bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024‒09‒22
forty-one papers selected by
Viktor Korolchuk, Newcastle University
  1. TBK1 adaptor AZI2/NAP1 regulates NDP52-driven mitochondrial autophagy.
  2. Potential application of natural compounds in ischaemic stroke: Focusing on the mechanisms underlying "lysosomocentric" dysfunction of the autophagy-lysosomal pathway.
  3. Autophagy3D: a comprehensive autophagy structure database.
  4. The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.
  5. HLH-30/TFEB modulates autophagy to improve proteostasis in Aβ transgenic Caenorhabditis elegans.
  6. Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation.
  7. Macroautophagy/autophagy promotes resistance to KRASG12D-targeted therapy through glutathione synthesis.
  8. The interplay between probiotics and host autophagy: mechanisms of action and emerging insights.
  9. Autophagy in Oligodendrocyte Lineage Cells Controls Oligodendrocyte Numbers and Myelin Integrity in an Age-dependent Manner.
  10. Hyperactive mTORC1 in striatum dysregulates dopamine receptor expression and odor preference behavior.
  11. Helicobacter pylori CagA mediated mitophagy to attenuate the NLRP3 inflammasome activation and enhance the survival of infected cells.
  12. ER-phagy restrains inflammatory responses through its receptor UBAC2.
  13. Mitophagy Responds to the Environmental Temperature and Regulates Mitochondrial Mass in Adipose Tissues.
  14. Targeting Autophagy for Acetaminophen-Induced Liver Injury: An Update.
  15. Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways.
  16. Migfilin promotes autophagic flux through direct interaction with SNAP29 and Vamp8.
  17. FYVE1/FREE1 is involved in glutamine-responsive TORC1 activation in plants.
  18. Activation of parkin by a molecular glue.
  19. Bidirectional Effect of Long-Term Δ9-Tetrahydrocannabinol Treatment on mTOR Activity and Metabolome.
  20. Biologic activity and treatment resistance to gastrointestinal cancer: the role of circular RNA in autophagy regulation.
  21. Transcriptional changes impact hepatic proteome in autophagy-impaired liver.
  22. A FRET biosensor constructed using pH sensitive G-quadruplex DNA for detecting mitochondrial autophagy.
  23. VPS34 Governs Oocyte Developmental Competence by Regulating Mito/Autophagy: A Novel Insight into the Significance of RAB7 Activity and Its Subcellular Location.
  24. An intelligent NIR fluorescent dye with dual response to pH and viscosity for investigating the interactions between LDs and mitochondria.
  25. Serine ubiquitination of SQSTM1 regulates NFE2L2-dependent redox homeostasis.
  26. COMMD5 counteracts cisplatin-induced nephrotoxicity by maintaining tubular epithelial integrity and autophagy flux.
  27. Adipose stem cell exosomes promote mitochondrial autophagy through the PI3K/AKT/mTOR pathway to alleviate keloids.
  28. VPS13D affects epileptic seizures by regulating mitochondrial fission and autophagy in epileptic rats.
  29. The role of rapamycin in the PINK1/Parkin signaling pathway in mitophagy in podocytes.
  30. α-Synuclein amyloid fibril directly binds to LC3B and suppresses SQSTM1/p62-mediated selective autophagy.
  31. iPLA2β loss leads to age-related cognitive decline and neuroinflammation by disrupting neuronal mitophagy.
  32. The Roles of Autophagy-related miRNAs in Gynecologic Tumors: A Review of Current Knowledge for Possible Targeted Therapy.
  33. Lysosome-related organelle integrity suppresses TIR-1 aggregation to restrain toxic propagation of p38 innate immunity.
  34. Autophagy unrelated transcriptional mechanisms of hydroxychloroquine resistance revealed by integrated multi-omics of evolved cancer cells.
  35. The role of mitochondrial autophagy in osteoarthritis.
  36. Autophagic cell death induced by pH modulation for enhanced iron-based chemodynamic therapy.
  37. Mitophagy deficiency activates stimulator of interferon genes activation and aggravates pathogenetic cardiac remodeling.
  38. Relationship between ferroptosis and mitophagy in acute lung injury: a mini-review.
  39. Iron regulatory protein 2 facilitates ferritinophagy and DNA damage/repair through guiding ATG9A trafficking.
  40. ZIKV induces P62-mediated autophagic degradation of TRAF6 through TRAF6-NS1 interaction.
  41. Non-autophagic Golgi-LC3 lipidation facilitates TFE3 stress response against Golgi dysfunction.
  1. J Biol Chem. 2024 Sep 12. pii: S0021-9258(24)02276-2. [Epub ahead of print] 107775
    TBK1 adaptor AZI2/NAP1 regulates NDP52-driven mitochondrial autophagy.
