bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024‒07‒14
fifty-four papers selected by
Viktor Korolchuk, Newcastle University
  1. mTORC2: A neglected player in aging regulation.
  2. Pho81 is a novel regulator of pexophagy induced by phosphate starvation.
  3. Let's talk about flux: the rising potential of autophagy rate measurements in disease.
  4. Unraveling the ultrastructure and dynamics of autophagic vesicles: Insights from advanced imaging techniques.
  5. Autophagy alterations in obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease: the evidence from human studies.
  6. Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies.
  7. Ca2+-triggered Atg11-Bmh1/2-Snf1 complex assembly initiates autophagy upon glucose starvation.
  8. Ragopathies and the rising influence of RagGTPases on human diseases.
  9. Enhanced autophagic clearance of amyloid-β via HDAC6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo.
  10. Harnessing autophagy: A potential breakthrough in digestive disease treatment.
  11. BL-918 activates PINK1/Parkin signaling pathway to ameliorate the progression of Parkinson's disease.
  12. Rab27b promotes lysosomal function and alpha-synuclein clearance in neurons.
  13. High frequency electrical stimulation reduces α-synuclein levels and α-synuclein-mediated autophagy dysfunction.
  14. Non-coding RNAs as regulators of autophagy in chondrocytes: Mechanisms and implications for osteoarthritis.
  15. PINK1 regulated mitophagy is evident in skeletal muscles.
  16. Unlocking a New Path: An Autophagometer that Measures Flux Using a Non-Fluorescent Immunohistochemistry Method.
  17. PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.
  18. Role of autophagy and ferroptosis in the development of endometriotic cysts (Review).
  19. Investigating TIP30-Mediated regulation of mTORC1 signaling as a therapeutic strategy for coxsackievirus B3-Induced viral myocarditis.
  20. Exploratory bibliometric analysis and text mining to reveal research trends in cardiac aging.
  21. Selective host autophagy is induced during the intracellular parasite Toxoplasma gondii infection controlling amino acid levels.
  22. Selective Termination of Autophagy-Dependent Cancers.
  23. New developments in AMPK and mTORC1 cross-talk.
  24. The Roles of mTOR Signaling in Nasopharyngeal Carcinoma: From Pathogenesis to Therapy.
  25. Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
  26. Pressure sensing of lysosomes enables control of TFEB responses in macrophages.
  27. The role of MNK1-mTORC1 pathway in modulating macrophage responses to Vibrio vulnificus infection.
  28. tRNA m1A modification regulate HSC maintenance and self-renewal via mTORC1 signaling.
  29. Blockage of Autophagy for Cancer Therapy: A Comprehensive Review.
  30. Autophagy is suppressed by low temperatures and is dispensable for cold acclimation in Arabidopsis.
  31. Lens autophagy protein ATG16L1: a potential target for cataract treatment.
  32. The Alzheimer's disease gene SORL1 regulates lysosome function in human microglia.
  33. Chemotherapy's effects on autophagy in the treatment of Hodgkin's lymphoma: a scoping review.
  34. Proteomic Methods to Study Autophagy in Skin Exposed to Pollutants.
  35. Protective Proteolysis in Huntington's Disease: Unraveling the Role of Post-Translational Myristoylation of Huntingtin in Autophagy.
  36. Hypoxia-Preconditioned BMSC-Derived Exosomes Induce Mitophagy via the BNIP3-ANAX2 Axis to Alleviate Intervertebral Disc Degeneration.
  37. SlMDH3 Interacts with Autophagy Receptor Protein SlATI1 and Positively Regulates Tomato Heat Tolerance.
  38. Endonucleosis mediates internalization of cytoplasm into the nucleus.
  39. Role of mitophagy in pulmonary hypertension: Targeting the mechanism and pharmacological intervention.
  40. BMSCs promote alveolar epithelial cell autophagy to reduce pulmonary fibrosis by inhibiting core fucosylation modifications.
  41. Inhibition of autophagy induced by tetrandrine promotes the accumulation of reactive oxygen species and sensitizes efficacy of tetrandrine in pancreatic cancer.
  42. Egg multivesicular bodies elicit an LC3-associated phagocytosis-like pathway to degrade paternal mitochondria after fertilization.
  43. Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.
  44. Role of AMPK-regulated autophagy in retinal pigment epithelial cell homeostasis: A review.
  45. Lipid Droplet-Mitochondria Contacts in Health and Disease.
  46. Dietary salt promotes cognitive impairment through repression of SIRT3/PINK1-mediated mitophagy and fission.
  47. Genetically Encoded and Modular SubCellular Organelle Probes (GEM-SCOPe) reveal lysosomal and mitochondrial dysfunction driven by PRKN knockout.
  48. Perillaldehyde alleviates polyQ-induced neurodegeneration through the induction of autophagy and mitochondrial UPR in Caenorhabditis elegans.
  49. Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles.
  50. Lysosomal TRPML1 triggers global Ca2+ signals and nitric oxide release in human cerebrovascular endothelial cells.
  51. Computational and Experimental Approaches Towards Understanding the Role of ATG8 in Autophagy: A Therapeutic Paradigm in Leishmaniasis.
  52. Canagliflozin Mitigates Diabetic Cardiomyopathy through Enhanced PINK1-Parkin Mitophagy.
  53. The role of autophagy/lipophagy in the response of osteoblastic cells to hyperlipidemia (Review).
  54. Inhibition of NLRP3 inflammasome ameliorates LPS-induced neuroinflammatory injury in mice via PINK1/Parkin pathway.
  1. J Cell Physiol. 2024 Jul 10. e31363
    mTORC2: A neglected player in aging regulation.
    Weitong Xu, Honghan Chen, Hengyi Xiao.
      Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a pivotal role in various biological processes, through integrating external and internal signals, facilitating gene transcription and protein translation, as well as by regulating mitochondria and autophagy functions. mTOR kinase operates within two distinct protein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which engage separate downstream signaling pathways impacting diverse cellular processes. Although mTORC1 has been extensively studied as a pro-proliferative factor and a pro-aging hub if activated aberrantly, mTORC2 received less attention, particularly regarding its implication in aging regulation. However, recent studies brought increasing evidence or clues for us, which implies the associations of mTORC2 with aging, as the genetic elimination of unique subunits of mTORC2, such as RICTOR, has been shown to alleviate aging progression in comparison to mTORC1 inhibition. In this review, we first summarized the basic characteristics of mTORC2, including its protein architecture and signaling network. We then focused on reviewing the molecular signaling regulation of mTORC2 in cellular senescence and organismal aging, and proposed the multifaceted regulatory characteristics under senescent and nonsenescent contexts. Next, we outlined the research progress of mTOR inhibitors in the field of antiaging and discussed future prospects and challenges. It is our pleasure if this review article could provide meaningful information for our readers and call forth more investigations working on this topic.
    Keywords:  aging; apoptosis; autophagy; diabetes; mTORC2; neurodegenerative
    DOI:  https://doi.org/10.1002/jcp.31363
  2. Autophagy. 2024 Jul 11. 1-2
    Pho81 is a novel regulator of pexophagy induced by phosphate starvation.
    Yuxiang Huang, Daniel J Klionsky.
      In the budding yeast Saccharomyces cerevisiae, macroautophagy/autophagy can be induced by various types of starvation. It is thought that potential autophagic substrates vary to meet specific nutritional demands under different starvation conditions. In a recent study, Gross et al. found that autophagy induced by phosphate starvation includes many selective aspects. For example, this work identified Pho81 as a regulator of pexophagy under conditions of phosphate starvation. Pho81 senses phosphate metabolites and directly interacts with Atg11 to promote Atg1-mediated Atg11 phosphorylation. This finding provides an example of how modulation of the Atg1/ULK kinase complex can convey specific metabolic information to regulate autophagic substrates.Abbreviation: AKC: Atg1/ULK kinase complex.
    Keywords:  Atg11 phosphorylation; GFP-Atg8 processing assay; SPX domain; autophagy; proteomics
    DOI:  https://doi.org/10.1080/15548627.2024.2377421
  3. Autophagy. 2024 Jul 10. 1-7
    Let's talk about flux: the rising potential of autophagy rate measurements in disease.
    Nitin Sai Beesabathuni, Matthew W Kenaston, Ritika Gangaraju, Neil Alvin B Adia, Vardhan Peddamallu, Priya S Shah.
      Macroautophagy/autophagy is increasingly implicated in a variety of diseases, making it an attractive therapeutic target. However, many aspects of autophagy are not fully understood and its impact on many diseases remains debatable and context-specific. The lack of systematic and dynamic measurements in these cases is a key reason for this ambiguity. In recent years, Loos et al. 2014 and Beesabathuni et al. 2022 developed methods to quantitatively measure autophagy holistically. In this commentary, we pose some of the unresolved biological questions regarding autophagy and consider how quantitative measurements may address them. While the applications are ever-expanding, we provide specific use cases in cancer, virus infection, and mechanistic screening. We address how the rate measurements themselves are central to developing cancer therapies and present ways in which these tools can be leveraged to dissect the complexities of virus-autophagy interactions. Screening methods can be combined with rate measurements to mechanistically decipher the labyrinth of autophagy regulation in cancer and virus infection. Taken together, these approaches have the potential to illuminate the underlying mechanisms of various diseases.Abbreviation MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; R1: rate of autophagosome formation; R2: rate of autophagosome-lysosome fusion; R3: rate of autolysosome turnover.
    Keywords:  Autophagy flux; autophagy perturbation; autophagy temporal dynamics; autophagy-dependent cell death; cancer; virus infection
    DOI:  https://doi.org/10.1080/15548627.2024.2371708
  4. FASEB Bioadv. 2024 Jul;6(7): 189-199
    Unraveling the ultrastructure and dynamics of autophagic vesicles: Insights from advanced imaging techniques.
    Ting Jiang, Chaoye Ma, Hao Chen.
      Autophagy, an intracellular self-degradation process, is governed by a complex interplay of signaling pathways and interactions between proteins and organelles. Its fundamental purpose is to efficiently clear and recycle cellular components that are damaged or redundant. Central to this process are autophagic vesicles, specialized structures that encapsulate targeted cellular elements, playing a pivotal role in autophagy. Despite growing interest in the molecular components of autophagic machinery and their regulatory mechanisms, capturing the detailed ultrastructural dynamics of autophagosome formation continues to present significant challenges. However, recent advancements in microscopy, particularly in electron microscopy, have begun to illuminate the dynamic regulatory processes underpinning autophagy. This review endeavors to provide an exhaustive overview of contemporary research on the ultrastructure of autophagic processes. By synthesizing observations from diverse technological methodologies, this review seeks to deepen our understanding of the genesis of autophagic vesicles, their membrane origins, and the dynamic alterations that transpire during the autophagy process. The aim is to bridge gaps in current knowledge and foster a more comprehensive comprehension of this crucial cellular mechanism.
    Keywords:  autophagy; ultrastructure; volume electron microscope
    DOI:  https://doi.org/10.1096/fba.2024-00035
  5. Intern Emerg Med. 2024 Jul 06.
    Autophagy alterations in obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease: the evidence from human studies.
    Patrycja Jakubek, Barbara Pakula, Martin Rossmeisl, Paolo Pinton, Alessandro Rimessi, Mariusz Roman Wieckowski.
