol represents a novel anti-AD and other tauopathies drug candidate.Abbreviations: AD: Alzheimer disease; ALP: autophagy-lysosomal pathway; MAPT/tau: microtubule-associated protein tau; MTORC1: mechanistic target of rapamycin kinase complex 1; TFEB: transcription factor EB.
    Keywords:  Alzheimer disease; MTOR; TFEB; autophagy; celastrol; lysosome; tau
    DOI:  https://doi.org/10.1080/15548627.2022.2046437
  2. Autophagy. 2022 Mar 08. 1-2
    The V-ATPase complex regulates non-canonical Atg8-family protein lipidation through ATG16L1 recruitment.
    Lewis Timimi, Carmen Figueras-Novoa, Elena Marcassa, Oliver Florey, J Kenneth Baillie, Rupert Beale, Rachel Ulferts.
      Conjugation of the Atg8 (autophagy related 8) family of ubiquitin-like proteins to phospholipids of the phagophore is a hallmark of macroautophagy/autophagy. Consequently, Atg8 family members, especially LC3B, are commonly used as a marker of autophagosomes. However, the Atg8 family of proteins are not found solely attached to double-membrane autophagosomes. In non-canonical Atg8-family protein lipidation they become conjugated to single membranes. We have shown that this process is triggered by recruitment of ATG16L1 by the vacuolar-type H+-translocating ATPase (V-ATPase) proton pump, suggesting a role for pH sensing in recruitment of Atg8-family proteins to single membranes.
    Keywords:  ATG16L1; Atg4; Atg8; CASM; SopF; V-ATPase; influenza; lipidation; non-canonical autophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2029233
  3. Autophagy. 2022 Mar 10. 1-16
    Lamp1 mediates lipid transport, but is dispensable for autophagy in Drosophila.
    Norin Chaudhry, Margaux Sica, Satya Surabhi, David Sanchez Hernandez, Ana Mesquita, Adem Selimovic, Ayesha Riaz, Laury Lescat, Hua Bai, Gustavo C Macintosh, Andreas Jenny.
      The endolysosomal system not only is an integral part of the cellular catabolic machinery that processes and recycles nutrients for synthesis of biomaterials, but also acts as signaling hub to sense and coordinate the energy state of cells with growth and differentiation. Lysosomal dysfunction adversely influences vesicular transport-dependent macromolecular degradation and thus causes serious problems for human health. In mammalian cells, loss of the lysosome associated membrane proteins LAMP1 and LAMP2 strongly affects autophagy and cholesterol trafficking. Here we show that the previously uncharacterized Drosophila Lamp1 is a bona fide ortholog of vertebrate LAMP1 and LAMP2. Surprisingly and in contrast to lamp1 lamp2 double-mutant mice, Drosophila Lamp1 is not required for viability or autophagy, suggesting that fly and vertebrate LAMP proteins acquired distinct functions, or that autophagy defects in lamp1 lamp2 mutants may have indirect causes. However, Lamp1 deficiency results in an increase in the number of acidic organelles in flies. Furthermore, we find that Lamp1 mutant larvae have defects in lipid metabolism as they show elevated levels of sterols and diacylglycerols (DAGs). Because DAGs are the main lipid species used for transport through the hemolymph (blood) in insects, our results indicate broader functions of Lamp1 in lipid transport. Our findings make Drosophila an ideal model to study the role of LAMP proteins in lipid assimilation without the confounding effects of their storage and without interfering with autophagic processes.Abbreviations: aa: amino acid; AL: autolysosome; AP: autophagosome; APGL: autophagolysosome; AV: autophagic vacuole (i.e. AP and APGL/AL); AVi: early/initial autophagic vacuoles; AVd: late/degradative autophagic vacuoles; Atg: autophagy-related; CMA: chaperone-mediated autophagy; Cnx99A: Calnexin 99A; DAG: diacylglycerol; eMI: endosomal microautophagy; ESCRT: endosomal sorting complexes required for transport; FB: fat body; HDL: high-density lipoprotein; Hrs: Hepatocyte growth factor regulated tyrosine kinase substrate; LAMP: lysosomal associated membrane protein; LD: lipid droplet; LDL: low-density lipoprotein; Lpp: lipophorin; LTP: Lipid transfer particle; LTR: LysoTracker Red; MA: macroautophagy; MCC: Manders colocalization coefficient; MEF: mouse embryonic fibroblast MTORC: mechanistic target of rapamycin kinase complex; PV: parasitophorous vacuole; SNARE: soluble N-ethylmaleimide sensitive factor attachment protein receptor; Snap: Synaptosomal-associated protein; st: starved; TAG: triacylglycerol; TEM: transmission electron microscopy; TFEB/Mitf: transcription factor EB; TM: transmembrane domain; tub: tubulin; UTR: untranslated region.
    Keywords:  Autophagy; Drosophila; LAMP proteins; lipid transport; lysosome
    DOI:  https://doi.org/10.1080/15548627.2022.2038999
  4. Autophagy. 2022 Mar 10. 1-18
    KAT7-mediated CANX (calnexin) crotonylation regulates leucine-stimulated MTORC1 activity.
    Guokai Yan, Xiuzhi Li, Zilong Zheng, Weihua Gao, Changqing Chen, Xinkai Wang, Zhongyi Cheng, Jie Yu, Geng Zou, Muhammad Zahid Farooq, Xiaoyan Zhu, Weiyun Zhu, Qing Zhong, Xianghua Yan.
      Amino acids play crucial roles in the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) pathway. However, the underlying mechanisms are not fully understood. Here, we establish a cell-free system to mimic the activation of MTORC1, by which we identify CANX (calnexin) as an essential regulator for leucine-stimulated MTORC1 pathway. CANX translocates to lysosomes after leucine deprivation, and its loss of function renders either the MTORC1 activity or the lysosomal translocation of MTOR insensitive to leucine deprivation. We further find that CANX binds to LAMP2 (lysosomal associated membrane protein 2), and LAMP2 is required for leucine deprivation-induced CANX interaction with the Ragulator to inhibit Ragulator activity toward RRAG GTPases. Moreover, leucine deprivation promotes the lysine (K) 525 crotonylation of CANX, which is another essential condition for the lysosomal translocation of CANX. Finally, we find that KAT7 (lysine acetyltransferase 7) mediates the K525 crotonylation of CANX. Loss of KAT7 renders the MTORC1 insensitivity to leucine deprivation. Our findings provide new insights for the regulatory mechanism of the leucine-stimulated MTORC1 pathway.
    Keywords:  CANX; KAT7; LAMP2; MTORC1; leucine; lysine crotonylation; ragulator
    DOI:  https://doi.org/10.1080/15548627.2022.2047481
  5. EMBO J. 2022 Mar 09. e109992
    Autophagy-mediated plasma membrane removal promotes the formation of epithelial syncytia.
    Parisa Kakanj, Sourabh Bhide, Bernard Moussian, Maria Leptin.
      Epithelial wound healing in Drosophila involves the formation of multinucleate cells surrounding the wound. We show that autophagy, a cellular degradation process often deployed in stress responses, is required for the formation of a multinucleated syncytium during wound healing, and that autophagosomes that appear near the wound edge acquire plasma membrane markers. In addition, uncontrolled autophagy in the unwounded epidermis leads to the degradation of endo-membranes and the lateral plasma membrane, while apical and basal membranes and epithelial barrier function remain intact. Proper functioning of TORC1 is needed to prevent destruction of the larval epidermis by autophagy, in a process that depends on phagophore initiation and expansion but does not require autophagosomes fusion with lysosomes. Autophagy induction can also affect other sub-cellular membranes, as shown by its suppression of experimentally induced laminopathy-like nuclear defects. Our findings reveal a function for TORC1-mediated regulation of autophagy in maintaining membrane integrity and homeostasis in the epidermis and during wound healing.
    Keywords:  cell junction; gut barrier; myosin; nuclear morphology; wound healing
    DOI:  https://doi.org/10.15252/embj.2021109992
  6. Autophagy. 2022 Mar 11. 1-3
    Iron chelation promotes mitophagy through SENP3-mediated deSUMOylation of FIS1.
    Kevin A Wilkinson, Chun Guo.
      The selective clearance of mitochondria by mitophagy is an important quality control mechanism for maintaining mitochondrial and cellular health. Iron chelation, for example by the compound deferiprone (DFP), leads to a specific form of PINK1-PRKN/Parkin-independent mitophagy; however, the molecular mechanisms underlying this are poorly understood. In our recent paper, we examined the role of the deSUMOylating enzyme SENP3 in DFP-induced mitophagy. We observed that SENP3 levels are enhanced by DFP treatment, and that SENP3 is essential for DFP-induced mitophagy. Furthermore, we identified the mitochondrial protein FIS1, which is also required for DFP-induced mitophagy, as a novel SUMO substrate. Our data demonstrate that SENP3-dependent deSUMOylation of FIS1 enhances FIS1 mitochondrial targeting, to promote mitophagy in response to DFP treatment. These findings offer new insight into the mechanisms underlying mitophagy upon iron chelation, and have relevance to the therapeutic potential of DFP in a number of disorders, including Parkinson disease. Abbreviations DFP: deferiprone; OMM: outer mitochondrial membrane. PD: Parkinson disease; SUMO: small ubiquitin like modifier.