    Ryu Endo, Hiroki Kinefuchi, Momoha Sawada, Reika Kikuchi, Waka Kojima, Noriyuki Matsuda, Koji Yamano.
      Damaged mitochondria are selectively eliminated in a process called mitophagy. PINK1 and Parkin amplify ubiquitin signals on damaged mitochondria, which are then recognized by autophagy adaptors to induce local autophagosome formation. NDP52 and OPTN, two essential mitophagy adaptors, facilitate de novo synthesis of pre-autophagosomal membranes near damaged mitochondria by linking ubiquitinated mitochondria and ATG8 family proteins and by recruiting core autophagy initiation components. The multifunctional serine/threonine kinase TBK1 also plays important roles in mitophagy. OPTN directly binds TBK1 to form a positive feedback loop for isolation membrane expansion. TBK1 is also thought to indirectly interact with NDP52; however, its role in NDP52-driven mitophagy remains largely unknown. Here, we focused on two TBK1 adaptors, AZI2/NAP1 and TBKBP1/SINTBAD, that are thought to mediate the TBK1-NDP52 interaction. We found that both AZI2 and TBKBP1 are recruited to damaged mitochondria during Parkin-mediated mitophagy. Further, a series of AZI2 and TBKBP1 knockout constructs combined with an OPTN knockout showed that AZI2, but not TBKBP1, impacts NDP52-driven mitophagy. In addition, we found that AZI2 at S318 is phosphorylated during mitophagy, the impairment of which slightly inhibits mitochondrial degradation. These results suggest that AZI2, in concert with TBK1, plays an important role in NDP52-driven mitophagy.
    Keywords:  autophagy; mitochondria; mitophagy; polyubiquitin chain; serine/threonine protein kinase
    DOI:  https://doi.org/10.1016/j.jbc.2024.107775
  2. Pharmacol Ther. 2024 Sep 14. pii: S0163-7258(24)00141-4. [Epub ahead of print]263 108721
    Potential application of natural compounds in ischaemic stroke: Focusing on the mechanisms underlying "lysosomocentric" dysfunction of the autophagy-lysosomal pathway.
    Yueyang Liu, Qingbo Liu, Hanxiao Shang, Jichong Li, He Chai, Kaixuan Wang, Zhenkun Guo, Tianyu Luo, Shiqi Liu, Yan Liu, Xuemei Wang, Hangyi Zhang, Chunfu Wu, Shao-Jiang Song, Jingyu Yang.
      Ischaemic stroke (IS) is the second leading cause of death and a major cause of disability worldwide. Currently, the clinical management of IS still depends on restoring blood flow via pharmacological thrombolysis or mechanical thrombectomy, with accompanying disadvantages of narrow therapeutic time window and risk of haemorrhagic transformation. Thus, novel pathophysiological mechanisms and targeted therapeutic candidates are urgently needed. The autophagy-lysosomal pathway (ALP), as a dynamic cellular lysosome-based degradative process, has been comprehensively studied in recent decades, including its upstream regulatory mechanisms and its role in mediating neuronal fate after IS. Importantly, increasing evidence has shown that IS can lead to lysosomal dysfunction, such as lysosomal membrane permeabilization, impaired lysosomal acidity, lysosomal storage disorder, and dysfunctional lysosomal ion homeostasis, which are involved in the IS-mediated defects in ALP function. There is tightly regulated crosstalk between transcription factor EB (TFEB), mammalian target of rapamycin (mTOR) and lysosomal function, but their relationship remains to be systematically summarized. Notably, a growing body of evidence emphasizes the benefits of naturally derived compounds in the treatment of IS via modulation of ALP function. However, little is known about the roles of natural compounds as modulators of lysosomes in the treatment of IS. Therefore, in this context, we provide an overview of the current understanding of the mechanisms underlying IS-mediated ALP dysfunction, from a lysosomal perspective. We also provide an update on the effect of natural compounds on IS, according to their chemical structural types, in different experimental stroke models, cerebral regions and cell types, with a primary focus on lysosomes and autophagy initiation. This review aims to highlight the therapeutic potential of natural compounds that target lysosomal and ALP function for IS treatment.