      Autophagy is an evolutionarily conserved process that plays a pivotal role in the maintenance of cellular homeostasis and its impairment has been implicated in the pathogenesis of various metabolic diseases including obesity, type 2 diabetes (T2D), and metabolic dysfunction-associated steatotic liver disease (MASLD). This review synthesizes the current evidence from human studies on autophagy alterations under these metabolic conditions. In obesity, most data point to autophagy upregulation during the initiation phase of autophagosome formation, potentially in response to proinflammatory conditions in the adipose tissue. Autophagosome formation appears to be enhanced under hyperglycemic or insulin-resistant conditions in patients with T2D, possibly acting as a compensatory mechanism to eliminate damaged organelles and proteins. Other studies have proposed that prolonged hyperglycemia and disrupted insulin signaling hinder autophagic flux, resulting in the accumulation of dysfunctional cellular components that can contribute to β-cell dysfunction. Evidence from patients with MASLD supports autophagy inhibition in disease progression. Nevertheless, given the available data, it is difficult to ascertain whether autophagy is enhanced or suppressed in these conditions because the levels of autophagy markers depend on the overall metabolism of specific organs, tissues, experimental conditions, or disease duration. Owing to these constraints, determining whether the observed shifts in autophagic activity precede or result from metabolic diseases remains challenging. Additionally, autophagy-modulating strategies are shortly discussed. To conclude, more studies investigating autophagy impairment are required to gain a more comprehensive understanding of its role in the pathogenesis of obesity, T2D, and MASLD and to unveil novel therapeutic strategies for these conditions.
    Keywords:  Autophagy modulators; Cellular quality control; Metabolic diseases; Patients; Therapies; Tissue biopsy
    DOI:  https://doi.org/10.1007/s11739-024-03700-w
  6. ACS Omega. 2024 Jul 02. 9(26): 27832-27852
    Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies.
    Nada Walweel, Omer Aydin.
      The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.
    DOI:  https://doi.org/10.1021/acsomega.4c02234
  7. J Cell Biol. 2024 Sep 02. pii: e202310049. [Epub ahead of print]223(9):
    Ca2+-triggered Atg11-Bmh1/2-Snf1 complex assembly initiates autophagy upon glucose starvation.
    Weijing Yao, Yingcong Chen, Yi Zhang, Shu Zhong, Miaojuan Ye, Yuting Chen, Siyu Fan, Miao Ye, Huan Yang, Yixing Li, Choufei Wu, Mingzhu Fan, Shan Feng, Zhaoxiang He, Long Zhou, Liqin Zhang, Yigang Wang, Wei Liu, Jingjing Tong, Du Feng, Cong Yi.
      Autophagy is essential for maintaining glucose homeostasis. However, the mechanism by which cells sense and respond to glucose starvation to induce autophagy remains incomplete. Here, we show that calcium serves as a fundamental triggering signal that connects environmental sensing to the formation of the autophagy initiation complex during glucose starvation. Mechanistically, glucose starvation instigates the release of vacuolar calcium into the cytoplasm, thus triggering the activation of Rck2 kinase. In turn, Rck2-mediated Atg11 phosphorylation enhances Atg11 interactions with Bmh1/2 bound to the Snf1-Sip1-Snf4 complex, leading to recruitment of vacuolar membrane-localized Snf1 to the PAS and subsequent Atg1 activation, thereby initiating autophagy. We also identified Glc7, a protein phosphatase-1, as a critical regulator of the association between Bmh1/2 and the Snf1 complex. We thus propose that calcium-triggered Atg11-Bmh1/2-Snf1 complex assembly initiates autophagy by controlling Snf1-mediated Atg1 activation in response to glucose starvation.
    DOI:  https://doi.org/10.1083/jcb.202310049
  8. Nat Commun. 2024 Jul 10. 15(1): 5812
    Ragopathies and the rising influence of RagGTPases on human diseases.
    Irene Sambri, Marco Ferniani, Andrea Ballabio.
      RagGTPases (Rags) play an essential role in the regulation of cell metabolism by controlling the activities of both mechanistic target of rapamycin complex 1 (mTORC1) and Transcription factor EB (TFEB). Several diseases, herein named ragopathies, are associated to Rags dysfunction. These diseases may be caused by mutations either in genes encoding the Rags, or in their upstream regulators. The resulting phenotypes may encompass a variety of clinical features such as cataract, kidney tubulopathy, dilated cardiomyopathy and several types of cancer. In this review, we focus on the key clinical, molecular and physio-pathological features of ragopathies, aiming to shed light on their underlying mechanisms.
    DOI:  https://doi.org/10.1038/s41467-024-50034-4
  9. Neural Regen Res. 2024 Jul 10.
    Enhanced autophagic clearance of amyloid-β via HDAC6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo.
    Zhimin Long, Chuanhua Ge, Yueyang Zhao, Yuanjie Liu, Qinghua Zeng, Qing Tang, Zhifang Dong, Guiqiong He.
      ABSTRACT: Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-β in neurons, which is a key step in senile plaque formation. Therefore, restoring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease. Microtubule acetylation/deacetylation plays a central role in lysosomal acidification. Here, we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease. Furthermore, we found that treatment with valproic acid markedly enhanced autophagy, promoted clearance of amyloid-β aggregates, and ameliorated cognitive deficits in a mouse model of Alzheimer's disease. Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease, in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-01633
  10. World J Gastroenterol. 2024 Jun 28. 30(24): 3036-3043
    Harnessing autophagy: A potential breakthrough in digestive disease treatment.
    Mukaddes Esrefoglu.
      Autophagy, a conserved cellular degradation process, is crucial for various cellular processes such as immune responses, inflammation, metabolic and oxidative stress adaptation, cell proliferation, development, and tissue repair and remodeling. Dysregulation of autophagy is suspected in numerous diseases, including cancer, neurodegenerative diseases, digestive disorders, metabolic syndromes, and infectious and inflammatory diseases. If autophagy is disrupted, for example, this can have serious consequences and lead to chronic inflammation and tissue damage, as occurs in diseases such as Chron's disease and ulcerative colitis. On the other hand, the influence of autophagy on the development and progression of cancer is not clear. Autophagy can both suppress and promote the progression and metastasis of cancer at various stages. From inflammatory bowel diseases to gastrointestinal cancer, researchers are discovering the intricate role of autophagy in maintaining gut health and its potential as a therapeutic target. Researchers should carefully consider the nature and progression of diseases such as cancer when trying to determine whether inhibiting or stimulating autophagy is likely to be beneficial. Multidisciplinary approaches that combine cutting-edge research with clinical expertise are key to unlocking the full therapeutic potential of autophagy in digestive diseases.
    Keywords:  Autophagy; Digestive disease; Gastrointestinal cancer; Harnessing autophagy; Inflammatory bowel disease
    DOI:  https://doi.org/10.3748/wjg.v30.i24.3036
  11. J Biol Chem. 2024 Jul 09. pii: S0021-9258(24)02044-1. [Epub ahead of print] 107543
    BL-918 activates PINK1/Parkin signaling pathway to ameliorate the progression of Parkinson's disease.
    Yi Wang, Siyuan Luo, Huili Su, Zhimeng Wang, Ling Chu, Conggang Zhang.
      The pathogenesis of Parkinson's disease (PD) has been associated with mitochondrial dysfunction. Given that the PINK1/Parkin pathway governs mitochondrial quality control by inducing mitophagy to remove damaged mitochondria, therapeutic approaches to activate PINK1/Parkin-mediated mitophagy have the potential in the treatment of PD. Here, we have identified a new small molecule, BL-918, as an inducer of mitophagy via activating the PINK1/Parkin pathway. BL-918 triggers PINK1 accumulation and Parkin mitochondrial translocation to initiate PINK1/Parkin-mediated mitophagy. We found that mitochondrial membrane potential and mitochondrial permeability transition (mPT) pore were involved in BL-918-induced PINK1/Parkin pathway activation. Moreover, we showed that BL-918 mitigated PD progression in MPTP-induced PD mice in a PINK1-dependent manner. Our results unravel a new activator of the PINK1/Parkin signaling pathway and provide a potential strategy for the treatment of PD and other diseases with dysfunctional mitochondria.
    Keywords:  Mitochondrial quality control; Mitophagy; PINK1; Parkin; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.jbc.2024.107543
  12. bioRxiv. 2024 Jun 24. pii: 2024.06.20.599785. [Epub ahead of print]
    Rab27b promotes lysosomal function and alpha-synuclein clearance in neurons.
    Kasandra Scholz, Rudradip Pattanayak, Ekkatine Roschonporn, Frank Sanders Pair, Amber Nobles, Talene A Yacoubian.
      Alpha-synuclein (αsyn) is the key pathogenic protein implicated in synucleinopathies including Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). In these diseases, αsyn is thought to spread between cells where it accumulates and induces pathology; however, mechanisms that drive its propagation or aggregation are poorly understood. We have previously reported that the small GTPase Rab27b is elevated in human PD and DLB and that it can mediate the autophagic clearance and toxicity of αsyn in a paracrine αsyn cell culture neuronal model. Here, we expanded our previous work and further characterized a role for Rab27b in neuronal lysosomal processing and αsyn clearance. We found that Rab27b KD in this αsyn inducible neuronal model resulted in lysosomal dysfunction and increased αsyn levels in lysosomes. Similar lysosomal proteolytic defects and enzymatic dysfunction were observed in both primary neuronal cultures and brain lysates from Rab27b knockout (KO) mice. αSyn aggregation was exacerbated in Rab27b KO neurons upon treatment with αsyn preformed fibrils. We found no changes in lysosomal counts or lysosomal pH in either model, but we did identify defects in acidic vesicle trafficking in Rab27b KO primary neurons which may drive lysosomal dysfunction and promote αsyn aggregation. Rab27b OE enhanced lysosomal activity and reduced insoluble αsyn accumulation. Finally we found elevated Rab27b levels in human postmortem incidental Lewy Body Disease (iLBD) subjects relative to healthy controls. These data suggest a role for Rab27b in neuronal lysosomal activity and identify it as a potential therapeutic target in synucleinopathies.
    DOI:  https://doi.org/10.1101/2024.06.20.599785
  13. Sci Rep. 2024 Jul 12. 14(1): 16091
    High frequency electrical stimulation reduces α-synuclein levels and α-synuclein-mediated autophagy dysfunction.
    Jimmy George, Kashfia Shafiq, Minesh Kapadia, Lorraine V Kalia, Suneil K Kalia.
      Accumulation of α-synuclein (α-Syn) has been implicated in proteasome and autophagy dysfunction in Parkinson's disease (PD). High frequency electrical stimulation (HFS) mimicking clinical parameters used for deep brain stimulation (DBS) in vitro or DBS in vivo in preclinical models of PD have been found to reduce levels of α-Syn and, in certain cases, provide possible neuroprotection. However, the mechanisms by which this reduction in α-Syn improves cellular dysfunction associated with α-Syn accumulation remains elusive. Using HFS parameters that recapitulate DBS in vitro, we found that HFS led to a reduction of mutant α-Syn and thereby limited proteasome and autophagy impairments due to α-Syn. Additionally, we observed that HFS modulates via the ATP6V0C subunit of V-ATPase and mitigates α-Syn mediated autophagic dysfunction. This study highlights a role for autophagy in reduction of α-Syn due to HFS which may prove to be a viable approach to decrease pathological protein accumulation in neurodegeneration.
    Keywords:  ATPases; Alpha-synuclein; Autophagy; Deep brain stimulation; High frequency stimulation; Parkinson’s disease
    DOI:  https://doi.org/10.1038/s41598-024-64131-3
  14. Ageing Res Rev. 2024 Jul 05. pii: S1568-1637(24)00222-8. [Epub ahead of print]99 102404
    Non-coding RNAs as regulators of autophagy in chondrocytes: Mechanisms and implications for osteoarthritis.
    Chenyu Zhu, Lingli Zhang, Xiaoqing Ding, Wei Wu, Jun Zou.