    Keywords:  FIS1; SENP3; SUMO; iron chelation; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2046898
  7. Front Cell Dev Biol. 2022 ;10 836021
    ULK1 Signaling in the Liver: Autophagy Dependent and Independent Actions.
    Sangam Rajak, Sana Raza, Rohit Anthony Sinha.
      Liver is the primary organ for energy metabolism and detoxification in the human body. Not surprisingly, a derangement in liver function leads to several metabolic diseases. Autophagy is a cellular process, which primarily deals with providing molecules for energy production, and maintains cellular health. Autophagy in the liver has been implicated in several hepatic metabolic processes, such as, lipolysis, glycogenolysis, and gluconeogenesis. Autophagy also provides protection against drugs and pathogens. Deregulation of autophagy is associated with the development of non-alcoholic fatty liver disease (NAFLD) acute-liver injury, and cancer. The process of autophagy is synchronized by the action of autophagy family genes or autophagy (Atg) genes that perform key functions at different steps. The uncoordinated-51-like kinases 1 (ULK1) is a proximal kinase member of the Atg family that plays a crucial role in autophagy. Interestingly, ULK1 actions on hepatic cells may also involve some autophagy-independent signaling. In this review, we provide a comprehensive update of ULK1 mediated hepatic action involving lipotoxicity, acute liver injury, cholesterol synthesis, and hepatocellular carcinoma, including both its autophagic and non-autophagic functions.
    Keywords:  ULK1; autophagy; hepatocellular carcinoma; liver; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.3389/fcell.2022.836021
  8. Cells. 2022 Mar 03. pii: 871. [Epub ahead of print]11(5):
    The Interplay between Autophagy and Virus Pathogenesis-The Significance of Autophagy in Viral Hepatitis and Viral Hemorrhagic Fevers.
    Dominika Bębnowska, Paulina Niedźwiedzka-Rystwej.
      Autophagy is a process focused on maintaining the homeostasis of organisms; nevertheless, the role of this process has also been widely documented in viral infections. Thus, xenophagy is a selective form of autophagy targeting viruses. However, the relation between autophagy and viruses is ambiguous-this process may be used as a strategy to fight with a virus, but is also in favor of the virus's replication. In this paper, we have gathered data on autophagy in viral hepatitis and viral hemorrhagic fevers and the relations impacting its viral pathogenesis. Thus, autophagy is a potential therapeutic target, but research is needed to fully understand the mechanisms by which the virus interacts with the autophagic machinery. These studies must be performed in specific research models other than the natural host for many reasons. In this paper, we also indicate Lagovirus europaeus virus as a potentially good research model for acute liver failure and viral hemorrhagic disease.
    Keywords:  Lagovirus europaeus; animal model; autophagy; rabbit hemorrhagic disease; viral hemorrhagic fever (VHF); viral hepatitis
    DOI:  https://doi.org/10.3390/cells11050871
  9. Front Cell Dev Biol. 2022 ;10 812728
    Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease).
    William D Kim, Morgan L D M Wilson-Smillie, Aruban Thanabalasingam, Stephane Lefrancois, Susan L Cotman, Robert J Huber.
      The neuronal ceroid lipofuscinoses (NCLs), also referred to as Batten disease, are a family of neurodegenerative diseases that affect all age groups and ethnicities around the globe. At least a dozen NCL subtypes have been identified that are each linked to a mutation in a distinct ceroid lipofuscinosis neuronal (CLN) gene. Mutations in CLN genes cause the accumulation of autofluorescent lipoprotein aggregates, called ceroid lipofuscin, in neurons and other cell types outside the central nervous system. The mechanisms regulating the accumulation of this material are not entirely known. The CLN genes encode cytosolic, lysosomal, and integral membrane proteins that are associated with a variety of cellular processes, and accumulated evidence suggests they participate in shared or convergent biological pathways. Research across a variety of non-mammalian and mammalian model systems clearly supports an effect of CLN gene mutations on autophagy, suggesting that autophagy plays an essential role in the development and progression of the NCLs. In this review, we summarize research linking the autophagy pathway to the NCLs to guide future work that further elucidates the contribution of altered autophagy to NCL pathology.
    Keywords:  Batten disease; autophagosome; autophagy; lysosome; mTOR; model system; neurodegeneration; neuronal ceroid lipofucinosis
    DOI:  https://doi.org/10.3389/fcell.2022.812728
  10. Clin Transl Oncol. 2022 Mar 12.
    BAG family proteins contributes to autophagy-mediated multidrug resistance of tumor.
    Jufang Guo, Xuelian Du, Chaolin Li.
      Multidrug resistance (MDR) is a significant cause of tumor treatment failure. Accumulating evidence suggests that autophagy plays a significant role in the development of MDR. Autophagy is a conserved mechanism that maintains tumor homeostasis by removing damaged mitochondria. However, the specific regulatory mechanism is unclear. Here, we summarize recent studies on the role of autophagy in the development of MDR and the initiation of mitophagy by Bcl-2-associated athanogene (BAG) family proteins. Additionally, this mini-review emphasizes the regulatory role of BAG family proteins, which maintain mitochondrial homeostasis by regulating the PINK1/Parkin pathway. Elucidation of the regulatory mechanisms of mitophagy may foster the development of clinical therapeutic strategies for MDR tumors.
    Keywords:  Autophagy; BAG; Mitochondria; Mitophagy; Multidrug resistance
    DOI:  https://doi.org/10.1007/s12094-022-02819-6
  11. Autophagy. 2022 Mar 06. 1-22
    OSBPL2 mutations impair autophagy and lead to hearing loss, potentially remedied by rapamycin.
    Young Ik Koh, Kyung Seok Oh, Jung Ah Kim, Byunghwa Noh, Hye Ji Choi, Sun Young Joo, John Hoon Rim, Hye-Youn Kim, Dong Yun Kim, Seyoung Yu, Da Hye Kim, Sang-Guk Lee, Jinsei Jung, Jae Young Choi, Heon Yung Gee.
      Intracellular accumulation of mutant proteins causes proteinopathies, which lack targeted therapies. Autosomal dominant hearing loss (DFNA67) is caused by frameshift mutations in OSBPL2. Here, we show that DFNA67 is a toxic proteinopathy. Mutant OSBPL2 accumulated intracellularly and bound to macroautophagy/autophagy proteins. Consequently, its accumulation led to defective endolysosomal homeostasis and impaired autophagy. Transgenic mice expressing mutant OSBPL2 exhibited hearing loss, but osbpl2 knockout mice or transgenic mice expressing wild-type OSBPL2 did not. Rapamycin decreased the accumulation of mutant OSBPL2 and partially rescued hearing loss in mice. Rapamycin also partially improved hearing loss and tinnitus in individuals with DFNA67. Our findings indicate that dysfunctional autophagy is caused by mutant proteins in DFNA67; hence, we recommend rapamycin for DFNA67 treatment.
    Keywords:  Autophagy; DFNA67; OSBPL2; hearing loss; rapamycin
    DOI:  https://doi.org/10.1080/15548627.2022.2040891
  12. Front Mol Neurosci. 2022 ;15 805087
    Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson's Disease.
    Denisse Sepúlveda, Marisol Cisternas-Olmedo, Javiera Arcos, Melissa Nassif, René L Vidal.
      Parkinson's disease (PD) is caused by the degeneration of dopaminergic neurons due to an accumulation of intraneuronal abnormal alpha-synuclein (α-syn) protein aggregates. It has been reported that the levels of exosomal α-syn of neuronal origin in plasma correlate significantly with motor dysfunction, highlighting the exosomes containing α-syn as a potential biomarker of PD. In addition, it has been found that the selective autophagy-lysosomal pathway (ALP) contributes to the secretion of misfolded proteins involved in neurodegenerative diseases. In this review, we describe the evidence that supports the relationship between the ALP and α-syn exosomal secretion on the PD progression and its implications in the diagnosis and progression of this pathology.
    Keywords:  Parkinson’s disease progression; autophagy-lysosomal pathway; biomarker; degradation; α-syn exosomal secretion
    DOI:  https://doi.org/10.3389/fnmol.2022.805087
  13. IUBMB Life. 2022 Mar 10.
    Golgi quality control and autophagy.
    Hsiang-Yi Chang, Wei Yuan Yang.
      Organelles can easily be disrupted by intracellular and extracellular factors. Studies on ER and mitochondria indicate that a wide range of responses are elicited upon organelle disruption. One response thought to be of particular importance is autophagy. Cells can target entire organelles into autophagosomes for removal. This wholesale nature makes autophagy a robust means for eliminating compromised organelles. Recently, it was demonstrated that the Golgi apparatus is a substrate of autophagy. On the other hand, various reports have shown that components traffic away from the Golgi for elimination in an autophagosome-independent manner when the Golgi apparatus is stressed. Future studies will reveal how these different pieces of machinery coordinate to drive Golgi degradation. Quantitative measurements will be needed to determine how much autophagy contributes to the maintenance of the Golgi apparatus.