    Keywords:  Autophagy; Ischaemic stroke; Lysosome; Natural compounds; Transcription factor EB; mTOR
    DOI:  https://doi.org/10.1016/j.pharmthera.2024.108721
  3. Database (Oxford). 2024 Sep 19. pii: baae088. [Epub ahead of print]2024
    Autophagy3D: a comprehensive autophagy structure database.
    Neha, Jesu Castin, Saman Fatihi, Deepanshi Gahlot, Akanksha Arun, Lipi Thukral.
      Autophagy pathway plays a central role in cellular degradation. The proteins involved in the core autophagy process are mostly localised on membranes or interact indirectly with lipid-associated proteins. Therefore, progress in structure determination of 'core autophagy proteins' remained relatively limited. Recent paradigm shift in structural biology that includes cutting-edge cryo-EM technology and robust AI-based Alphafold2 predicted models has significantly increased data points in biology. Here, we developed Autophagy3D, a web-based resource that provides an efficient way to access data associated with 40 core human autophagic proteins (80322 structures), their protein-protein interactors and ortholog structures from various species. Autophagy3D also offers detailed visualizations of protein structures, and, hence deriving direct biological insights. The database significantly enhances access to information as full datasets are available for download. The Autophagy3D can be publicly accessed via https://autophagy3d.igib.res.in. Database URL: https://autophagy3d.igib.res.in.
    DOI:  https://doi.org/10.1093/database/baae088
  4. Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2400531121
    The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.
    Xiying Wang, Ji Geng, Suman Rimal, Yuxiu Sui, Jie Pan, Zhenghong Qin, Bingwei Lu.
      It is well established that DNA Damage Regulated Autophagy Modulator 1 (DRAM1), a lysosomal protein and a target of p53, participates in autophagy. The cellular functions of DRAM1 beyond autophagy remain elusive. Here, we show p53-dependent upregulation of DRAM1 in mitochondrial damage-induced Parkinson's disease (PD) models and exacerbation of disease phenotypes by DRAM1. We find that the lysosomal location of DRAM1 relies on its intact structure including the cytosol-facing C-terminal domain. Excess DRAM1 disrupts endoplasmic reticulum (ER) structure, triggers ER stress, and induces protective ER-phagy. Mechanistically, DRAM1 interacts with stromal interacting molecule 1 (STIM1) to tether lysosomes to the ER and perturb STIM1 function in maintaining intracellular calcium homeostasis. STIM1 overexpression promotes cellular health by restoring calcium homeostasis, ER stress response, ER-phagy, and AMP-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) signaling in cells with excess DRAM1. Thus, by promoting organelle contact between lysosomes and the ER, DRAM1 modulates ER structure and function and cell survival under stress. Our results suggest that DRAM1 as a lysosomal protein performs diverse roles in cellular homeostasis and stress response. These findings may have significant implications for our understanding of the role of the p53/DRAM1 axis in human diseases, from cancer to neurodegenerative diseases.
    Keywords:  DRAM1; ER; ER-phagy; calcium homeostasis; lysosome
    DOI:  https://doi.org/10.1073/pnas.2400531121
  5. Front Pharmacol. 2024 ;15 1433030
    HLH-30/TFEB modulates autophagy to improve proteostasis in Aβ transgenic Caenorhabditis elegans.
    Hongru Lin, Chen Zhang, Yehui Gao, Yi Zhou, Botian Ma, Jinyun Jiang, Xue Long, Nuerziya Yimamu, Kaixin Zhong, Yingzi Li, Xianghuan Cui, Hongbing Wang.
      Alzheimer's disease (AD) is a complex neurodegenerative disease that affects elderly individuals, characterized by senile plaques formed by extracellular amyloid beta (Aβ). Autophagy dysfunction is a manifestation of protein homeostasis imbalance in patients with AD, but its relationship with Aβ remains unclear. Here, we showed that in Aβ transgenic Caenorhabditis elegans, Aβ activated the TOR pathway and reduced the nuclear entry of HLH-30, leading to autophagy dysfunction characterized by autophagosome accumulation. Then, utilizing RNA-seq, we investigated the regulatory mechanisms by which HLH-30 modulates autophagy in C. elegans. We found that HLH-30 elevated the transcript levels of v-ATPase and cathepsin, thus enhancing lysosomal activity. This led to an increase in autophagic flux, facilitating more pronounced degradation of Aβ. Moreover, HLH-30 reduced the level of ROS induction by Aβ and enhanced the antioxidant stress capacity of the worms through the gsto-1 gene. Additionally, we identified two HLH-30/TFEB activators, saikosaponin B2 and hypericin, that improved autophagic flux, thereby enhancing protein homeostasis in C. elegans. Overall, our findings suggested that HLH-30/TFEB plays a key role in modulating autophagy and can be considered a promising drug target for AD treatments.