      Osteoarthritis (OA) is a chronic degenerative joint disease with multiple causative factors such as aging, mechanical injury, and obesity. Autophagy is a complex dynamic process that is involved in the degradation and modification of intracellular proteins and organelles under different pathophysiological conditions. Autophagy, as a cell survival mechanism under various stress conditions, plays a key role in regulating chondrocyte life cycle metabolism and cellular homeostasis. Non-coding RNAs (ncRNAs) are heterogeneous transcripts that do not possess protein-coding functions, but they can act as effective post-transcriptional and epigenetic regulators of gene and protein expression, thus participating in numerous fundamental biological processes. Increasing evidence suggests that ncRNAs, autophagy, and their crosstalk play crucial roles in OA pathogenesis. Therefore, we summarized the complex role of autophagy in OA chondrocytes and focused on the regulatory role of ncRNAs in OA-associated autophagy to elucidate the complex pathological mechanisms of the ncRNA-autophagy network in the development of OA, thus providing new research targets for the clinical diagnosis and treatment of OA.
    Keywords:  Autophagy; Chrondrocyte; Circular RNAs; Long non-coding RNAs; Micro RNAs; Non-coding RNAs; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.arr.2024.102404
  15. Autophagy Rep. 2024 Mar 11. 3(1): 2326402
    PINK1 regulated mitophagy is evident in skeletal muscles.
    Francois Singh, Lea Wilhelm, Alan R Prescott, Kevin Ostacolo, Jin-Feng Zhao, Margret H Ogmundsdottir, Ian G Ganley.
      PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.
    Keywords:  PINK1; POLG; Parkinson’s; mitophagy; muscle; mutator
    DOI:  https://doi.org/10.1080/27694127.2024.2326402
  16. bioRxiv. 2024 Jun 30. pii: 2024.06.26.600741. [Epub ahead of print]
    Unlocking a New Path: An Autophagometer that Measures Flux Using a Non-Fluorescent Immunohistochemistry Method.
    Shahla Shojaei, Amir Barzegar Behrooz, Marco Cordani, Mahmood Aghaei, Negar Azarpira, Daniel J Klionsky, Saeid Ghavami.
      Macroautophagy/autophagy, a crucial cellular process, is typically measured using fluorescence-based techniques, which can be costly, complex, and impractical for clinical settings. In this paper, we introduce a novel, cost-effective, non-fluorescent immunohistochemistry (IHC) method for evaluating autophagy flux. This technique, based on antigen-antibody reactions and chromogenic detection, provides clear, quantifiable results under standard light microscopy, eliminating the need for expensive equipment and specialized reagents. Our method simplifies technical requirements, making it accessible to routine clinical laboratories and research settings with limited resources. By comparing our approach with traditional fluorescence methods, we demonstrate its superior effectiveness, cost-efficiency, and applicability to patient samples. This innovative technique has the potential to significantly advance autophagy research and improve clinical diagnostics, offering a practical and robust tool for studying autophagy mechanisms in diseases such as cancer and neurodegenerative disorders. Our non-fluorescent IHC method represents a significant step forward in evaluating autophagy flux, making it more accessible and reliable, with the promise of enhancing our understanding and treatment of autophagy-related diseases.
    DOI:  https://doi.org/10.1101/2024.06.26.600741
  17. EMBO Rep. 2024 Jul 11.
    PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.
    Giang Thanh Nguyen-Dien, Brendan Townsend, Prajakta Gosavi Kulkarni, Keri-Lyn Kozul, Soo Siang Ooi, Denaye N Eldershaw, Saroja Weeratunga, Meihan Liu, Mathew Jk Jones, S Sean Millard, Dominic Ch Ng, Michele Pagano, Alexis Bonfim-Melo, Tobias Schneider, David Komander, Michael Lazarou, Brett M Collins, Julia K Pagan.
      Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy.
    Keywords:  BNIP3; FBXL4; Mitophagy; NIX; PPTC7
    DOI:  https://doi.org/10.1038/s44319-024-00181-y
  18. Int J Mol Med. 2024 Sep;pii: 78. [Epub ahead of print]54(3):
    Role of autophagy and ferroptosis in the development of endometriotic cysts (Review).
    Hiroshi Kobayashi, Shogo Imanaka, Chiharu Yoshimoto, Sho Matsubara, Hiroshi Shigetomi.
      It is considered that the etiology of endometriosis is retrograde menstruation of endometrial tissue. Although shed endometrial cells are constantly exposed to a challenging environment with iron overload, oxidative stress and hypoxia, a few cells are able to survive and continue to proliferate and invade. Ferroptosis, an iron‑dependent form of non‑apoptotic cell death, is known to play a major role in the development and course of endometriosis. However, few papers have concentrated on the dynamic interaction between autophagy and ferroptosis throughout the progression of diseases. The present review summarized the current understanding of the mechanisms underlying autophagy and ferroptosis in endometriosis and discuss their role in disease development and progression. For the present narrative review electronic databases including PubMed and Google Scholar were searched for literature published up to the October 31, 2023. Autophagy and ferroptosis may be activated at early stages in endometriosis development. On the other hand, excessive activation of intrinsic pathways (e.g., estrogen and mechanistic target of rapamycin) may promote disease progression through autophagy inhibition. Furthermore, suppression of ferroptosis may cause further progression of endometriotic lesions. In conclusion, the autophagy and ferroptosis pathways may play a dual role in disease initiation and progression. The present review discussed the temporal transition of non‑apoptotic cell death regulation during disease progression from retrograde endometrium to early lesions to established lesions.
    Keywords:  autophagy; endometriosis; ferroptosis; regulated cell death
    DOI:  https://doi.org/10.3892/ijmm.2024.5402
  19. Virology. 2024 Jun 21. pii: S0042-6822(24)00177-6. [Epub ahead of print]597 110156
    Investigating TIP30-Mediated regulation of mTORC1 signaling as a therapeutic strategy for coxsackievirus B3-Induced viral myocarditis.
    Xi-Lei Liu, Yu-Yan Hou, Shu-Hong Su, Xiao Wu, Zhi-Fang Wang.
      This study aims to elucidate the role of TIP30 (30 KDa HIV-1 TAT-Interacting Protein) in the progression of coxsackievirus B3 (CVB3)-induced viral myocarditis. TIP30 knockout and wildtype mice were intraperitoneally infected with CVB3 and evaluated at day 7 post-infection. HeLa cells were transfected with TIP30 lentiviral particles and subsequently infected with CVB3 to evaluate viral replication, cellular pathogenesis, and mechanistic target of rapamycin complex 1 (mTORC1) signaling. Deletion of the TIP30 gene heightened heart virus titers and mortality rates in mice with CVB3-induced myocarditis, exacerbating cardiac damage and fibrosis, and elevating pro-inflammatory factors level. In vitro experiments demonstrated the modulation of mTORC1 signaling by TIP30 during CVB3 infection in HeLa cells. TIP30 overexpression mitigated CVB3-induced cellular pathogenesis and VP1 expression, with rapamycin, an mTOR1 inhibitor, reversing these effects. These findings suggest TIP30 plays a critical protective role against CVB3-induced myocarditis by regulating mTORC1 signaling.
    Keywords:  30 KDa HIV-1 TAT-Interacting protein; Coxsackievirus B3; Viral myocarditis; mTORC1 signaling
    DOI:  https://doi.org/10.1016/j.virol.2024.110156
  20. Aging Med (Milton). 2024 Jun;7(3): 301-311
    Exploratory bibliometric analysis and text mining to reveal research trends in cardiac aging.
    Takahiro Kamihara, Ken Tanaka, Takuya Omura, Shinji Kaneko, Akihiro Hirashiki, Manabu Kokubo, Atsuya Shimizu.
      Objectives: We conducted a text mining analysis of 40 years of literature on cardiac aging from PubMed to investigate the current understanding on cardiac aging and its mechanisms. This study aimed to embody what most researchers consider cardiac aging to be.Methods: We used multiple text mining and machine learning tools to extract important information from a large amount of text.
    Results: Analysis revealed that the terms most frequently associated with cardiac aging include "diastolic," "hypertrophy," "fibrosis," "apoptosis," "mitochondrial," "oxidative," and "autophagy." These terms suggest that cardiac aging is characterized by mitochondrial dysfunction, oxidative stress, and impairment of autophagy, especially mitophagy. We also revealed an increase in the frequency of occurrence of "autophagy" in recent years, suggesting that research on autophagy has made a breakthrough in the field of cardiac aging. Additionally, the frequency of occurrence of "mitophagy" has increased significantly since 2019, suggesting that mitophagy is an important factor in cardiac aging.
    Conclusions: Cardiac aging is a complex process that involves mitochondrial dysfunction, oxidative stress, and impairment of autophagy, especially mitophagy. Further research is warranted to elucidate the mechanisms of cardiac aging and develop strategies to mitigate its detrimental effects.
    Keywords:  autophagy; cardiac aging; mitophagy
    DOI:  https://doi.org/10.1002/agm2.12329
  21. mSphere. 2024 Jul 09. e0036924
    Selective host autophagy is induced during the intracellular parasite Toxoplasma gondii infection controlling amino acid levels.
    Matthew D White, Rajendra K Angara, Leticia Torres Dias, Dhananjay D Shinde, Vinai C Thomas, Leonardo Augusto.
      Toxoplasma gondii, a widespread parasite, has the ability to infect nearly any nucleated cell in warm-blooded vertebrates. It is estimated that around 2 billion people globally have been infected by this pathogen. Although most healthy individuals can effectively control parasite replication, certain parasites may evade the immune response, establishing cysts in the brain that are refractory to the immune system and resistant to available drugs. For its chronic persistence in the brain, the parasite relies on host cells' nutrients, particularly amino acids and lipids. Therefore, understanding how latent parasites persist in the brain is crucial for identifying potential drug targets against chronic forms. While shielded within parasitophorous vacuoles (PVs) or cysts, Toxoplasma exploits the host endoplasmic reticulum (ER) metabolism to sustain its persistence in the brain, resulting in host neurological alterations. In this study, we demonstrate that T. gondii disrupts the host ER homeostasis, resulting in the accumulation of unfolded protein within the host ER. The host counters this stress by initiating an autophagic pathway known as ER-phagy, which breaks down unfolded proteins into amino acids, promoting their recycling. Our findings unveil the underlying mechanisms employed by T. gondii to exploit host ER and lysosomal pathways, enhancing nutrient levels during infection. These insights provide new strategies for the treatment of toxoplasmosis.IMPORTANCE: Intracellular parasites employ several mechanisms to manipulate the cellular environment, enabling them to persist in the host. Toxoplasma gondii, a single-celled parasite, possesses the ability to infect virtually any nucleated cell of warm-blooded vertebrates, including nearly 2 billion people worldwide. Unfortunately, existing treatments and immune responses are not entirely effective in eliminating the chronic persisting forms of the parasite. This study reveals that T. gondii induces the host's autophagic pathway to boost amino acid levels in infected cells. The depletion of amino acids, in turn, influences the persistence of the parasite's chronic forms. Significantly, our investigation establishes the crucial role of host endoplasmic reticulum (ER)-phagy in the parasite's persistence within the host during latent infection.
    Keywords:  ER-phagy; Toxoplasma gondii; amino acid; behavior; endoplasmic reticulum
    DOI:  https://doi.org/10.1128/msphere.00369-24
  22. Cells. 2024 Jun 25. pii: 1096. [Epub ahead of print]13(13):
    Selective Termination of Autophagy-Dependent Cancers.
    Ajit Roy, Melvin L DePamphilis.