    Keywords:  Golgi apparatus; Golgi fragmentation; Golgi-derived vesicles; autophagy; biogenesis; proteasome
    DOI:  https://doi.org/10.1002/iub.2611
  14. J Plant Physiol. 2022 Mar 02. pii: S0176-1617(22)00039-6. [Epub ahead of print]271 153653
    The emerging roles of ATG1/ATG13 kinase complex in plants.
    Qiuling Wang, Suiwen Hou.
      Autophagy is a conserved system from yeast to mammals that mediates the degradation and renovation of cellular components. This process is mainly driven by numerous autophagy-related (ATG) proteins. Among these components, the ATG1/ATG13 complex plays an essential role in initiating autophagy, sensing nutritional status signals, recruiting downstream ATG proteins to the autophagosome formation site, and governing autophagosome formation. In this review, we will focus on the ATG1/ATG13 kinase complex, summarizing and discussing the current views on the composition, structure, function, and regulation of this complex in plants.
    Keywords:  ATG1; ATG11; ATG13; Autophagy; Plants; Regulation
    DOI:  https://doi.org/10.1016/j.jplph.2022.153653
  15. Exp Neurol. 2022 Mar 05. pii: S0014-4886(22)00057-7. [Epub ahead of print] 114032
    Role of autophagy and transcriptome regulation in acute brain injury.
    Vijay Arruri, Raghu Vemuganti.
      Autophagy is an evolutionarily conserved intracellular system that routes distinct cytoplasmic cargo to lysosomes for degradation and recycling. Accumulating evidence highlight the mechanisms of autophagy, such as clearance of proteins, carbohydrates, lipids and damaged organelles. The critical role of autophagy in selective degradation of the transcriptome is still emerging and could shape the total proteome of the cell, and thus can regulate the homeostasis under stressful conditions. Unregulated autophagy that potentiates secondary brain damage is a key pathological features of acute CNS injuries such as stroke and traumatic brain injury. This review discussed the mutual modulation of autophagy and RNA and its significance in mediating the functional consequences of acute CNS injuries.
    Keywords:  Non-coding RNAs; RNautophagy; Stroke; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.expneurol.2022.114032
  16. Redox Biol. 2022 Feb 28. pii: S2213-2317(22)00047-7. [Epub ahead of print]51 102275
    Peroxiredoxin 3 deficiency induces cardiac hypertrophy and dysfunction by impaired mitochondrial quality control.
    Seong Keun Sonn, Eun Ju Song, Seungwoon Seo, Young Yeon Kim, Jee-Hyun Um, Franklin Joonyeop Yeo, Da Seul Lee, Sejin Jeon, Mi-Ni Lee, Jing Jin, Hyae Yon Kweon, Tae Kyeong Kim, Sinai Kim, Shin Hye Moon, Sue Goo Rhee, Jongkyeong Chung, Jaemoon Yang, Jin Han, Eui-Young Choi, Sung Bae Lee, Jeanho Yun, Goo Taeg Oh.
      Mitochondrial quality control (MQC) consists of multiple processes: the prevention of mitochondrial oxidative damage, the elimination of damaged mitochondria via mitophagy and mitochondrial fusion and fission. Several studies proved that MQC impairment causes a plethora of pathological conditions including cardiovascular diseases. However, the precise molecular mechanism by which MQC reverses mitochondrial dysfunction, especially in the heart, is unclear. The mitochondria-specific peroxidase Peroxiredoxin 3 (Prdx3) plays a protective role against mitochondrial dysfunction by removing mitochondrial reactive oxygen species. Therefore, we investigated whether Prdx3-deficiency directly leads to heart failure via mitochondrial dysfunction. Fifty-two-week-old Prdx3-deficient mice exhibited cardiac hypertrophy and dysfunction with giant and damaged mitochondria. Mitophagy was markedly suppressed in the hearts of Prdx3-deficient mice compared to the findings in wild-type and Pink1-deficient mice despite the increased mitochondrial damage induced by Prdx3 deficiency. Under conditions inducing mitophagy, we identified that the damaged mitochondrial accumulation of PINK1 was completely inhibited by the ablation of Prdx3. We propose that Prdx3 interacts with the N-terminus of PINK1, thereby protecting PINK1 from proteolytic cleavage in damaged mitochondria undergoing mitophagy. Our results provide evidence of a direct association between MQC dysfunction and cardiac function. The dual function of Prdx3 in mitophagy regulation and mitochondrial oxidative stress elimination further clarifies the mechanism of MQC in vivo and thereby provides new insights into developing a therapeutic strategy for mitochondria-related cardiovascular diseases such as heart failure.
    Keywords:  Damaged mitochondria; Heart failure; Mitochondrial quality control; Mitophagy; PINK1; Peroxiredoxin 3
    DOI:  https://doi.org/10.1016/j.redox.2022.102275
  17. Med Res Rev. 2022 Mar 11.
    Incomplete autophagy: Trouble is a friend.
    Qiang Zhang, Shijie Cao, Feng Qiu, Ning Kang.
      Incomplete autophagy is an impaired self-eating process of intracellular macromolecules and organelles in which accumulated autophagosomes do not fuse with lysosomes for degradation, resulting in the blockage of autophagic flux. In this review, we summarized the literature over the past decade describing incomplete autophagy, and found that different from the double-edged sword effect of general autophagy on promoting cell survival or death, incomplete autophagy plays a crucial role in disrupting cellular homeostasis, and promotes only cell death. What matters is that incomplete autophagy is closely relevant to the pathogenesis and progression of various human diseases, which, meanwhile, intimately linking to the pharmacologic and toxicologic effects of several compounds. Here, we comprehensively reviewed the latest progress of incomplete autophagy on molecular mechanisms and signaling pathways. Moreover, implications of incomplete autophagy for pharmacotherapy are also discussed, which has great relevance for our understanding of the distinctive role of incomplete autophagy in cellular physiology and disease. Consequently, targeting incomplete autophagy may contribute to the development of novel generation therapeutic agents for diverse human diseases.
    Keywords:  autophagic flux; incomplete autophagy; molecular mechanisms; pharmacotherapy; toxicology
    DOI:  https://doi.org/10.1002/med.21884
  18. Cell Immunol. 2022 Feb 17. pii: S0008-8749(22)00008-9. [Epub ahead of print]374 104484
    Substrate-specific presentation of MHC class I-restricted antigens via autophagy pathway.
    Maria C Tovar Fernandez, Ewa M Sroka, Mathilde Lavigne, Aikaterini Thermou, Chrysoula Daskalogianni, Bénédicte Manoury, Rodrigo Prado Martins, Robin Fahraeus.
      The accumulation of protein aggregates is toxic and linked to different diseases such as neurodegenerative disorders, but the role of the immune system to target and destroy aggregate-carrying cells is still relatively unknown. Here we show a substrate-specific presentation of antigenic peptides to the direct MHC class I pathway via autophagy. We observed no difference in presentation of peptides derived from the viral EBNA1 protein following suppression of autophagy by knocking down Atg5 and Atg12. However, the same knock down treatment suppressed the presentation from ovalbumin. Fusing the aggregate-prone poly-glutamine (PolyQ) to the ovalbumin had no effect on antigen presentation via autophagy. Interestingly, fusing the EBNA1-derived gly-ala repeat (GAr) sequence to ovalbumin rendered the presentation Atg5/12 independent. We also demonstrate that the relative levels of protein expression did not affect autophagy-mediated antigen presentation. These data suggest a substrate-dependent presentation of antigenic peptides for the MHC class I pathway via autophagy and indicate that the GAr of the EBNA1 illustrates a novel virus-mediated mechanism for immune evasion of autophagy-dependent antigen presentation.
    Keywords:  Autophagy; EBV-encoded EBNA1; MHC class I restricted antigen presentation; Protein aggregates
    DOI:  https://doi.org/10.1016/j.cellimm.2022.104484
  19. Sci Adv. 2022 Mar 11. 8(10): eabi4797
    Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism.
    Alexander S Häusl, Thomas Bajaj, Lea M Brix, Max L Pöhlmann, Kathrin Hafner, Meri De Angelis, Joachim Nagler, Frederik Dethloff, Georgia Balsevich, Karl-Werner Schramm, Patrick Giavalisco, Alon Chen, Mathias V Schmidt, Nils C Gassen.
      The mediobasal hypothalamus (MBH) is the central region in the physiological response to metabolic stress. The FK506-binding protein 51 (FKBP51) is a major modulator of the stress response and has recently emerged as a scaffolder regulating metabolic and autophagy pathways. However, the detailed protein-protein interactions linking FKBP51 to autophagy upon metabolic challenges remain elusive. We performed mass spectrometry-based metabolomics of FKBP51 knockout (KO) cells revealing an increased amino acid and polyamine metabolism. We identified FKBP51 as a central nexus for the recruitment of the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. Furthermore, we demonstrated that MBH FKBP51 deletion strongly induces obesity, while its overexpression protects against high-fat diet (HFD)-induced obesity. Our study provides an important novel regulatory function of MBH FKBP51 within the stress-adapted autophagy response to metabolic challenges.