    Keywords:  Caenorhabditis elegans; HLH-30; HLH-30/TFEB activators; amyloid beta; autophagy
    DOI:  https://doi.org/10.3389/fphar.2024.1433030
  6. Elife. 2024 Sep 16. pii: RP90992. [Epub ahead of print]13
    Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation.
    Saira Amir, Olatunbosun Arowolo, Ekaterina Mironova, Joseph McGaunn, Oladele Oluwayiose, Oleg Sergeyev, J Richard Pilsner, Alexander Suvorov.
      Over the past several decades, a trend toward delayed childbirth has led to increases in parental age at the time of conception. Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. The mechanism(s) linking paternal age with epigenetic changes in sperm remain unknown. The sperm epigenome is shaped in a compartment protected by the blood-testes barrier (BTB) known to deteriorate with age. Permeability of the BTB is regulated by the balance of two mTOR complexes in Sertoli cells where mTOR complex 1 (mTORC1) promotes the opening of the BTB and mTOR complex 2 (mTORC2) promotes its integrity. We hypothesized that this balance is also responsible for age-dependent changes in the sperm epigenome. To test this hypothesis, we analyzed reproductive outcomes, including sperm DNA methylation in transgenic mice with Sertoli cell-specific suppression of mTORC1 (Rptor KO) or mTORC2 (Rictor KO). mTORC2 suppression accelerated aging of the sperm DNA methylome and resulted in a reproductive phenotype concordant with older age, including decreased testes weight and sperm counts, and increased percent of morphologically abnormal spermatozoa and mitochondrial DNA copy number. Suppression of mTORC1 resulted in the shift of DNA methylome in sperm opposite to the shift associated with physiological aging - sperm DNA methylome rejuvenation and mild changes in sperm parameters. These results demonstrate for the first time that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging. Thus, mTOR pathway in Sertoli cells may be used as a novel target of therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers.
    Keywords:  DNA methylation; aging; developmental biology; epigenetic; mTOR; mouse; rejuvenation; sperm
    DOI:  https://doi.org/10.7554/eLife.90992
  7. Cancer Lett. 2024 Sep 12. pii: S0304-3835(24)00653-0. [Epub ahead of print]604 217258
    Macroautophagy/autophagy promotes resistance to KRASG12D-targeted therapy through glutathione synthesis.
    Leng Han, Lingjun Meng, Jiao Liu, Yangchun Xie, Rui Kang, Daniel J Klionsky, Daolin Tang, Yuanyuan Jia, Enyong Dai.
      KRASG12D mutation-driven pancreatic ductal adenocarcinoma (PDAC) represents a major challenge in medicine due to late diagnosis and treatment resistance. Here, we report that macroautophagy (hereafter autophagy), a cellular degradation and recycling process, contributes to acquired resistance against novel KRASG12D-targeted therapy. The KRASG12D protein inhibitor MRTX1133 induces autophagy in KRASG12D-mutated PDAC cells by blocking MTOR activity, and increased autophagic flux prevents apoptosis. Mechanistically, autophagy facilitates the generation of glutamic acid, cysteine, and glycine for glutathione synthesis. Increased glutathione levels reduce reactive oxygen species production, which impedes CYCS translocation from mitochondria to the cytosol, ultimately preventing the formation of the APAF1 apoptosome. Consequently, genetic interventions (utilizing ATG5 or BECN1 knockout) or pharmacological inhibition of autophagy (with chloroquine, bafilomycin A1, or spautin-1) enhance the anticancer activity of MRTX1133 in vitro and in various animal models (subcutaneous, patient-derived xenograft, and orthotopic). Moreover, the release of histones by apoptotic cells triggers an adaptive immune response when combining an autophagy inhibitor with MRTX1133 in immunocompetent mice. These findings establish a new strategy to overcome KRASG12D-targeted therapy resistance by inhibiting autophagy-dependent glutathione synthesis.
    Keywords:  Autophagy; Drug resistance; Glutathione; KRAS mutation; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.canlet.2024.217258
  8. Autophagy. 2024 Sep 18.
    The interplay between probiotics and host autophagy: mechanisms of action and emerging insights.