      The goal of cancer research is to identify characteristics of cancer cells that allow them to be selectively eliminated without harming the host. One such characteristic is autophagy dependence. Cancer cells survive, proliferate, and metastasize under conditions where normal cells do not. Thus, the requirement in cancer cells for more energy and macromolecular biosynthesis can evolve into a dependence on autophagy for recycling cellular components. Recent studies have revealed that autophagy, as well as different forms of cellular trafficking, is regulated by five phosphoinositides associated with eukaryotic cellular membranes and that the enzymes that synthesize them are prime targets for cancer therapy. For example, PIKFYVE inhibitors rapidly disrupt lysosome homeostasis and suppress proliferation in all cells. However, these inhibitors selectively terminate PIKFYVE-dependent cancer cells and cancer stem cells with not having adverse effect on normal cells. Here, we describe the biochemical distinctions between PIKFYVE-sensitive and -insensitive cells, categorize PIKFYVE inhibitors into four groups that differ in chemical structure, target specificity and efficacy on cancer cells and normal cells, identify the mechanisms by which they selectively terminate autophagy-dependent cancer cells, note their paradoxical effects in cancer immunotherapy, and describe their therapeutic applications against cancers.
    Keywords:  PIKFYVE; PIP4K2C; PIP5K1C; apoptosis; autophagy; cancer; endoplasmic reticulum stress
    DOI:  https://doi.org/10.3390/cells13131096
  23. Essays Biochem. 2024 Jul 12. pii: EBC20240007. [Epub ahead of print]
    New developments in AMPK and mTORC1 cross-talk.
    William J Smiles, Ashley J Ovens, Bruce E Kemp, Sandra Galic, Janni Petersen, Jonathan S Oakhill.
      Metabolic homeostasis and the ability to link energy supply to demand are essential requirements for all living cells to grow and proliferate. Key to metabolic homeostasis in all eukaryotes are AMPK and mTORC1, two kinases that sense nutrient levels and function as counteracting regulators of catabolism (AMPK) and anabolism (mTORC1) to control cell survival, growth and proliferation. Discoveries beginning in the early 2000s revealed that AMPK and mTORC1 communicate, or cross-talk, through direct and indirect phosphorylation events to regulate the activities of each other and their shared protein substrate ULK1, the master initiator of autophagy, thereby allowing cellular metabolism to rapidly adapt to energy and nutritional state. More recent reports describe divergent mechanisms of AMPK/mTORC1 cross-talk and the elaborate means by which AMPK and mTORC1 are activated at the lysosome. Here, we provide a comprehensive overview of current understanding in this exciting area and comment on new evidence showing mTORC1 feedback extends to the level of the AMPK isoform, which is particularly pertinent for some cancers where specific AMPK isoforms are implicated in disease pathogenesis.
    Keywords:  AMPK; cancer; mechanistic target of rapamycin; metabolism; signalling
    DOI:  https://doi.org/10.1042/EBC20240007
  24. Curr Mol Pharmacol. 2024 Jul 10.
    The Roles of mTOR Signaling in Nasopharyngeal Carcinoma: From Pathogenesis to Therapy.
    Ting Gong, Gui Cao, Danyang Sun, Tongtong Ge, Ping Li.
      Nasopharyngeal carcinoma (NPC) is an epithelial malignancy caused by cancer of the mucosal epithelial cells of the nasopharynx. Most patients with NPC present with distant metastases and treatment resistance, both of which challenge current anti-tumour drugs. The mammalian target of the rapamycin (mTOR) signalling pathway is one of the most highly activated signalling pathways in NPC and plays an important role in various cellular activities. Dysfunction of mTOR and related signalling pathways induces tumour metabolism and growth. In this review, we summarize current evidence to evaluate the potential mechanisms by which mTOR is implicated in NPC. It was found that activating mTOR and its upstream and downstream signalling can promote tumor growth and survival of NPC. It is possible that EMT and autophagy regulated by cellular mTOR signalling activities may be implicated in the metastases and radioresistance of NPC.
    Keywords:  Autophagy; EMT.; Nasopharyngeal carcinoma; Tumor therapy; mTOR
    DOI:  https://doi.org/10.2174/0118761429293675240709061332
  25. Life Sci Alliance. 2024 Sep;pii: e202402765. [Epub ahead of print]7(9):
    Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
    Lianjie Wei, Mehmet Oguz Gok, Jordyn D Svoboda, Keri-Lyn Kozul, Merima Forny, Jonathan R Friedman, Natalie M Niemi.
      PPTC7 is a mitochondrial-localized phosphatase that suppresses BNIP3- and NIX-mediated mitophagy, but the mechanisms underlying this regulation remain ill-defined. Here, we demonstrate that loss of PPTC7 upregulates BNIP3 and NIX post-transcriptionally and independent of HIF-1α stabilization. Loss of PPTC7 prolongs the half-life of BNIP3 and NIX while blunting their accumulation in response to proteasomal inhibition, suggesting that PPTC7 promotes the ubiquitin-mediated turnover of BNIP3 and NIX. Consistently, overexpression of PPTC7 limits the accumulation of BNIP3 and NIX protein levels, which requires an intact catalytic motif but is surprisingly independent of its targeting to mitochondria. Consistently, we find that PPTC7 is dual-localized to the outer mitochondrial membrane and the matrix. Importantly, anchoring PPTC7 to the outer mitochondrial membrane is sufficient to blunt BNIP3 and NIX accumulation, and proximity labeling and fluorescence co-localization experiments demonstrate that PPTC7 dynamically associates with BNIP3 and NIX within the native cellular environment. Collectively, these data reveal that a fraction of PPTC7 localizes to the outer mitochondrial membrane to promote the proteasomal turnover of BNIP3 and NIX, limiting basal mitophagy.
    DOI:  https://doi.org/10.26508/lsa.202402765
  26. Nat Cell Biol. 2024 Jul 12.
    Pressure sensing of lysosomes enables control of TFEB responses in macrophages.
    Ruiqi Cai, Ori Scott, Gang Ye, Trieu Le, Ekambir Saran, Whijin Kwon, Subothan Inpanathan, Blayne A Sayed, Roberto J Botelho, Amra Saric, Stefan Uderhardt, Spencer A Freeman.
      Polymers are endocytosed and hydrolysed by lysosomal enzymes to generate transportable solutes. While the transport of diverse organic solutes across the plasma membrane is well studied, their necessary ongoing efflux from the endocytic fluid into the cytosol is poorly appreciated by comparison. Myeloid cells that employ specialized types of endocytosis, that is, phagocytosis and macropinocytosis, are highly dependent on such transport pathways to prevent the build-up of hydrostatic pressure that otherwise offsets lysosomal dynamics including vesiculation, tubulation and fission. Without undergoing rupture, we found that lysosomes incurring this pressure owing to defects in solute efflux, are unable to retain luminal Na+, which collapses its gradient with the cytosol. This cation 'leak' is mediated by pressure-sensitive channels resident to lysosomes and leads to the inhibition of mTORC1, which is normally activated by Na+-coupled amino acid transporters driven by the Na+ gradient. As a consequence, the transcription factors TFEB/TFE3 are made active in macrophages with distended lysosomes. In addition to their role in lysosomal biogenesis, TFEB/TFE3 activation causes the release of MCP-1/CCL2. In catabolically stressed tissues, defects in efflux of solutes from the endocytic pathway leads to increased monocyte recruitment. Here we propose that macrophages respond to a pressure-sensing pathway on lysosomes to orchestrate lysosomal biogenesis as well as myeloid cell recruitment.
    DOI:  https://doi.org/10.1038/s41556-024-01459-y
  27. Microbiol Spectr. 2024 Jul 09. e0334023
    The role of MNK1-mTORC1 pathway in modulating macrophage responses to Vibrio vulnificus infection.
    Yong-Liang Lou, Dan-Li Xie, Xian-Hui Huang, Meng-Meng Zheng, Na Chen, Ji-Ru Xu.
      Vibrio vulnificus (Vv) is known to cause life-threatening infections, particularly septicemia. These patients often exhibit elevated levels of pro-inflammatory cytokines. While it is established that mitogen-activated protein kinase (MAPK)-interacting kinase (MNK) contributes to the production of pro-inflammatory cytokines, the role of MNK in macrophages during Vv infection remains unclear. In this study, we investigate the impact of MNK on macrophages. We demonstrate that the inhibition of MNK in J774A.1 cells, when treated with lipopolysaccharide or Vv, resulted in decreased production of tumor necrosis factor alpha and interleukin-6, without affecting their transcription. Interestingly, treatment with MNK inhibitor CGP57380 led to enhanced phosphorylation of MNK1 but decreased phosphorylation of eIF4E. Moreover, MNK1 knockout cells exhibited an increased capacity for phagocytosis and clearance of Vv, with more acidic phagosomes than the parental cells. Notably, CGP57380 did not impact phagocytosis, bacterial clearance, or phagosome acidification in Vv-infected J774A.1 cells. Considering the reported association between MNK and mammalian target of rapamycin complex 1 (mTORC1) activation, we investigated the mTORC1 signaling in MNK1 knockout cells infected with Vv. Our results revealed that attenuation of the mTORC1 signaling in these cells and treatment with the mTORC1 inhibitor rapamycin significantly enhanced bacterial clearance in J774A.1 cells following Vv infection. In summary, our findings suggest that MNK promotes the Vv-induced cytokine production in J774A.1 cells without affecting their transcription levels. MNK1 appears to impair the phagocytosis, bacterial clearance, and phagosome acidification in Vv-infected J774A.1 cells through the MNK1-mTORC1 signaling pathway rather than the MNK1-eIF4E signaling pathway. Our findings highlight the importance of the MNK1-mTORC1 pathway in modulating macrophage responses to Vv infection.IMPORTANCE: Mitogen-activated protein kinase (MAPK)-interacting kinase (MNK) plays a role in promoting the production of tumor necrosis factor alpha and interleukin-6 in macrophages during Vibrio vulnificus (Vv) infection. Inhibition or knockout of MNK1 in J774A.1 cells resulted in reduced cytokine production without affecting their transcription levels. MNK1 also impairs phagocytosis, bacterial clearance, and phagosome acidification in Vv-infected cells through the MNK1-mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. The findings highlight the importance of the MNK1-mTORC1 pathway in modulating macrophage responses to Vv infection.
    Keywords:  MNK; Vibrio vulnificus; bactericidal activity; inflammation; mTOR; macrophage; phagocytosis
    DOI:  https://doi.org/10.1128/spectrum.03340-23
  28. Nat Commun. 2024 Jul 08. 15(1): 5706
    tRNA m1A modification regulate HSC maintenance and self-renewal via mTORC1 signaling.
    Hongna Zuo, Aiwei Wu, Mingwei Wang, Liquan Hong, Hu Wang.
      Haematopoietic stem cells (HSCs) possess unique physiological adaptations to sustain blood cell production and cope with stress responses throughout life. To maintain these adaptations, HSCs rely on maintaining a tightly controlled protein translation rate. However, the mechanism of how HSCs regulate protein translation remains to be fully elucidated. In this study, we investigate the role of transfer RNA (tRNA) m1A58 'writer' proteins TRMT6 and TRMT61A in regulating HSCs function. Trmt6 deletion promoted HSC proliferation through aberrant activation of mTORC1 signaling. TRMT6-deficient HSCs exhibited an impaired self-renewal ability in competitive transplantation assay. Mechanistically, single cell RNA-seq analysis reveals that the mTORC1 signaling pathway is highly upregulated in HSC-enriched cell populations after Trmt6 deletion. m1A-tRNA-seq and Western blot analysis suggest that TRMT6 promotes methylation modification of specific tRNA and expression of TSC1, fine-tuning mTORC1 signaling levels. Furthermore, Pharmacological inhibition of the mTORC1 pathway rescued functional defect in TRMT6-deficient HSCs. To our knowledge, this study is the first to elucidate a mechanism by which TRMT6-TRMT61A complex-mediated tRNA-m1A58 modification regulates HSC homeostasis.