    DOI:  https://doi.org/10.1126/sciadv.abi4797
  20. J Control Release. 2022 Mar 03. pii: S0168-3659(22)00111-0. [Epub ahead of print]
    Targeting autophagy, oxidative stress, and ER stress for neurodegenerative diseases treatment.
    Yasaman Esmaeili, Zahra Yarjanli, Fatemeh Pakniya, Elham Bidram, Marek J Los, Mehdi Eshraghi, Daniel J Klionsky, Saeid Ghavami, Ali Zarrabi.
      Protein homeostasis is a vital process for cell function and, therefore, disruption of the molecular mechanisms involved in this process, such as autophagy, may contribute to neurodegenerative diseases (NDs). Apart from autophagy disruption, excess oxidative stress and endoplasmic reticulum (ER) stress are additional main molecular mechanisms underlying neurodegeneration, leading to protein aggregation, and mitochondrial dysfunction. Notably, these primary molecular processes are interconnected pathways which have synergistic effects on each other. Therefore, we propose that targeting of the crosstalk between autophagy, oxidative stress and ER stress simultaneously may play a critical role in healing NDs. NeuroNanoTechnology, as a revolutionized approach, in combination with an in-silico strategy, holds great promise for developing de-novo structures for targeting and modulating neuro-molecular pathways. Accordingly, this review outlines the contributions of autophagy, oxidative stress, and ER stress in neurodegenerative conditions along with a particular focus on the crosstalk among these pathways. Furthermore, we provide a comprehensive discussion on the potential of nanomaterials to target this crosstalk and suggest this potential as a promising opportunity in neuroprotection.
    Keywords:  Autophagy; Endoplasmic reticulum stress; Nanotechnology; Neurodegeneration; Oxidative stress
    DOI:  https://doi.org/10.1016/j.jconrel.2022.03.001
  21. Front Neurol. 2022 ;13 841394
    The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis-Frontotemporal Dementia.
    Eveljn Scarian, Giuseppe Fiamingo, Luca Diamanti, Ilaria Palmieri, Stella Gagliardi, Orietta Pansarasa.
      Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurological diseases which, respectively, and primarily affect motor neurons and frontotemporal lobes. Although they can lead to different signs and symptoms, it is now evident that these two pathologies form a continuum and that hallmarks of both diseases can be present within the same person in the so-called ALS-FTD spectrum. Many studies have focused on the genetic overlap of these pathologies and it is now clear that different genes, such as C9orf72, TARDBP, SQSTM1, FUS, and p97/VCP can be mutated in both the diseases. VCP was one of the first genes associated with both FTD and ALS representing an early example of gene overlapping. VCP belongs to the type II AAA (ATPases Associated with diverse cellular activities) family and is involved in ubiquitinated proteins degradation, autophagy, lysosomal clearance and mitochondrial quality control. Since its numerous roles, mutations in this gene lead to different pathological features, first and foremost TDP-43 mislocalization. This review aims to outline recent findings on VCP roles and on how its mutations are linked to the neuropathology of ALS and FTD.
    Keywords:  ALS; FTD; VCP; autophagy; lysophagy; mitophagy; protein clearance
    DOI:  https://doi.org/10.3389/fneur.2022.841394
  22. Biochem Biophys Res Commun. 2022 Mar 04. pii: S0006-291X(22)00133-4. [Epub ahead of print]603 7-12
    α-synuclein and phosphoinositide-binding proteins: α-synuclein inhibits the association of PX- but not FYVE-containing proteins with vesicles in vivo.
    Santhanasabapathy Rajasekaran, Dhaval Patel, Stephan N Witt.
      By an unknown mechanism, alpha-synuclein (α-syn) inhibits autophagy in yeast and human cells. Herein, using the yeast Saccharomyces cerevisiae, we tested the hypothesis that α-syn disrupts autophagy by inhibiting the required association of sorting nexin 4 (Snx4) with phagophores. Snx4 contains a phox (PX) homology domain that selectively binds membranes enriched in phosphatidylinositol 3-phosphate (PI3P). Using fluorescence microscopy, we show that upon nitrogen starvation, 70% of the cells exhibited green puncta (phagophores); whereas identically treated cells expressing α-syn exhibited a significantly lower percentage of cells (30%) with such puncta. Our interpretation is that α-syn outcompetes Snx4 for binding to membranes enriched in PI3P, resulting in fewer phagophores and consequently inefficient induction of autophagy. As a control, we tested whether α-syn disrupts the binding of Vps27-GFP to late endosomes/multivesicular bodies (MVBs). Vps27 contains a PI3P-binding domain called FYVE. α-Syn did not disrupt the binding of Vps27-GFP to late endosomes. α-Syn likely inhibits the binding of PX- but not FYVE-containing proteins to PI3P because FYVE domains bind more than two-orders of magnitude tighter than PX domains. We propose that in all cells, whether yeast or human, α-syn has the potential to inhibit protein trafficking pathways that are dependent on PX-domain proteins such as sorting nexins.
    Keywords:  Autophagy; Multivesicular body; Parkinson's disease; Retromer; Sorting nexin; α-synuclein
    DOI:  https://doi.org/10.1016/j.bbrc.2022.01.101
  23. Trends Neurosci. 2022 Mar 03. pii: S0166-2236(22)00017-0. [Epub ahead of print]
    Mitochondria-lysosome contact site dynamics and misregulation in neurodegenerative diseases.
    Jasmine Cisneros, Tayler B Belton, George C Shum, Catherine G Molakal, Yvette C Wong.
      Neurons rely heavily on properly regulated mitochondrial and lysosomal homeostasis, with multiple neurodegenerative diseases linked to dysfunction in these two organelles. Interestingly, mitochondria-lysosome membrane contact sites have been identified as a key pathway mediating their crosstalk in neurons. Recent studies have further elucidated the regulation of mitochondria-lysosome contact dynamics via distinct tethering/untethering protein machinery. Moreover, this pathway has been shown to have additional functions in regulating organelle network dynamics and metabolite transfer between lysosomes and mitochondria. In this review, we highlight recent advances in the field of mitochondria-lysosome contact sites and their misregulation across multiple neurodegenerative disorders, which further underscore a potential role for this pathway in neuronal homeostasis and disease.
    Keywords:  Charcot-Marie-Tooth disease; Parkinson’s disease; inter-organelle contact sites; lysosomal storage disorders; lysosomes; mitochondria
    DOI:  https://doi.org/10.1016/j.tins.2022.01.005
  24. Aging Cell. 2022 Mar 09. e13583
    Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.
    Andrea Irazoki, Marta Martinez-Vicente, Pilar Aparicio, Cecilia Aris, Esmaeil Alibakhshi, Maria Rubio-Valera, Juan Castellanos, Luis Lores, Manuel Palacín, Anna Gumà, Antonio Zorzano, David Sebastián.
      Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria (MIT) in muscle could trigger inflammation in the context of aging is still unknown. Here, we demonstrate that BCL2 interacting protein 3 (BNIP3) plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of Toll-like receptor 9 (TLR9)-dependent inflammation and activation of the NLRP3 (nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3) inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans. Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.
    Keywords:  aging; inflammation; lysosome; mitochondria; mitophagy; muscle
    DOI:  https://doi.org/10.1111/acel.13583
  25. Autophagy. 2022 Mar 06. 1-21
    Therapeutic targeting of the USP2-E2F4 axis inhibits autophagic machinery essential for zinc homeostasis in cancer progression.
    Wenjing Xiao, Jianqun Wang, Xiaojing Wang, Shuang Cai, Yanhua Guo, Lin Ye, Dan Li, Anpei Hu, Shikai Jin, Boling Yuan, Yi Zhou, Qilan Li, Qiangsong Tong, Liduan Zheng.
      Macroautophagy/autophagy is a conserved cellular process associated with tumorigenesis and aggressiveness, while mechanisms regulating expression of autophagic machinery genes in cancers still remain elusive. Herein, we identified E2F4 (E2F transcription factor 4) as a novel transcriptional activator of cytoprotective autophagy crucial for zinc homeostasis in cancer cells. Gain- and loss-of-function studies showed that E2F4 promoted autophagy in a cell cycle-dependent manner, resulting in facilitated degradation of MT (metallothionein) proteins, elevated distribution of Zn2+ within autophagosomes, decreased labile intracellular zinc ions, and increased growth, invasion, and metastasis of gastric cancer cells. Mechanistically, E2F4 directly regulated the transcription of ATG2A (autophagy related 2A) and ULK2 (unc-51 like autophagy activating kinase 2), leading to autophagic degradation of MT1E, MT1M, and MT1X, while USP2 (ubiquitin specific peptidase 2) stabilized E2F4 protein to induce its transactivation via physical interaction and deubiquitination in cancer cells. Rescue experiments revealed that USP2 harbored oncogenic properties via E2F4-facilitated autophagy and zinc homeostasis. Emetine, a small chemical inhibitor of autophagy, was able to block interaction between UPS2 and E2F4, increase labile intracellular zinc ions, and suppress tumorigenesis and aggressiveness. In clinical gastric cancer specimens, both USP2 and E2F4 were upregulated and associated with poor outcome of patients. These findings indicate that therapeutic targeting of the USP2-E2F4 axis inhibits autophagic machinery essential for zinc homeostasis in cancer progression.Abbreviations: 3-MA: 3-methyladenine; ANOVA: analysis of variance; ATG2A: autophagy related 2A; ATG5: autophagy related 5; ATP: adenosine triphosphate; BECN1: beclin 1; BiFC: bimolecular fluorescence complementation; CCND1: cyclin D1; CDK: cyclin dependent kinase; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2-phenylindole; E2F4: E2F transcription factor 4; eATP: extracellular adenosine triphosphate; EBSS: Earle's balanced salt solution; FP: first progression; FRET: fluorescence resonance energy transfer; FUCCI: fluorescent ubiquitination-based cell cycle indicator; GFP: green fluorescent protein; GST: glutathione S-transferase; HA: hemagglutinin; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MDM2: MDM2 proto-oncogene; MKI67/Ki-67: marker of proliferation Ki-67; MT: metallothionein; MT1E: metallothionein 1E; MT1M: metallothionein 1M; MT1X: metallothionein 1X; MTT: 3-(4,5-dimethyltriazol-2-yl)-2,5-diphenyl tetrazolium bromide; OS: overall survival; PECAM1/CD31: platelet and endothelial cell adhesion molecule 1; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; qPCR: quantitative PCR; RFP: red fluorescent protein; SQSTM1/p62: sequestosome 1; UBXN1: UBX domain protein 1; Ub: ubiquitin; ULK2: unc-51 like autophagy activating kinase 2; USP14: ubiquitin specific peptidase 14; USP2: ubiquitin specific peptidase 2; USP5: ubiquitin specific peptidase 5; USP7: ubiquitin specific peptidase 7; ZnCl2: zinc chloride.
    Keywords:  Autophagy; E2F transcription factor 4; gastric cancer; ubiquitin specific peptidase 2; zinc homeostasis
    DOI:  https://doi.org/10.1080/15548627.2022.2044651
  26. Autophagy. 2022 Mar 10. 1-18
    TRAF6 autophagic degradation by avibirnavirus VP3 inhibits antiviral innate immunity via blocking NFKB/NF-κB activation.
    Tingjuan Deng, Boli Hu, Xingbo Wang, Shuxiang Ding, Lulu Lin, Yan Yan, Xiran Peng, Xiaojuan Zheng, Min Liao, Yulan Jin, Weiren Dong, Jinyan Gu, Jiyong Zhou.
      Ubiquitination is an important reversible post-translational modification. Many viruses hijack the host ubiquitin system to enhance self-replication. In the present study, we found that Avibirnavirus VP3 protein was ubiquitinated during infection and supported virus replication by ubiquitination. Mass spectrometry and mutation analysis showed that VP3 was ubiquitinated at residues K73, K135, K158, K193, and K219. Virus rescue showed that ubiquitination at sites K73, K193, and K219 on VP3 could enhance the replication abilities of infectious bursal disease virus (IBDV), and that K135 was essential for virus survival. Binding of the zinc finger domain of TRAF6 (TNF receptor associated factor 6) to VP3 mediated K11- and K33-linked ubiquitination of VP3, which promoted its nuclear accumulation to facilitate virus replication. Additionally, VP3 could inhibit TRAF6-mediated NFKB/NF-κB (nuclear factor kappa B) activation and IFNB/IFN-β (interferon beta) production to evade host innate immunity by inducing TRAF6 autophagic degradation in an SQSTM1/p62 (sequestosome 1)-dependent manner. Our findings demonstrated a macroautophagic/autophagic mechanism by which Avibirnavirus protein VP3 blocked NFKB-mediated IFNB production by targeting TRAF6 during virus infection, and provided a potential drug target for virus infection control.Abbreviations: ATG: autophagy related; BafA1: bafilomycin A1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; Cas9: CRISPR-associated protein 9; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GST: glutathione S-transferase; IBDV: infectious bursal disease virus; IF: indirect immunofluorescence; IFNB/IFN-β: interferon beta; mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; MS: mass spectrometry; NFKB/NF-κB: nuclear factor kappa B; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; pAb: polyclonal antibody; PRRs: pattern recognition receptors; RNF125: ring finger protein 125; RNF135/Riplet: ring finger protein 135; SQSTM1/p62: sequestosome 1; TAX1BP1: tax1 binding protein1; TCID50: 50% tissue culture infective dose; TRAF3: TNF receptor associated factor 3; TRAF6: TNF receptor associated factor 6; TRIM25: tripartite motif containing 25; Ub: ubiquitin; Wort: wortmannin; WT: wild type.
    Keywords:  AvibirnavirusVP3 ubiquitination; SQSTM1; TRAF6 degradation; innate antiviral immune; nuclear trafficking; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2047384
  27. Int J Mol Sci. 2022 Mar 04. pii: 2814. [Epub ahead of print]23(5):
    Dysregulation of mTOR Signaling after Brain Ischemia.
    Mario Villa-González, Gerardo Martín-López, María José Pérez-Álvarez.
      In this review, we provide recent data on the role of mTOR kinase in the brain under physiological conditions and after damage, with a particular focus on cerebral ischemia. We cover the upstream and downstream pathways that regulate the activation state of mTOR complexes. Furthermore, we summarize recent advances in our understanding of mTORC1 and mTORC2 status in ischemia-hypoxia at tissue and cellular levels and analyze the existing evidence related to two types of neural cells, namely glia and neurons. Finally, we discuss the potential use of mTORC1 and mTORC2 as therapeutic targets after stroke.
    Keywords:  MCAo; astrocytes; brain ischemia; glia; mTOR; mTORC1; mTORC2; microglia; neuron; oligodendrocytes
    DOI:  https://doi.org/10.3390/ijms23052814
  28. Gen Physiol Biophys. 2022 Jan;41(1): 71-78
    FAM134B-mediated ER-phagy alleviates endoplasmic reticulum stress of rat soleus muscle in response to acute exercise.
    Songlin Jin, Lunyu Li, Zaifang Ren, Junping Li, Ruiyuan Wang, Haili Ding.
      ER-phagy is a selective endoplasmic reticulum (ER) autophagy mediated by ER-localized receptors, which ensures proper cellular homeostasis under stress. However, it remains unclear whether ER-phagy is involved in skeletal muscle response to exercise stress. Male 8-week-old Sprague-Dawley rats were subjected to an exercise protocol comprising a 90-min downhill run with a slope of -16° and a speed of 16 m/min. The soleus of the rats was sampled at 0, 12, 24, 48, and 72 h after exercise. After exercise, the sarcoplasmic/ER calcium ATPase (SERCA) content decreased, the protein disulphide isomerase (PDI) content increased, and ER stress (GRP78 and CRT) and autophagy (FAM134B and LC3)-related protein expression increased in the soleus muscle of rats, and gradually recovered with time. We also used pharmacological methods to simulate the effects of exercise stress on skeletal muscle cells to further explore the mechanism of ER-phagy in skeletal muscle cells. Thapsigargin was used to inhibit the SERCA pump of L6 myoblasts and successfully induce ER stress and activate ER-phagy. During this process, the ER-phagy receptor FAM134B anchors and fragments ER, and then binds with LC3 to form autophagosomes. These results suggest that ER-phagy is involved in the skeletal muscle cell response to exercise stress, which helps to maintain cellular ER homeostasis during exercise.
    DOI:  https://doi.org/10.4149/gpb_2021046
  29. Autophagy. 2022 Mar 09. 1-20
    RTN4/Nogo-A-S1PR2 negatively regulates angiogenesis and secondary neural repair through enhancing vascular autophagy in the thalamus after cerebral cortical infarction.
    Peiyi Xiao, Jinmin Gu, Wei Xu, Xingyang Niu, Jian Zhang, Jingjing Li, Yicong Chen, Zhong Pei, Jinsheng Zeng, Shihui Xing.
      Cerebral infarction induces angiogenesis in the thalamus and influences functional recovery. The mechanisms underlying angiogenesis remain unclear. This study aimed to investigate the role of RTN4/Nogo-A in mediating macroautophagy/autophagy and angiogenesis in the thalamus following middle cerebral artery occlusion (MCAO). We assessed secondary neuronal damage, angiogenesis, vascular autophagy, RTN4 and S1PR2 signaling in the thalamus. The effects of RTN4-S1PR2 on vascular autophagy and angiogenesis were evaluated using lentiviral and pharmacological approaches. The results showed that RTN4 and S1PR2 signaling molecules were upregulated in parallel with angiogenesis in the ipsilateral thalamus after MCAO. Knockdown of Rtn4 by siRNA markedly reduced MAP1LC3B-II conversion and levels of BECN1 and SQSTM1 in vessels, coinciding with enhanced angiogenesis in the ipsilateral thalamus. This effect coincided with rescued neuronal loss of the thalamus and improved cognitive function. Conversely, activating S1PR2 augmented vascular autophagy, along with suppressed angiogenesis and aggravated neuronal damage of the thalamus. Further inhibition of autophagic initiation with 3-methyladenine or spautin-1 enhanced angiogenesis while blockade of lysosomal degradation by bafilomycin A1 suppressed angiogenesis in the ipsilateral thalamus. The control of autophagic flux by RTN4-S1PR2 was verified in vitro. Additionally, ROCK1-BECN1 interaction along with phosphorylation of BECN1 (Thr119) was identified in the thalamic vessels after MCAO. Knockdown of Rtn4 markedly reduced BECN1 phosphorylation whereas activating S1PR2 increased its phosphorylation in vessels. These results suggest that blockade of RTN4-S1PR2 interaction promotes angiogenesis and secondary neural repair in the thalamus by suppressing autophagic activation and alleviating dysfunction of lysosomal degradation in vessels after cerebral infarction.