    DOI:  https://doi.org/10.1038/s41467-024-50110-9
  29. Int J Mol Sci. 2024 Jul 07. pii: 7459. [Epub ahead of print]25(13):
    Blockage of Autophagy for Cancer Therapy: A Comprehensive Review.
    Ahmed Mostafa Ibrahim Abdelrahman Hassan, Yuxin Zhao, Xiuping Chen, Chengwei He.
      The incidence and mortality of cancer are increasing, making it a leading cause of death worldwide. Conventional treatments such as surgery, radiotherapy, and chemotherapy face significant limitations due to therapeutic resistance. Autophagy, a cellular self-degradation mechanism, plays a crucial role in cancer development, drug resistance, and treatment. This review investigates the potential of autophagy inhibition as a therapeutic strategy for cancer. A systematic search was conducted on Embase, PubMed, and Google Scholar databases from 1967 to 2024 to identify studies on autophagy inhibitors and their mechanisms in cancer therapy. The review includes original articles utilizing in vitro and in vivo experimental methods, literature reviews, and clinical trials. Key terms used were "Autophagy", "Inhibitors", "Molecular mechanism", "Cancer therapy", and "Clinical trials". Autophagy inhibitors such as chloroquine (CQ) and hydroxychloroquine (HCQ) have shown promise in preclinical studies by inhibiting lysosomal acidification and preventing autophagosome degradation. Other inhibitors like wortmannin and SAR405 target specific components of the autophagy pathway. Combining these inhibitors with chemotherapy has demonstrated enhanced efficacy, making cancer cells more susceptible to cytotoxic agents. Clinical trials involving CQ and HCQ have shown encouraging results, although further investigation is needed to optimize their use in cancer therapy. Autophagy exhibits a dual role in cancer, functioning as both a survival mechanism and a cell death pathway. Targeting autophagy presents a viable strategy for cancer therapy, particularly when integrated with existing treatments. However, the complexity of autophagy regulation and the potential side effects necessitate further research to develop precise and context-specific therapeutic approaches.
    Keywords:  autophagy inhibitors; cancer therapy; clinical trials
    DOI:  https://doi.org/10.3390/ijms25137459
  30. Physiol Plant. 2024 Jul-Aug;176(4):176(4): e14409
    Autophagy is suppressed by low temperatures and is dispensable for cold acclimation in Arabidopsis.
    Akito Sato, Sena Inayoshi, Kohei Kitawaki, Ryota Mihara, Kosei Yoneda, Yasuko Ito-Inaba, Takehito Inaba.
      Plants have evolved various mechanisms to adapt to the ever-changing external environment. Autophagy is one such mechanism and has been suggested to play a key role in responding to and adapting to abiotic stresses in plants. However, the role of autophagy in adaptation to cold and freezing stresses remains to be characterized in detail. Here, we investigated the role of autophagy in the low-temperature response of Arabidopsis using atg mutants. Both the atg5-1 and atg10-1 mutants exhibited normal freezing tolerance, regardless of cold acclimation. A comparison of fresh weights indicated that the difference in growth between the wild-type and atg plants under cold conditions was rather small compared with that under normal conditions. Analysis of COLD-REGULATED gene expression showed no significant differences between the atg mutants and wild type. Treatment with 3-methyladenine, an inhibitor of autophagy, did not impair the induction of COR15Apro::LUC expression upon exposure to low temperature. Evaluation of autophagic activity using transgenic plants expressing RBCS-mRFP demonstrated that autophagy was rarely induced by cold exposure, even in the dark. Taken together, these data suggest that autophagy is suppressed by low temperatures and is dispensable for cold acclimation and freezing tolerance in Arabidopsis.
    DOI:  https://doi.org/10.1111/ppl.14409
  31. Theranostics. 2024 ;14(10): 3984-3996
    Lens autophagy protein ATG16L1: a potential target for cataract treatment.
    Yilei Cui, Xiaoning Yu, Jing Bao, Xiyuan Ping, Silu Shi, Yuxin Huang, Qichuan Yin, Hao Yang, Ruoqi Chen, Ke Yao, Xiangjun Chen, Xingchao Shentu.
      Rationale: Cataract is the leading cause of blindness and low vision worldwide, yet its pathological mechanism is not fully understood. Although macroautophagy/autophagy is recognized as essential for lens homeostasis and has shown potential in alleviating cataracts, its precise mechanism remains unclear. Uncovering the molecular details of autophagy in the lens could provide targeted therapeutic interventions alongside surgery. Methods: We monitored autophagic activities in the lens and identified the key autophagy protein ATG16L1 by immunofluorescence staining, Western blotting, and transmission electron microscopy. The regulatory mechanism of ATG16L1 ubiquitination was analyzed by co-immunoprecipitation and Western blotting. We used the crystal structure of E3 ligase gigaxonin and conducted the docking screening of a chemical library. The effect of the identified compound riboflavin was tested in vitro in cells and in vivo animal models. Results: We used HLE cells and connexin 50 (cx50)-deficient cataract zebrafish model and confirmed that ATG16L1 was crucial for lens autophagy. Stabilizing ATG16L1 by attenuating its ubiquitination-dependent degradation could promote autophagy activity and relieve cataract phenotype in cx50-deficient zebrafish. Mechanistically, the interaction between E3 ligase gigaxonin and ATG16L1 was weakened during this process. Leveraging these mechanisms, we identified riboflavin, an E3 ubiquitin ligase-targeting drug, which suppressed ATG16L1 ubiquitination, promoted autophagy, and ultimately alleviated the cataract phenotype in autophagy-related models. Conclusions: Our study identified an unrecognized mechanism of cataractogenesis involving ATG16L1 ubiquitination in autophagy regulation, offering new insights for treating cataracts.
    Keywords:  ATG16L1; E3 ligase; autophagy; cataract; ubiquitination
    DOI:  https://doi.org/10.7150/thno.93864
  32. bioRxiv. 2024 Jun 25. pii: 2024.06.25.600648. [Epub ahead of print]
    The Alzheimer's disease gene SORL1 regulates lysosome function in human microglia.
    Swati Mishra, Nader Morshed, Chizuru Kinoshita, Beth Stevens, Suman Jayadev, Jessica E Young.
      The SORL1 gene encodes the sortilin related receptor protein SORLA, a sorting receptor that regulates endo-lysosomal trafficking of various substrates. Loss of function variants in SORL1 are causative for Alzheimer's disease (AD) and decreased expression of SORLA has been repeatedly observed in human AD brains. SORL1 is highly expressed by microglia, the tissue resident immune cells of the brain. Loss of SORLA leads to enlarged lysosomes in hiPSC-derived microglia like cells (hMGLs). However, whether SORLA deficiency contributes to microglia dysfunction and how this is relevant to AD is not known. In this study, we show that loss of SORLA results in decreased lysosomal degradation and lysosomal enzyme activity due to altered trafficking of lysosomal enzymes in hMGLs. Furthermore, lysosomal exocytosis, an important process involved in immune responses and cellular signaling, is also impaired in SORL1 deficient microglia. Phagocytic uptake of fibrillar amyloid beta 1-42 and synaptosomes is increased in SORLA deficient hMGLs, but due to reduced lysosomal degradation, these substrates aberrantly accumulate in lysosomes. Overall, these data highlight the microglial endo-lysosomal network as a potential novel pathway through which SORL1 may increase AD risk and contribute to development of AD. Additionally, our findings may inform development of novel lysosome and microglia associated drug targets for AD.
    DOI:  https://doi.org/10.1101/2024.06.25.600648
  33. Discov Oncol. 2024 Jul 08. 15(1): 269
    Chemotherapy's effects on autophagy in the treatment of Hodgkin's lymphoma: a scoping review.
    Roro Wahyudianingsih, Ardo Sanjaya, Timothy Jonathan, Emmy Hermiyanti Pranggono, Dimyati Achmad, Bethy Suryawathy Hernowo.
      BACKGROUND: Classical Hodgkin Lymphomas (HL) are a unique malignant growth with an excellent initial prognosis. However, 10-30% of patients will still relapse after remission. One primary cellular function that has been the focus of tumor progression is autophagy. This process can preserve cellular homeostasis under stressful conditions. Several studies have shown that autophagy may play a role in developing HL. Therefore, this review aimed to explore chemotherapy's effect on autophagy in HL, and the effects of autophagy on HL.METHODS: A scoping review in line with the published PRISMA extension for scoping reviews (PRISMA-ScR) was conducted. A literature search was conducted on the MEDLINE database and the Cochrane Central Register of Controlled Trials (CENTRAL). All results were retrieved and screened, and the resulting articles were synthesized narratively.
    RESULTS: The results showed that some cancer chemotherapy also induces autophagic flux. Although the data on HL is limited, since the mechanisms of action of these drugs are similar, we can infer a similar relationship. However, this increased autophagy activity may reflect a mechanism for increasing tumor growth or a cellular compensation to inhibit its growth. Although evidence supports both views, we argued that autophagy allowed cancer cells to resist cell death, mainly due to DNA damage caused by cytotoxic drugs.
    CONCLUSION: Autophagy reflects the cell's adaptation to survive and explains why chemotherapy generally induces autophagy functions. However, further research on autophagy inhibition is needed as it presents a viable treatment strategy, especially against drug-resistant populations that may arise from HL chemotherapy regimens.
    Keywords:  Antineoplastic Agents; Autophagy; DNA damage; Hodgkin's lymphoma
    DOI:  https://doi.org/10.1007/s12672-024-01142-6
  34. Methods Mol Biol. 2024 Jul 13.
    Proteomic Methods to Study Autophagy in Skin Exposed to Pollutants.
    Mohammad Fayyad-Kazan, Sandrine Bourgoin-Voillard, Walid Rachidi, Michel Seve.
      Autophagy refers to the natural cellular process by which cells degrade and recycle their own damaged or dysfunctional cellular components. It is an essential mechanism for maintaining cellular homeostasis removing toxic substances and providing energy during times of stress or nutrient deprivation. When autophagy is dysregulated or impaired, it can have detrimental effects on cell function and overall health. Studying autophagy in skin exposed to pollutants can provide valuable insights into the cellular mechanisms underlying pollutant-induced skin damage. Proteomic methods, which involve the large-scale analysis of proteins, can be employed to investigate the changes in protein expression associated with biological processes including autophagy. Here, we thus describe a method where LC-MS/MS was applied to identify the deregulated proteins in pollutant exposed-skin. Using bioinformatics and statistical analysis, we extracted the qualitative and quantitative information for proteins involved in autophagy. These deregulated proteins were then validated by immunohistochemistry (IHC). These methods help to understand how the pollutants affect the autophagy process.
    Keywords:  Autophagy; Diseases; Proteomics; Skin
    DOI:  https://doi.org/10.1007/7651_2024_555
  35. J Huntingtons Dis. 2024 Jul 08.
    Protective Proteolysis in Huntington's Disease: Unraveling the Role of Post-Translational Myristoylation of Huntingtin in Autophagy.
    Yasmeen Alshehabi, Dale D O Martin.
       Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by impaired motor function and cognitive decline, ultimately leading to death. HD is caused by a polyglutamine expansion in the N-terminal region of the huntingtin (HTT) protein, which is linked to decreased HTT turnover, increased HTT proteolysis, increased HTT aggregation, and subsequent neuronal death. In this review, we explore the mechanism of the protective effect of blocking HTT proteolysis at D586, which has been shown to rescue the HD phenotype in HD mouse models. Until recently, the mechanism remained unclear. Herein, we discuss how blocking HTT proteolysis at D586 promotes HTT turnover by correcting autophagy, and making HTT a better autophagy substrate, through post-translational myristoylation of HTT at G553.
    Keywords:  Autophagy; huntingtin; myristoylation; neurodegeneration; proteolysis
    DOI:  https://doi.org/10.3233/JHD-240028
  36. Adv Sci (Weinh). 2024 Jul 08. e2404275
    Hypoxia-Preconditioned BMSC-Derived Exosomes Induce Mitophagy via the BNIP3-ANAX2 Axis to Alleviate Intervertebral Disc Degeneration.
    Yuxin Jin, Ouqiang Wu, Qizhu Chen, Linjie Chen, Zhiguang Zhang, Haijun Tian, Hao Zhou, Kai Zhang, Jianyuan Gao, Xinzhou Wang, Zhenyu Guo, Jing Sun, Kenny Yat Hong Kwan, Morgan Jones, Yan Michael Li, Ehsan Nazarzadeh Zare, Pooyan Makvandi, Xiangyang Wang, Shuying Shen, Aimin Wu.
      Intervertebral disc degeneration (IVDD) is a chronic degenerative disease involving the aging and loss of proliferative capacity of nucleus pulposus cells (NPCs), processes heavily dependent on mitochondrial dynamics and autophagic flux. This study finds that the absence of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is associated with senescence-related NPC degeneration, disrupting mitochondrial quality control. Bone marrow mesenchymal stem cells (BMSCs) have multidirectional differentiation potential and produce extracellular vesicles containing cellular activators. Therefore, in this study, BMSCs are induced under hypoxic stimulation to deliver BNIP3-rich extracellular vesicles to NPCs, thereby alleviating aging-associated mitochondrial autophagic flux, promoting damaged mitochondrial clearance, and restoring mitochondrial quality control. Mechanistically, BNIP3 is shown to interact with the membrane-bound protein annexin A2 (ANXA2), enabling the liberation of the transcription factor EB (TFEB) from the ANXA2-TFEB complex, promoting TFEB nuclear translocation, and regulating autophagy and lysosomal gene activation. Furthermore, a rat model of IVDD is established and verified the in vivo efficacy of the exosomes in repairing disc injuries, delaying NPC aging, and promoting extracellular matrix (ECM) synthesis. In summary, hypoxia-induced BMSC exosomes deliver BNIP3-rich vesicles to alleviate disc degeneration by activating the mitochondrial BNIP3/ANXA2/TFEB axis, providing a new target for IVDD treatment.
    Keywords:  Intervertebral disc degeneration; bone marrow mesenchymal stem cells; exosomes; hypoxia‐preconditioned mesenchymal stem cells; matrix reconstruction; mitophagy
    DOI:  https://doi.org/10.1002/advs.202404275
  37. Int J Mol Sci. 2024 Jun 26. pii: 7000. [Epub ahead of print]25(13):
    SlMDH3 Interacts with Autophagy Receptor Protein SlATI1 and Positively Regulates Tomato Heat Tolerance.
    Sitian Wang, Li Zhang, Linyang Zhang, Kang Yong, Tao Chen, Lijun Cao, Minghui Lu.
      Autophagy, a highly conserved protein degradation system, plays an important role in protecting cells from adverse environmental conditions. ATG8-INTERACTING PROTEIN1 (ATI1) acts as an autophagy receptor, but its functional mechanisms in plants' heat stress tolerance remain unclear. In this study, using LC-MS/MS, we identified malate dehydrogenase (SlMDH3) as a SlATI1-interacting protein. Further studies showed that heat stress induced the expression of SlMDH3 and SlMDH3 co-localized with SlATI1 under both 22 °C and 42 °C heat treatment conditions. Moreover, silencing of SlMDH3 increased the sensitivity of tomato to heat stress, as evidenced by exacerbated degradation of chlorophyll; accumulation of MDA, H2O2, and dead cells; increased relative conductivity; and inhibition of stress-related gene expression. Conversely, overexpression of SlMDH3 improved tomato's heat tolerance, leading to opposite effects on physiological indicators and gene expression compared to SlMDH3 silencing. Taken together, our study suggests that SlMDH3 interacts with SlATI1 and positively regulates tomato heat tolerance.
    Keywords:  ATI1; autophagy; heat stress; malate dehydrogenase; tomato
    DOI:  https://doi.org/10.3390/ijms25137000
  38. Nat Commun. 2024 Jul 11. 15(1): 5843
    Endonucleosis mediates internalization of cytoplasm into the nucleus.
    Ourania Galanopoulou, Evangelia C Tachmatzidi, Elena Deligianni, Dimitris Botskaris, Kostas C Nikolaou, Sofia Gargani, Yannis Dalezios, Georges Chalepakis, Iannis Talianidis.
      Setd8 regulates transcription elongation, mitotic DNA condensation, DNA damage response and replication licensing. Here we show that, in mitogen-stimulated liver-specific Setd8-KO mice, most of the hepatocytes are eliminated by necrosis but a significant number of them survive via entering a stage exhibiting several senescence-related features. Setd8-deficient hepatocytes had enlarged nuclei, chromosomal hyperploidy and nuclear engulfments progressing to the formation of intranuclear vesicles surrounded by nuclear lamina. These vesicles contain glycogen, cytoplasmic proteins and even entire organelles. We term this process "endonucleosis". Intranuclear vesicles are absent in hepatocytes of Setd8/Atg5 knockout mice, suggesting that the process requires the function of the canonical autophagy machinery. Endonucleosis and hyperploidization are temporary, early events in the surviving Setd8-deficient cells. Larger vesicles break down into microvesicles over time and are eventually eliminated. The results reveal sequential events in cells with extensive DNA damage, which function as part of survival mechanisms to prevent necrotic death.
    DOI:  https://doi.org/10.1038/s41467-024-50259-3
  39. Mitochondrion. 2024 Jul 09. pii: S1567-7249(24)00086-2. [Epub ahead of print]78 101928
    Role of mitophagy in pulmonary hypertension: Targeting the mechanism and pharmacological intervention.
    Jia-Jing Wan, Jian Yi, Fei-Ying Wang, Xia Li, Chao Zhang, Lan Song, Ai-Guo Dai.
      Mitophagy, a crucial pathway in eukaryotic cells, selectively eliminates dysfunctional mitochondria, thereby maintaining cellular homeostasis via mitochondrial quality control. Pulmonary hypertension (PH) refers to a pathological condition where pulmonary arterial pressure is abnormally elevated due to various reasons, and the underlying pathogenesis remains elusive. This article examines the molecular mechanisms underlying mitophagy, emphasizing its role in PH and the progress in elucidating related molecular signaling pathways. Additionally, it highlights current drug regulatory pathways, aiming to provide novel insights into the prevention and treatment of pulmonary hypertension.
    Keywords:  Mechanism; Mitophagy; Pulmonary hypertension
    DOI:  https://doi.org/10.1016/j.mito.2024.101928
  40. Stem Cells. 2024 Jul 10. pii: sxae044. [Epub ahead of print]
    BMSCs promote alveolar epithelial cell autophagy to reduce pulmonary fibrosis by inhibiting core fucosylation modifications.
    Jinying Hu, Nan Wang, Yu Jiang, Yina Li, Biaojie Qin, Zhongzhen Wang, Lili Gao.
      BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive interstitial lung disease characterized by alveolar epithelial cell (AEC) injury and fibroblast activation. Inadequate autophagy in AECs may result from the activation of several signaling pathways following AEC injury, with glycoproteins serving as key receptor proteins. The core fucosylation (CF) modification in glycoproteins is crucial. Mesenchymal stem cells derived from bone marrow (BMSCs) have the ability to regenerate damaged tissue and treat pulmonary fibrosis (PF). This study aimed to elucidate the relationship and mechanism of interaction between BMSCs, CF modification, and autophagy in PF.METHODS: C57BL/6 male mice, alveolar epithelial cell-specific FUT8 conditional knockout (CKO) mice, and MLE12 cells were administered bleomycin (BLM), FUT8 siRNA, and mouse BMSCs, respectively. Experimental techniques including tissue staining, western blotting, immunofluorescence, autophagic flux detection, and flow cytometry were utilized in this study.
    RESULTS: First, we found that autophagy was inhibited while FUT8 expression was elevated in PF mice and BLM-induced AEC injury models. Subsequently, CKO mice and MLE12 cells transfected with FUT8 siRNA were employed to demonstrate that inhibition of CF modification induces autophagy in AECs and mitigates PF. Finally, mouse BMSCs were utilized to demonstrate that they alleviate the detrimental autophagy of AECs by inhibiting CF modification and decreasing PF.
    CONCLUSIONS: Suppression of CF modification enhanced the suppression of AEC autophagy and reduced PF in mice. Additionally, through the prevention of CF modification, BMSCs can assist AECs deficient in autophagy and partially alleviate PF.
    Keywords:  alveolar epithelial cells; autophagy; bone marrow mesenchymal stem cells; core fucosylation modification; pulmonary fibrosis
    DOI:  https://doi.org/10.1093/stmcls/sxae044
  41. Cancer Cell Int. 2024 Jul 10. 24(1): 241
    Inhibition of autophagy induced by tetrandrine promotes the accumulation of reactive oxygen species and sensitizes efficacy of tetrandrine in pancreatic cancer.
    Yiwei Wang, Ting Xu, Hongcheng Wang, Guanggai Xia, Xinyu Huang.
      Pancreatic cancer, characterized by its poor prognosis, exhibits a marked resistance to conventional chemotherapy and immunotherapy, underscoring the urgent need for more effective treatment modalities. In light of this, the present study is designed to assess the potential antineoplastic efficacy of a combined regimen involving tetrandrine, a plant-derived alkaloid, and autophagy inhibitors in the context of pancreatic cancer. Electron microscopy and immunoblots showed that tetrandrine promoted the formation of autophagosomes and the upregulation of LC3II and the downregulation of p62 expression, indicating that tetrandrine induced autophagy in pancreatic cancer cells. Western blot revealed that tetrandrine inhibited the phosphorylation of AKT and mTOR, as well as the expression of Bcl-2, while upregulating Beclin-1 expression. Moreover, tetrandrine promoted the transcription and protein expression of ATG7. Following the combination of autophagy inhibitors and tetrandrine, the apoptotic rate and cell death significantly increased in pancreatic cancer cells. Consistent results were obtained when ATG7 was silenced. Additionally, tetrandrine induced the generation of ROS, which was involved in the activation of autophagy and apoptosis. Further investigation revealed that upon autophagy inhibition, ROS accumulated in pancreatic cancer cells, resulting in decreased mitochondrial membrane potential and further induction of apoptosis. The results of treating subcutaneous xenograft tumors with a combination of tetrandrine and chloroquine validated that autophagy inhibition enhances the toxicity of tetrandrine against pancreatic cancer in vivo. Altogether, our study demonstrates that tetrandrine induces cytoprotective autophagy in pancreatic cancer cells. Inhibiting tetrandrine-induced autophagy promotes the accumulation of ROS and enhances its toxicity against pancreatic cancer.
    Keywords:  Apoptosis; Autophagy; Pancreatic cancer; Reactive oxygen species; Tetrandrine
    DOI:  https://doi.org/10.1186/s12935-024-03410-5
  42. Nat Commun. 2024 Jul 08. 15(1): 5715
    Egg multivesicular bodies elicit an LC3-associated phagocytosis-like pathway to degrade paternal mitochondria after fertilization.