    Keywords:  Angiogenesis; RTN4; autophagy; cerebral infarction; secondary neurodegeneration; thalamus
    DOI:  https://doi.org/10.1080/15548627.2022.2047344
  30. Cells. 2022 Mar 01. pii: 851. [Epub ahead of print]11(5):
    Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress.
    Yanan Li, Shujing Li, Huijian Wu.
      In response to environmental stimuli, cells make a series of adaptive changes to combat the injury, repair the damage, and increase the tolerance to the stress. However, once the damage is too serious to repair, the cells will undergo apoptosis to protect the overall cells through suicidal behavior. Upon external stimulation, some intracellular proteins turn into unfolded or misfolded protein, exposing their hydrophobic regions to form protein aggregation, which may ultimately produce serious damage to the cells. Ubiquitin plays an important role in the degradation of these unnatural proteins by tagging with ubiquitin chains in the ubiquitin-proteasome or autophagy system. If the two processes fail to eliminate the abnormal protein aggregates, the cells will move to apoptosis and death. Dysregulation of ubiquitin-proteasome system (UPS) and autophagy may result in the development of numerous diseases. This review focuses on the molecular mechanisms of UPS and autophagy in clearance of intracellular protein aggregates, and the relationship between dysregulation of ubiquitin network and diseases.
    Keywords:  autophagy; cell stress; endoplasmic reticulum stress; ubiquitin; ubiquitin–proteasome system; unfolded protein response
    DOI:  https://doi.org/10.3390/cells11050851
  31. Cells. 2022 Feb 23. pii: 780. [Epub ahead of print]11(5):
    Maintaining Golgi Homeostasis: A Balancing Act of Two Proteolytic Pathways.
    Ron Benyair, Avital Eisenberg-Lerner, Yifat Merbl.
      The Golgi apparatus is a central hub for cellular protein trafficking and signaling. Golgi structure and function is tightly coupled and undergoes dynamic changes in health and disease. A crucial requirement for maintaining Golgi homeostasis is the ability of the Golgi to target aberrant, misfolded, or otherwise unwanted proteins to degradation. Recent studies have revealed that the Golgi apparatus may degrade such proteins through autophagy, retrograde trafficking to the ER for ER-associated degradation (ERAD), and locally, through Golgi apparatus-related degradation (GARD). Here, we review recent discoveries in these mechanisms, highlighting the role of the Golgi in maintaining cellular homeostasis.
    Keywords:  EGAD; GARD; GOMED; Golgi; autophagy; proteasomal degradation; proteostasis
    DOI:  https://doi.org/10.3390/cells11050780
  32. Autophagy. 2022 Mar 08. 1-18
    Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.
    Silvia Magalhaes-Novais, Jan Blecha, Ravindra Naraine, Jana Mikesova, Pavel Abaffy, Alena Pecinova, Mirko Milosevic, Romana Bohuslavova, Jan Prochazka, Shawez Khan, Eliska Novotna, Radek Sindelka, Radek Machan, Mieke Dewerchin, Erik Vlcak, Joanna Kalucka, Sona Stemberkova Hubackova, Ales Benda, Jermaine Goveia, Tomas Mracek, Cyril Barinka, Peter Carmeliet, Jiri Neuzil, Katerina Rohlenova, Jakub Rohlena.
      Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence.Abbreviations: AMPK: AMP-activated protein kinase; AOX: alternative oxidase; Baf A: bafilomycin A1; CI, respiratory complexes I; DCF-DA: 2',7'-dichlordihydrofluorescein diacetate; DHE: dihydroethidium; DSS: dextran sodium sulfate; ΔΨmi: mitochondrial inner membrane potential; EdU: 5-ethynyl-2'-deoxyuridine; ETC: electron transport chain; FA: formaldehyde; HUVEC; human umbilical cord endothelial cells; IBD: inflammatory bowel disease; LC3B: microtubule associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; mtDNA: mitochondrial DNA; NAC: N-acetyl cysteine; OXPHOS: oxidative phosphorylation; PCs: proliferating cells; PE: phosphatidylethanolamine; PEITC: phenethyl isothiocyanate; QCs: quiescent cells; ROS: reactive oxygen species; PLA2: phospholipase A2, WB: western blot.
    Keywords:  ATG4B; biosynthesis; cell death; electron transport chain; endothelial cells; mitochondria; oxidative phosphorylation; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1080/15548627.2022.2038898
  33. Front Pharmacol. 2022 ;13 832750
    Autophagy-Inflammation Interplay During Infection: Balancing Pathogen Clearance and Host Inflammation.
    Yuqian Pang, Lanxi Wu, Cheng Tang, Hongna Wang, Yongjie Wei.
      Inflammation is an essential immune response of the host against infections but is often over-activated, leading to a variety of disorders. Autophagy, a conserved degradation pathway, also protects cells by capturing intracellular pathogens that enter the cell and transporting them to the lysosome for clearance. Dysfunctional autophagy is often associated with uncontrolled inflammatory responses during infection. In recent years, more and more research has focused on the crosstalk between autophagy and inflammation. In this paper, we review the latest research advances in this field, hoping to gain insight into the mechanisms by which the body balances autophagy and inflammation in infections and how this mechanism can be used to fight infections better.
    Keywords:  autophagy; bacteria; infection; inflammasome; inflammation; microbial; virus
    DOI:  https://doi.org/10.3389/fphar.2022.832750
  34. Cell Commun Signal. 2022 Mar 05. 20(1): 25
    Energy deprivation-induced AMPK activation inhibits milk synthesis by targeting PrlR and PGC-1α.
    Zhihui Wu, Qihui Li, Siwang Yang, Tenghui Zheng, Jiayuan Shao, Wutai Guan, Fang Chen, Shihai Zhang.
      BACKGROUND: The mammary gland is responsible for milk production and secretion, which is critical for neonatal health during lactation. Lactation efficiency is largely affected by energy status with unclear mechanism.RESULTS: In the current study, we found that synthesis of milk fat and protein was significantly inhibited under energy-deficient conditions, which is accompanied with AMP-activated protein kinase (AMPK) activation. Modulating the AMPK signaling pathway directly or indirectly affects the synthesis of milk fat and protein. Besides mammalian target of rapamycin complex 1 (mTORC1) signaling in the regulation of milk synthesis, we discovered that AMPK mainly regulates the synthesis of milk protein through prolactin signaling. Mechanistically, AMPK triggers the ubiquitination of prolactin receptor (PrlR) through regulating the activity of β-transducin repeat-containing protein (β-TrCP, an E3 ligase). Subsequently, PrlR is degraded by the endocytosis process of lysosomes, which further attenuates prolactin signaling. In addition, our results revealed that AMPK activation inhibits milk fat synthesis through decreasing and accelerating de novo synthesis and β-oxidation of fatty acids, respectively. To be precise, AMPK activation inhibits rate limiting enzymes and transcriptional regulatory factors involved in de novo fatty acid synthesis and decreases the acetylation process of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) to strengthen the oxidation of fatty acids.
    CONCLUSIONS: Taken together, AMPK regulates the synthesis of milk not only depends on canonical mTORC1 signaling and key rate-limiting enzymes, but also through manipulating the degradation of PrlR and the acetylation of PGC-1α. Video Abstract.
    Keywords:  AMPK; Mammary epithelial cells; Milk fat; Milk protein; PGC-1α; PrlR
    DOI:  https://doi.org/10.1186/s12964-022-00830-6
  35. Nutrients. 2022 Mar 07. pii: 1114. [Epub ahead of print]14(5):
    GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage.
    Premranjan Kumar, Ob W Osahon, Rajagopal V Sekhar.
      Determinants of length of life are not well understood, and therefore increasing lifespan is a challenge. Cardinal theories of aging suggest that oxidative stress (OxS) and mitochondrial dysfunction contribute to the aging process, but it is unclear if they could also impact lifespan. Glutathione (GSH), the most abundant intracellular antioxidant, protects cells from OxS and is necessary for maintaining mitochondrial health, but GSH levels decline with aging. Based on published human studies where we found that supplementing glycine and N-acetylcysteine (GlyNAC) improved/corrected GSH deficiency, OxS and mitochondrial dysfunction, we hypothesized that GlyNAC supplementation could increase longevity. We tested our hypothesis by evaluating the effect of supplementing GlyNAC vs. placebo in C57BL/6J mice on (a) length of life; and (b) age-associated GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage in the heart, liver and kidneys. Results showed that mice receiving GlyNAC supplementation (1) lived 24% longer than control mice; (2) improved/corrected impaired GSH synthesis, GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage. These studies provide proof-of-concept that GlyNAC supplementation can increase lifespan and improve multiple age-associated defects. GlyNAC could be a novel and simple nutritional supplement to improve lifespan and healthspan, and warrants additional investigation.
    Keywords:  GlyNAC; lifespan; mitochondria; mitophagy; oxidant damage; oxidative stress
    DOI:  https://doi.org/10.3390/nu14051114
  36. Front Pharmacol. 2022 ;13 816551
    The Mitochondrial Deubiquitinase USP30 Regulates AKT/mTOR Signaling.
    Ruohan Zhang, Serra Ozgen, Hongke Luo, Judith Krigman, Yutong Zhao, Gang Xin, Nuo Sun.
      Mitophagy is an intracellular mechanism to maintain mitochondrial health by removing dysfunctional mitochondria. The E3 ligase Parkin ubiquitinates the membrane proteins on targeted mitochondria to initiate mitophagy, whereas USP30 antagonizes Parkin-dependent mitophagy by removing ubiquitin from Parkin substrates. The AKT/mTOR signaling is a master regulator of cell proliferation, differentiation, apoptosis, and autophagy. Although mounting evidence suggests that perturbations in the AKT/mTOR signaling pathway may contribute to mitophagy regulation, the specific mechanisms between Parkin/USP30 and AKT/mTOR signaling have not been elucidated. In this study, we employ a set of genetic reagents to investigate the role of Parkin and USP30 in regulating the AKT/mTOR signaling during mitophagy. We demonstrated that, in the setting of mitochondrial stress, the AKT/mTOR signaling is regulated, at least in part, by the activity of Parkin and USP30. Parkin inhibits AKT/mTOR signaling following an in vitro mitochondrial stress, thereby promoting apoptosis. However, USP30 overexpression antagonizes the activity of Parkin to sustain AKT/mTOR activity and inhibit apoptosis. These findings provide new insights into Parkin and USP30's role in apoptosis and suggest that inhibiting USP30 might provide a specific strategy to synergize with AKT/mTOR inhibitors in cancer treatment.
    Keywords:  USP30; akt; cancer; leukemia; mTOR; mitophagy; parkin
    DOI:  https://doi.org/10.3389/fphar.2022.816551
  37. FEBS Lett. 2022 Mar 11.
    Annexins A1 and A2 are recruited to larger lysosomal injuries independently of ESCRTs to promote repair.
    Willa Wen-You Yim, Hayashi Yamamoto, Noboru Mizushima.
      Damaged lysosomes can be repaired by calcium release-dependent recruitment of the ESCRT machinery. However, the involvement of annexins, another group of calcium-responding membrane repair proteins, has not been fully addressed. Here, we show that although all ubiquitously expressed annexins (ANXA1, A2, A4, A5, A6, A7, and A11) localize to damaged lysosomes, only ANXA1 and ANXA2 are important for repair. Their recruitment is calcium-dependent, ESCRT-independent, and selective towards lysosomes with large injuries. Lysosomal leakage was more severe when ANXA1 or ANXA2 was depleted compared to that of ESCRT components. These findings suggest that ANXA1 and ANXA2 constitute an additional repair mechanism that serves to minimize leakage from damaged lysosomes.
    Keywords:  ESCRT; lysosome; membrane permeabilization; membrane repair
    DOI:  https://doi.org/10.1002/1873-3468.14329
  38. Theranostics. 2022 ;12(5): 2351-2369
    SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation.
    Wonseok Lee, Hyun Young Kim, You-Jin Choi, Seung-Hwan Jung, Yoon Ah Nam, Yunfan Zhang, Sung Ho Yun, Tong-Shin Chang, Byung-Hoon Lee.
      Rationale: While some non-steroidal anti-inflammatory drugs (NSAIDs) are reported to induce hepatic steatosis, the molecular mechanisms are poorly understood. This study presented the mechanism by which NSAIDs induce hepatic lipid accumulation. Methods: Mouse primary hepatocytes and HepG2 cells were used to examine the underlying mechanism of NSAID-induced hepatic steatosis. Lipid accumulation was measured using Nile-red assay and BODIPY 493/503. The activity of chaperone-mediated autophagy (CMA) was determined by western blotting, qRT-PCR, and confocal imaging. The effect of NSAID on CMA inhibition was evaluated in vivo using diclofenac and CMA activator (AR7) administered mice. Results: All tested NSAIDs in this study accumulated neutral lipids in hepatocytes, diclofenac having demonstrated the most potency in that regard. Diclofenac-induced lipid accumulation was confirmed in both mouse primary hepatocytes and the liver of mice. NSAIDs inhibited CMA, as reflected by the decreased expression of lysosome-associated membrane glycoprotein 2 isoform A (LAMP2A) protein, the increased expression of CMA substrate proteins such as PLIN2, and the decreased activity of photoactivatable KFERQ-PAmCherry reporter. Reactivation of CMA by treatment with AR7 or overexpression of LAMP2A inhibited diclofenac-induced lipid accumulation and hepatotoxicity. Upregulation of sorting nexin 10 (SNX10) via the CHOP-dependent endoplasmic reticulum stress response and thus maturation of cathepsin A (CTSA) was shown to be responsible for the lysosomal degradation of LAMP2A by diclofenac. Conclusion: We demonstrated that NSAIDs induced SNX10- and CTSA-dependent degradation of LAMP2A, thereby leading to the suppression of CMA. In turn, impaired CMA failed to degrade PLIN2 and disrupted cellular lipid homeostasis, thus leading to NSAID-induced steatosis and hepatotoxicity.
    Keywords:  Chaperone-mediated autophagy; Diclofenac; NSAIDs; Perilipin 2; Sorting nexin 10
    DOI:  https://doi.org/10.7150/thno.70692
  39. Neurosci Bull. 2022 Mar 10.
    Chaperone-mediated Autophagy Regulates Cell Growth by Targeting SMAD3 in Glioma.
    Hanqun Liu, Yuxuan Yong, Xingjian Li, Panghai Ye, Kai Tao, Guoyou Peng, Mingshu Mo, Wenyuan Guo, Xiang Chen, Yangfu Luo, Yuwan Lin, Jiewen Qiu, Zhiling Zhang, Liuyan Ding, Miaomiao Zhou, Xinling Yang, Lin Lu, Qian Yang, Pingyi Xu.
      Previous studies suggest that the reduction of SMAD3 (mothers against decapentaplegic homolog 3) has a great impact on tumor development, but its exact pathological function remains unclear. In this study, we found that the protein level of SMAD3 was greatly reduced in human-grade IV glioblastoma tissues, in which LAMP2A (lysosome-associated membrane protein type 2A) was significantly up-regulated. LAMP2A is a key rate-limiting protein of chaperone-mediated autophagy (CMA), a lysosome pathway of protein degradation that is activated in glioma. We carefully analyzed the amino-acid sequence of SMAD3 and found that it contained a pentapeptide motif biochemically related to KFERQ, which has been proposed to be a targeting sequence for CMA. In vitro, we confirmed that SMAD3 was degraded in either serum-free or KFERQ motif deleted condition, which was regulated by LAMP2A and interacted with HSC70 (heat shock cognate 71 kDa protein). Using isolated lysosomes, amino-acid residues 75 and 128 of SMAD3 were found to be of importance for this process, which affected the CMA pathway in which SMAD3 was involved. Similarly, down-regulating SMAD3 or up-regulating LAMP2A in cultured glioma cells enhanced their proliferation and invasion. Taken together, these results suggest that excessive activation of CMA regulates glioma cell growth by promoting the degradation of SMAD3. Therefore, targeting the SMAD3-LAMP2A-mediated CMA-lysosome pathway may be a promising approach in anti-cancer therapy.
    Keywords:  Cell growth; Chaperone-mediated autophagy; Glioma; SMAD3
    DOI:  https://doi.org/10.1007/s12264-022-00818-9
  40. Cells. 2022 Mar 02. pii: 862. [Epub ahead of print]11(5):
    Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.
    Jovian Lin Jing, Trishia Cheng Yi Ning, Federica Natali, Frank Eisenhaber, Mohammad Alfatah.