    Sharon Ben-Hur, Shoshana Sernik, Sara Afar, Alina Kolpakova, Yoav Politi, Liron Gal, Anat Florentin, Ofra Golani, Ehud Sivan, Nili Dezorella, David Morgenstern, Shmuel Pietrokovski, Eyal Schejter, Keren Yacobi-Sharon, Eli Arama.
      Mitochondria are maternally inherited, but the mechanisms underlying paternal mitochondrial elimination after fertilization are far less clear. Using Drosophila, we show that special egg-derived multivesicular body vesicles promote paternal mitochondrial elimination by activating an LC3-associated phagocytosis-like pathway, a cellular defense pathway commonly employed against invading microbes. Upon fertilization, these egg-derived vesicles form extended vesicular sheaths around the sperm flagellum, promoting degradation of the sperm mitochondrial derivative and plasma membrane. LC3-associated phagocytosis cascade of events, including recruitment of a Rubicon-based class III PI(3)K complex to the flagellum vesicular sheaths, its activation, and consequent recruitment of Atg8/LC3, are all required for paternal mitochondrial elimination. Finally, lysosomes fuse with strings of large vesicles derived from the flagellum vesicular sheaths and contain degrading fragments of the paternal mitochondrial derivative. Given reports showing that in some mammals, the paternal mitochondria are also decorated with Atg8/LC3 and surrounded by multivesicular bodies upon fertilization, our findings suggest that a similar pathway also mediates paternal mitochondrial elimination in other flagellated sperm-producing organisms.
    DOI:  https://doi.org/10.1038/s41467-024-50041-5
  43. Nat Commun. 2024 Jul 10. 15(1): 5818
    Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.
    Kazuhiro Yamada, Claudette St Croix, Donna B Stolz, Yulia Y Tyurina, Vladimir A Tyurin, Laura R Bradley, Alexander A Kapralov, Yanhan Deng, Xiuxia Zhou, Qi Wei, Bo Liao, Nobuhiko Fukuda, Mara Sullivan, John Trudeau, Anuradha Ray, Valerian E Kagan, Jinming Zhao, Sally E Wenzel.
      A stable mitochondrial pool is crucial for healthy cell function and survival. Altered redox biology can adversely affect mitochondria through induction of a variety of cell death and survival pathways, yet the understanding of mitochondria and their dysfunction in primary human cells and in specific disease states, including asthma, is modest. Ferroptosis is traditionally considered an iron dependent, hydroperoxy-phospholipid executed process, which induces cytosolic and mitochondrial damage to drive programmed cell death. However, in this report we identify a lipoxygenase orchestrated, compartmentally-targeted ferroptosis-associated peroxidation process which occurs in a subpopulation of dysfunctional mitochondria, without promoting cell death. Rather, this mitochondrial peroxidation process tightly couples with PTEN-induced kinase (PINK)-1(PINK1)-Parkin-Optineurin mediated mitophagy in an effort to preserve the pool of functional mitochondria and prevent cell death. These combined peroxidation processes lead to altered epithelial cell phenotypes and loss of ciliated cells which associate with worsened asthma severity. Ferroptosis-targeted interventions of this process could preserve healthy mitochondria, reverse cell phenotypic changes and improve disease outcomes.
    DOI:  https://doi.org/10.1038/s41467-024-50222-2
  44. Medicine (Baltimore). 2024 Jul 12. 103(28): e38908
    Role of AMPK-regulated autophagy in retinal pigment epithelial cell homeostasis: A review.
    Liangliang Zhou, Ya Mo, Haiyan Zhang, Mengdi Zhang, Jiayu Xu, Sumin Liang.
      The retinal pigment epithelium (RPE) is a regularly arranged monolayer of cells in the outermost layer of the retina. It is crucial for transporting nutrients and metabolic substances in the retina and maintaining the retinal barrier. RPE dysfunction causes diseases related to vision loss. Thus, understanding the mechanisms involved in normal RPE function is vital. Adenosine monophosphate-activated protein kinase (AMPK) is an RPE energy sensor regulating various signaling and metabolic pathways to maintain cellular energetic homeostasis. AMPK activation is involved in multiple signaling pathways regulated by autophagy in the RPE, thereby protecting the cells from oxidative stress and slowing RPE degeneration. In this review, we attempt to broaden the understanding of the pathogenesis of RPE dysfunction by focusing on the role and mechanism of AMPK regulation of autophagy in the RPE. The correlation between RPE cellular homeostasis and role of AMPK was determined by analyzing the structure and mechanism of AMPK and its signaling pathway in autophagy. The protective effect of AMPK-regulated autophagy on the RPE for gaining insights into the regulatory pathways of RPE dysfunction has been discussed.
    DOI:  https://doi.org/10.1097/MD.0000000000038908
  45. Int J Mol Sci. 2024 Jun 22. pii: 6878. [Epub ahead of print]25(13):
    Lipid Droplet-Mitochondria Contacts in Health and Disease.
    Hongjun Fan, Yanjie Tan.
      The orchestration of cellular metabolism and redox balance is a complex, multifaceted process crucial for maintaining cellular homeostasis. Lipid droplets (LDs), once considered inert storage depots for neutral lipids, are now recognized as dynamic organelles critical in lipid metabolism and energy regulation. Mitochondria, the powerhouses of the cell, play a central role in energy production, metabolic pathways, and redox signaling. The physical and functional contacts between LDs and mitochondria facilitate a direct transfer of lipids, primarily fatty acids, which are crucial for mitochondrial β-oxidation, thus influencing energy homeostasis and cellular health. This review highlights recent advances in understanding the mechanisms governing LD-mitochondria interactions and their regulation, drawing attention to proteins and pathways that mediate these contacts. We discuss the physiological relevance of these interactions, emphasizing their role in maintaining energy and redox balance within cells, and how these processes are critical in response to metabolic demands and stress conditions. Furthermore, we explore the pathological implications of dysregulated LD-mitochondria interactions, particularly in the context of metabolic diseases such as obesity, diabetes, and non-alcoholic fatty liver disease, and their potential links to cardiovascular and neurodegenerative diseases. Conclusively, this review provides a comprehensive overview of the current understanding of LD-mitochondria interactions, underscoring their significance in cellular metabolism and suggesting future research directions that could unveil novel therapeutic targets for metabolic and degenerative diseases.
    Keywords:  disease; lipid droplet; metabolism; mitochondria; redox
    DOI:  https://doi.org/10.3390/ijms25136878
  46. Mol Cell Biochem. 2024 Jul 13.
    Dietary salt promotes cognitive impairment through repression of SIRT3/PINK1-mediated mitophagy and fission.
    Haixia Fan, Minghao Yuan, Shenyuan Wang, Xu Yang, Liu Shu, Yinshuang Pu, Qian Zou, Xiaogang Zhang, Chuanling Wang, Zhiyou Cai.
      Dietary salt is increasingly recognized as an independent risk factor for cognitive impairment. However, the exact mechanisms are not yet fully understood. Mitochondria, which play a crucial role in energy metabolism, are implicated in cognitive function through processes such as mitochondrial dynamics and mitophagy. While mitochondrial dysfunction is acknowledged as a significant determinant of cognitive function, the specific relationship between salt-induced cognitive impairment and mitochondrial health has yet to be fully elucidated. Here, we explored the underlying mechanism of cognitive impairment of mice and N2a cells treated with high-salt focusing on the mitochondrial homeostasis with western blotting, immunofluorescence, electron microscopy, RNA sequencing, and more. We further explored the potential role of SIRT3 in salt-induced mitochondrial dysfunction and synaptic alteration through plasmid transfection and siRNA. High salt diet significantly inhibited mitochondrial fission and blocked mitophagy, leading to dysfunctional mitochondria and impaired synaptic plasticity. Our findings demonstrated that SIRT3 not only promote mitochondrial fission by modulating phosphorylated DRP1, but also rescue mitophagy through promoting PINK1/Parkin-dependent pathway. Overall, our data for the first time indicate that mitochondrial homeostasis imbalance is a driver of impaired synaptic plasticity in a cognitive impairment phenotype that is exacerbated by a long-term high-salt diet, and highlight the protective role of SIRT3 in this process.
    Keywords:  Cognitive impairment; Dietary salt; Mitochondrial homeostasis; Synaptic plasticity
    DOI:  https://doi.org/10.1007/s11010-024-05069-y
  47. bioRxiv. 2024 Jun 29. pii: 2024.05.21.594886. [Epub ahead of print]
    Genetically Encoded and Modular SubCellular Organelle Probes (GEM-SCOPe) reveal lysosomal and mitochondrial dysfunction driven by PRKN knockout.
    Camille Goldman, Tatyana Kareva, Lily Sarrafha, Braxton R Schuldt, Abhishek Sahasrabudhe, Tim Ahfeldt, Joel W Blanchard.
      Cellular processes including lysosomal and mitochondrial dysfunction are implicated in the development of many diseases. Quantitative visualization of mitochondria and lysosoesl is crucial to understand how these organelles are dysregulated during disease. To address a gap in live-imaging tools, we developed GEM-SCOPe (Genetically Encoded and Modular SubCellular Organelle Probes), a modular toolbox of fluorescent markers designed to inform on localization, distribution, turnover, and oxidative stress of specific organelles. We expressed GEM-SCOPe in differentiated astrocytes and neurons from a human pluripotent stem cell PRKN- knockout model of Parkinson's disease and identified disease-associated changes in proliferation, lysosomal distribution, mitochondrial transport and turnover, and reactive oxygen species. We demonstrate GEM-SCOPe is a powerful panel that provide critical insight into the subcellular mechanisms underlying Parkinson's disease in human cells. GEM-SCOPe can be expanded upon and applied to a diversity of cellular models to glean an understanding of the mechanisms that promote disease onset and progression.
    DOI:  https://doi.org/10.1101/2024.05.21.594886
  48. Biofactors. 2024 Jul 11.
    Perillaldehyde alleviates polyQ-induced neurodegeneration through the induction of autophagy and mitochondrial UPR in Caenorhabditis elegans.
    Minglv Fang, Ying Liu, Xiaoyan Gao, Jing Yu, Xiaohui Tu, Xueying Mo, Huanhu Zhu, Yan Zou, Cheng Huang, Shengjie Fan.
      Huntington's disease (HD) is a fatal neurodegenerative disease associated with autophagy disorder and mitochondrial dysfunction. Here, we identified therapeutic potential of perillaldehyde (PAE), a monoterpene compound obtained from Perilla frutescens (L.) Britt., in the Caenorhabditis elegans (C. elegans) model of HD, which included lifespan extension, healthspan improvement, decrease in polyglutamine (polyQ) aggregation, and preservation of mitochondrial network. Further analyses indicated that PAE was able to induce autophagy and mitochondrial unfolded protein reaction (UPRmt) activation and positively regulated expression of associated genes. In lgg-1 RNAi C. elegans or C. elegans with UPRmt-related genes knockdown, the effects of PAE treatment on polyQ aggregation or rescue polyQ-induced toxicity were attenuated, suggesting that its neuroprotective activity depended on autophagy and UPRmt. Moreover, we found that pharmacological and genetic activation of UPRmt generally protected C. elegans from polyQ-induced cytotoxicity. Finally, PAE promoted serotonin synthesis by upregulating expression of TPH-1, and serotonin synthesis and neurosecretion were required for PAE-mediated UPRmt activation and its neuroprotective activity. In conclusion, PAE is a potential therapy for polyQ-related diseases including HD, which is dependent on autophagy and cell-non-autonomous UPRmt activation.