      Aging is the greatest challenge to humankind worldwide. Aging is associated with a progressive loss of physiological integrity due to a decline in cellular metabolism and functions. Such metabolic changes lead to age-related diseases, thereby compromising human health for the remaining life. Thus, there is an urgent need to identify geroprotectors that regulate metabolic functions to target the aging biological processes. Nutrients are the major regulator of metabolic activities to coordinate cell growth and development. Iron is an important nutrient involved in several biological functions, including metabolism. In this study using yeast as an aging model organism, we show that iron supplementation delays aging and increases the cellular lifespan. To determine how iron supplementation increases lifespan, we performed a gene expression analysis of mitochondria, the main cellular hub of iron utilization. Quantitative analysis of gene expression data reveals that iron supplementation upregulates the expression of the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) genes. Furthermore, in agreement with the expression profiles of mitochondrial genes, ATP level is elevated by iron supplementation, which is required for increasing the cellular lifespan. To confirm, we tested the role of iron supplementation in the AMPK knockout mutant. AMPK is a highly conserved controller of mitochondrial metabolism and energy homeostasis. Remarkably, iron supplementation rescued the short lifespan of the AMPK knockout mutant and confirmed its anti-aging role through the enhancement of mitochondrial functions. Thus, our results suggest a potential therapeutic use of iron supplementation to delay aging and prolong healthspan.
    Keywords:  AMPK; Saccharomyces cerevisiae; cellular lifespan extension; chronological aging; iron; mitochondria
    DOI:  https://doi.org/10.3390/cells11050862
  41. Acta Pharm Sin B. 2022 Feb;12(2): 838-852
    Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy.
    Xin Sun, Yuhan Shu, Guiqin Ye, Caixia Wu, Mengting Xu, Ruilan Gao, Dongsheng Huang, Jianbin Zhang.
      Parkin, an E3 ubiquitin ligase, plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level, but the underlying mechanism is poorly understood. Here, our study demonstrated that inhibition of histone deacetylase (HDAC) by treatment of HDACis activates mitophagy through mediating Parkin acetylation, leading to inhibition of cervical cancer cell proliferation. Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer, indicating the low acetylation level of Parkin. Using mass spectrometry, Parkin is identified to interact with two upstream molecules, acetylase acetyl-CoA acetyltransferase 1 (ACAT1) and deacetylase HDAC2. Under treatment of suberoylanilide hydroxamic acid (SAHA), Parkin is acetylated at lysine residues 129, 220 and 349, located in different domains of Parkin protein. In in vitro experiments, combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1 (PINK1) and the function of Parkin in mitophagy induction and tumor suppression. In tumor xenografts, the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA. Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis, which offers a new mitophagy modulation strategy for cancer therapy.
    Keywords:  ACAT1; ACAT1, acetyl-CoA acetyltransferase 1; Acetylation; CCK-8, cell counting kit-8; COXⅣ, cytochrome c oxidase Ⅳ; Cervical cancer; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HDAC, histone deacetylase; HDAC2; HIF-1α, hypoxia inducible factor-1α; HSP60, heat shock protein 60 kDa; LC3, microtubule-associated proteins 1A/1B light chain 3; MFN2, mitofusion 2; MS, mass spectrometry; Mitophagy; PARK2, Parkin; PINK1, PTEN induced putative kinase 1; Parkin; ROS, reactive oxygen species; SAHA, suberoylanilide hydroxamic acid; TIM23, translocase of the inner membrane 23; TOMM20, translocase of outer mitochondrial membrane 20; TSA, trichostatin A; Tumor suppression; ULK1, unc-51 like autophagy activating kinase 1; Ubiquitination; VDAC1, voltage-dependent anion-selective channel protein 1
    DOI:  https://doi.org/10.1016/j.apsb.2021.07.003
  42. Cells. 2022 Mar 03. pii: 878. [Epub ahead of print]11(5):
    Modulation of Intestinal Epithelial Permeability via Protease-Activated Receptor-2-Induced Autophagy.
    Yuju Kim, Yunna Lee, Gwangbeom Heo, Sihyun Jeong, Soyeong Park, Jin-Wook Yoo, Yunjin Jung, Eunok Im.
      Protease-activated receptor 2 (PAR2) alleviates intestinal inflammation by upregulating autophagy. PAR2 also modulates tight junctions through β-arrestin signaling. Therefore, we investigated the effect of PAR2-induced autophagy on intestinal epithelial tight junctions and permeability. RT-PCR, Western blot analysis, and immunoprecipitation were performed to investigate the underlying molecular mechanisms by which PAR2 regulates autophagy and intestinal epithelial tight junctions. Inhibition of PAR2 by GB83, a PAR2 antagonist, decreased the expression of autophagy-related and tight-junction-related factors in Caco-2 cells. Moreover, inhibition of PAR2 decreased intestinal transepithelial electrical resistance. When PAR2 was activated, intestinal permeability was maintained, but when autophagy was suppressed by chloroquine, intestinal permeability was significantly increased. In addition, the prolongation of ERK1/2 phosphorylation by PAR2-ERK1/2-β-arrestin assembly was reduced under autophagy inhibition conditions. Therefore, PAR2 induces autophagy to regulate intestinal epithelial permeability, suggesting that it is related to the β-arrestin-ERK1/2 pathway. In conclusion, regulating intestinal epithelial permeability through PAR2-induced autophagy can help maintain mucosal barrier integrity. Therefore, these findings suggest that the regulation of PAR2 can be a suitable strategy to treat intestinal diseases caused by permeability dysfunction.
    Keywords:  PAR2; autophagy; permeability; tight junction; β-arrestin
    DOI:  https://doi.org/10.3390/cells11050878
  43. J Cell Sci. 2022 Mar 01. pii: jcs259402. [Epub ahead of print]135(5):
    Lipophagy at a glance.
    Micah B Schott, Cody N Rozeveld, Shaun G Weller, Mark A McNiven.
      Lipophagy is a central cellular process for providing the cell with a readily utilized, high energy source of neutral lipids. Since its discovery over a decade ago, we are just starting to understand the molecular components that drive lipophagy, how it is activated in response to nutrient availability, and its potential as a therapeutic target in disease. In this Cell Science at a Glance article and the accompanying poster, we first provide a brief overview of the different structural and enzymatic proteins that comprise the lipid droplet (LD) proteome and reside within the limiting phospholipid monolayer of this complex organelle. We then highlight key players in the catabolic breakdown of LDs during the functionally linked lipolysis and lipophagy processes. Finally, we discuss what is currently known about macro- and micro-lipophagy based on findings in yeast, mammalian and other model systems, and how impairment of these important functions can lead to disease states.
    Keywords:  Autophagy; Lipid droplet; Lipolysis; Lipophagy; Metabolism
    DOI:  https://doi.org/10.1242/jcs.259402
  44. PLoS Biol. 2022 Mar 09. 20(3): e3001578
    A light-inducible protein clustering system for in vivo analysis of α-synuclein aggregation in Parkinson disease.
    Morgan Bérard, Razan Sheta, Sarah Malvaut, Raquel Rodriguez-Aller, Maxime Teixeira, Walid Idi, Roxanne Turmel, Melanie Alpaugh, Marilyn Dubois, Manel Dahmene, Charleen Sales, Jérôme Lamontagne-Proulx, Marie-Kim St-Pierre, Omid Tavassoly, Wen Luo, Esther Del Cid-Pellitero, Raza Qazi, Jae-Woong Jeong, Thomas M Durcan, Luc Vallières, Marie-Eve Tremblay, Denis Soulet, Martin Lévesque, Francesca Cicchetti, Edward A Fon, Armen Saghatelyan, Abid Oueslati.
      Neurodegenerative disorders refer to a group of diseases commonly associated with abnormal protein accumulation and aggregation in the central nervous system. However, the exact role of protein aggregation in the pathophysiology of these disorders remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of protein aggregation, and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables spatiotemporal control of α-synuclein (α-syn) aggregation into insoluble deposits called Lewy bodies (LBs), the pathological hallmark of Parkinson disease (PD) and other proteinopathies. We demonstrate that LIPA-α-syn inclusions mimic key biochemical, biophysical, and ultrastructural features of authentic LBs observed in PD-diseased brains. In vivo, LIPA-α-syn aggregates compromise nigrostriatal transmission, induce neurodegeneration and PD-like motor impairments. Collectively, our findings provide a new tool for the generation, visualization, and dissection of the role of α-syn aggregation in PD.
    DOI:  https://doi.org/10.1371/journal.pbio.3001578
  45. Proc Natl Acad Sci U S A. 2022 Mar 15. 119(11): e2118479119
    Tsc2 knockout counteracts ubiquitin-proteasome system insufficiency and delays photoreceptor loss in retinitis pigmentosa.
    Yixiao Wang, Claudio Punzo, John D Ash, Ekaterina S Lobanova.
      SignificanceStudies in multiple experimental systems have demonstrated that an increase in proteolytic capacity of post-mitotic cells improves cellular resistance to a variety of stressors, delays cellular aging and senescence. Therefore, approaches to increase the ability of cells to degrade misfolded proteins could potentially be applied to the treatment of a broad spectrum of human disorders. An example would be retinal degenerations, which cause irreversible loss of vision and are linked to impaired protein degradation. This study suggests that chronic activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway in degenerating photoreceptor neurons could stimulate the degradation of ubiquitinated proteins and enhance proteasomal activity through phosphorylation.
    Keywords:  mTORC1; photoreceptor; proteasome; protein phosphorylation; retinal degeneration
    DOI:  https://doi.org/10.1073/pnas.2118479119
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