    Keywords:  C. elegans; Huntington's disease; Perillaldehyde; Polyglutamine; UPRmt; autophagy
    DOI:  https://doi.org/10.1002/biof.2089
  49. Neural Regen Res. 2025 Apr 01. 20(4): 1124-1134
    Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles.
    Yanting Liu, Wei Huang, Jiayi Wen, Xin Xiong, Ting Xu, Qi Wang, Xiusheng Chen, Xianxian Zhao, Shihua Li, Xiaojiang Li, Weili Yang.
      JOURNAL/nrgr/04.03/01300535-202504000-00028/figure1/v/2024-07-06T104127Z/r/image-tiff The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration. However, it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains. This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals. Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin. Recently, we showed that the PINK1 kinase is selectively expressed as a truncated form (PINK1-55) in the primate brain. In the present study, we used multiple antibodies, including our recently developed monoclonal anti-PINK1, to validate the selective expression of PINK1 in the primate brain. We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages, which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains. PINK1 was enriched in the membrane-bound fractionations, whereas Parkin was soluble with a distinguishable distribution. Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes, though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress. These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-01140
  50. Front Physiol. 2024 ;15 1426783
    Lysosomal TRPML1 triggers global Ca2+ signals and nitric oxide release in human cerebrovascular endothelial cells.
    Valentina Brunetti, Roberto Berra-Romani, Filippo Conca, Teresa Soda, Gerardo Rosario Biella, Andrea Gerbino, Francesco Moccia, Giorgia Scarpellino.
      Lysosomal Ca2+ signaling is emerging as a crucial regulator of endothelial Ca2+ dynamics. Ca2+ release from the acidic vesicles in response to extracellular stimulation is usually promoted via Two Pore Channels (TPCs) and is amplified by endoplasmic reticulum (ER)-embedded inositol-1,3,4-trisphosphate (InsP3) receptors and ryanodine receptors. Emerging evidence suggests that sub-cellular Ca2+ signals in vascular endothelial cells can also be generated by the Transient Receptor Potential Mucolipin 1 channel (TRPML1) channel, which controls vesicle trafficking, autophagy and gene expression. Herein, we adopted a multidisciplinary approach, including live cell imaging, pharmacological manipulation, and gene targeting, revealing that TRPML1 protein is expressed and triggers global Ca2+ signals in the human brain microvascular endothelial cell line, hCMEC/D3. The direct stimulation of TRPML1 with both the synthetic agonist, ML-SA1, and the endogenous ligand phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) induced a significant increase in [Ca2+]i, that was reduced by pharmacological blockade and genetic silencing of TRPML1. In addition, TRPML1-mediated lysosomal Ca2+ release was sustained both by lysosomal Ca2+ release and ER Ca2+- release through inositol-1,4,5-trisphophate receptors and store-operated Ca2+ entry. Notably, interfering with TRPML1-mediated lysosomal Ca2+ mobilization led to a decrease in the free ER Ca2+ concentration. Imaging of DAF-FM fluorescence revealed that TRPML1 stimulation could also induce a significant Ca2+-dependent increase in nitric oxide concentration. Finally, the pharmacological and genetic blockade of TRPML1 impaired ATP-induced intracellular Ca2+ release and NO production. These findings, therefore, shed novel light on the mechanisms whereby the lysosomal Ca2+ store can shape endothelial Ca2+ signaling and Ca2+-dependent functions in vascular endothelial cells.
    Keywords:  Ca2+ signaling; InsP3 receptors; TRPML1; endothelial cells; lysosomes; nitric oxide; store-operated Ca2+ entry
    DOI:  https://doi.org/10.3389/fphys.2024.1426783
  51. Protein J. 2024 Jul 09.
    Computational and Experimental Approaches Towards Understanding the Role of ATG8 in Autophagy: A Therapeutic Paradigm in Leishmaniasis.
    Vrushali Guhe, Anil Tambekar, Shailza Singh.
      In the realm of parasitology, autophagy has emerged as a critical focal point, particularly in combating Leishmaniasis. Central to this endeavour is the recognition of the protein ATG8 as pivotal for the survival and infectivity of the parasitic organism Leishmania major, thereby making it a potential target for therapeutic intervention. Consequently, there is a pressing need to delve into the structural characteristics of ATG8 to facilitate the design of effective drugs. In this study, our efforts centered on the purification of ATG8 from Leishmania major, which enabled novel insights into its structural features through meticulous spectroscopic analysis. We aimed to comprehensively assess the stability and behaviour of ATG8 in the presence of various denaturants, including urea, guanidinium chloride, and SDS-based chemicals. Methodically, our approach included secondary structural analysis utilizing CD spectroscopy, which not only validated but also augmented computationally predicted structures of ATG8 reported in previous investigations. Remarkably, our findings unveiled that the purified ATG8 protein retained its folded conformation, exhibiting the anticipated secondary structure. Moreover, our exploration extended to the influence of lipids on ATG8 stability, yielding intriguing revelations. We uncovered a nuanced perspective suggesting that targeting both the lipid composition of Leishmania major and ATG8 could offer a promising strategy for future therapeutic approaches in combating leishmaniasis. Collectively, our study underscores the importance of understanding the structural intricacies of ATG8 in driving advancements towards the development of targeted therapies against Leishmaniasis, thereby providing a foundation for future investigations in this field.
    Keywords:   Leishmania major ; ATG8; Autophagy; Circular dichroism; DMPC; Lipid membrane; MD simulations; POPC; POPE; Spectroscopy; Structural studies
    DOI:  https://doi.org/10.1007/s10930-024-10213-0
  52. Int J Mol Sci. 2024 Jun 26. pii: 7008. [Epub ahead of print]25(13):
    Canagliflozin Mitigates Diabetic Cardiomyopathy through Enhanced PINK1-Parkin Mitophagy.
    Chunru Yang, Cheng Xiao, Zerui Ding, Xiaojun Zhai, Jieying Liu, Miao Yu.
      Diabetic cardiomyopathy (DCM) is a major determinant of mortality in diabetic populations, and the potential strategies are insufficient. Canagliflozin has emerged as a potential cardioprotective agent in diabetes, yet its underlying molecular mechanisms remain unclear. We employed a high-glucose challenge (60 mM for 48 h) in vitro to rat cardiomyocytes (H9C2), with or without canagliflozin treatment (20 µM). In vivo, male C57BL/6J mice were subjected to streptozotocin and a high-fat diet to induce diabetes, followed by canagliflozin administration (10, 30 mg·kg-1·d-1) for 12 weeks. Proteomics and echocardiography were used to assess the heart. Histopathological alterations were assessed by the use of Oil Red O and Masson's trichrome staining. Additionally, mitochondrial morphology and mitophagy were analyzed through biochemical and imaging techniques. A proteomic analysis highlighted alterations in mitochondrial and autophagy-related proteins after the treatment with canagliflozin. Diabetic conditions impaired mitochondrial respiration and ATP production, alongside decreasing the related expression of the PINK1-Parkin pathway. High-glucose conditions also reduced PGC-1α-TFAM signaling, which is responsible for mitochondrial biogenesis. Canagliflozin significantly alleviated cardiac dysfunction and improved mitochondrial function both in vitro and in vivo. Specifically, canagliflozin suppressed mitochondrial oxidative stress, enhancing ATP levels and sustaining mitochondrial respiratory capacity. It activated PINK1-Parkin-dependent mitophagy and improved mitochondrial function via increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Notably, PINK1 knockdown negated the beneficial effects of canagliflozin on mitochondrial integrity, underscoring the critical role of PINK1 in mediating these protective effects. Canagliflozin fosters PINK1-Parkin mitophagy and mitochondrial function, highlighting its potential as an effective treatment for DCM.
    Keywords:  diabetic cardiomyopathy; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy; sodium-glucose co-transporter-2 inhibitor
    DOI:  https://doi.org/10.3390/ijms25137008
  53. Exp Ther Med. 2024 Aug;28(2): 328
    The role of autophagy/lipophagy in the response of osteoblastic cells to hyperlipidemia (Review).
    Yizhang He, Yantong Liu, Ran Li, Aoqi Xiang, Xiaochang Chen, Qi Yu, Peihong Su.
      There has been interest in the connection between cardiovascular diseases and osteoporosis, both of which share hyperlipidemia as a common pathological basis. Osteoporosis is a progressive metabolic bone disease characterized by reduced bone mass, deteriorated bone microstructure, increased bone fragility and heightened risk of bone fractures. Dysfunction of osteoblastic cells, vital for bone formation, is induced by excessive internalization of lipids under hyperlipidemic conditions, forming the crux of hyperlipidemia-associated osteoporosis. Autophagy, a process fundamental to cell self-regulation, serves a critical role in osteoblastic cell function and bone formation. When activated by lipids, lipophagy inhibits osteoblastic cell differentiation in response to elevated lipid concentrations, resulting in reduced bone mass and osteoporosis. However, an in-depth understanding of the precise roles and mechanisms of lipophagy in the regulation of osteoblastic cell function is required. Study of the molecular mechanisms governing osteoblastic cell response to excessive lipids can result in a clearer understanding of osteoporosis; therefore, potential strategies for preventing hyperlipidemia-induced osteoporosis can be developed. The present review discusses recent progress in elucidating the molecular mechanisms of lipophagy in the regulation of osteoblastic cell function, offering insights into hyperlipidemia-induced osteoporosis.
    Keywords:  autophagy; hyperlipidemia; lipophagy; osteoblastic cells; osteoporosis
    DOI:  https://doi.org/10.3892/etm.2024.12617
  54. Neuropharmacology. 2024 Jul 06. pii: S0028-3908(24)00232-6. [Epub ahead of print]257 110063
    Inhibition of NLRP3 inflammasome ameliorates LPS-induced neuroinflammatory injury in mice via PINK1/Parkin pathway.
    Ao Wang, Guangshang Zhong, Mengjiao Ying, Zhuling Fang, Ying Chen, Haojie Wang, Chunjing Wang, Changqing Liu, Yu Guo.
      Parkinson's disease (PD) is characterized by the severe loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor dysfunction. The onset of PD is often accompanied by neuroinflammation and α-Synuclein aggregation, and extensive research has focused on the activation of microglial NLRP3 inflammasomes in PD, which promotes the death of dopaminergic neurons. In this study, a model of cerebral inflammatory response was constructed in wild-type and Parkin＋/－ mice through bilateral intraventricular injection of LPS. LPS-induced activation of the NLRP3 inflammasome in wild-type mice promotes the progression of PD. The use of MCC950 in wild mice injected with LPS induces activation of Parkin/PINK and improves autophagy, which in turn improves mitochondrial turnover. It also inhibits LPS-induced inflammatory responses, improves motor function, protects dopaminergic neurons, and inhibits microglia activation. Furthermore, Parkin＋/－ mice exhibited motor dysfunction, loss of dopaminergic neurons, activation of the NLRP3 inflammasome, and α-Synuclein aggregation beginning at an early age. Parkin ± mice exhibited more pronounced microglia activation, greater NLRP3 inflammasome activation, more severe autophagy dysfunction, and more pronounced motor dysfunction after LPS injection compared to wild-type mice. Notably, the use of MCC950 in Parkin ± mice did not ameliorate NLRP3 inflammasome activation, autophagy dysfunction, or α-synuclein aggregation. Thus, MCC950 can only exert its effects in the presence of Parkin/PINK1, and targeting Parkin-mediated NLRP3 inflammasome activation is expected to be a potential therapeutic strategy for Parkinson's disease.
    Keywords:  MCC950; NLRP3 inflammasome; Parkin; Parkinson's disease; α-Synuclein
    DOI:  https://doi.org/10.1016/j.neuropharm.2024.110063
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