    Zahra Sadeghloo, Ali Nabavi-Rad, Mohammad Reza Zali, Daniel J Klionsky, Abbas Yadegar.
      Autophagy, a lysosome-dependent protein degradation mechanism, is a highly conserved catabolic process seen in all eukaryotes. This cell protection system, which is present in all tissues and functions at a basic level, can be up- or downregulated in response to various stresses. A disruption in the natural route of the autophagy process is frequently followed by an interruption in the inherent operation of the body's cells and organs. Probiotics are live bacteria that protect the host through various mechanisms. One of the processes through which probiotics exert their beneficial effects on various cells and tissues is autophagy. Autophagy can assist in maintaining host homeostasis by stimulating the immune system and affecting numerous physiological and pathological responses. In this review, we particularly focus on autophagy impairments occurring in several human illnesses and investigate how probiotics affect the autophagy process under various circumstances.
    Keywords:  Autophagy; cancer; infectious diseases; neurological diseases; obesity; postbiotics; prebiotics; probiotics
    DOI:  https://doi.org/10.1080/15548627.2024.2403277
  9. Neurosci Bull. 2024 Sep 16.
    Autophagy in Oligodendrocyte Lineage Cells Controls Oligodendrocyte Numbers and Myelin Integrity in an Age-dependent Manner.
    Hong Chen, Gang Yang, De-En Xu, Yu-Tong Du, Chao Zhu, Hua Hu, Li Luo, Lei Feng, Wenhui Huang, Yan-Yun Sun, Quan-Hong Ma.
      Oligodendrocyte lineage cells, including oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs), are essential in establishing and maintaining brain circuits. Autophagy is a conserved process that keeps the quality of organelles and proteostasis. The role of autophagy in oligodendrocyte lineage cells remains unclear. The present study shows that autophagy is required to maintain the number of OPCs/OLs and myelin integrity during brain aging. Inactivation of autophagy in oligodendrocyte lineage cells increases the number of OPCs/OLs in the developing brain while exaggerating the loss of OPCs/OLs with brain aging. Inactivation of autophagy in oligodendrocyte lineage cells impairs the turnover of myelin basic protein (MBP). It causes MBP to accumulate in the cytoplasm as multimeric aggregates and fails to be incorporated into integral myelin, which is associated with attenuated endocytic recycling. Inactivation of autophagy in oligodendrocyte lineage cells impairs myelin integrity and causes demyelination. Thus, this study shows autophagy is required to maintain myelin quality during aging by controlling the turnover of myelin components.
    Keywords:  Autophagy; Degradation; Myelin proteins; Myelination; Oligodendrocyte precursor cells; Oligodendrocytes; Turnover
    DOI:  https://doi.org/10.1007/s12264-024-01292-1
  10. Front Neurosci. 2024 ;18 1461178
    Hyperactive mTORC1 in striatum dysregulates dopamine receptor expression and odor preference behavior.
    Lin Chen, Ryo Saito, Shoko Noda-Narita, Hidetoshi Kassai, Atsu Aiba.
      Mechanistic target of rapamycin (mTOR) plays an important role in brain development and synaptic plasticity. Dysregulation of the mTOR pathway is observed in various human central nervous system diseases, including tuberous sclerosis complex, autism spectrum disorder (ASD), and neurodegenerative diseases, including Parkinson's disease and Huntington's disease. Numerous studies focused on the effects of hyperactivation of mTOR on cortical excitatory neurons, while only a few studies focused on inhibitory neurons. Here we generated transgenic mice in which mTORC1 signaling is hyperactivated in inhibitory neurons in the striatum, while cortical neurons left unaffected. The hyperactivation of mTORC1 signaling increased GABAergic inhibitory neurons in the striatum. The transgenic mice exhibited the upregulation of dopamine receptor D1 and the downregulation of dopamine receptor D2 in medium spiny neurons in the ventral striatum. Finally, the transgenic mice demonstrated impaired motor learning and dysregulated olfactory preference behavior, though the basic function of olfaction was preserved. These findings reveal that the mTORC1 signaling pathway plays an essential role in the development and function of the striatal inhibitory neurons and suggest the critical involvement of the mTORC1 pathway in the locomotor abnormalities in neurodegenerative diseases and the sensory defects in ASD.
    Keywords:  dopamine receptor; inhibitory neuron; mTOR; medium spiny neuron; olfactory behavior; olfactory tubercle
    DOI:  https://doi.org/10.3389/fnins.2024.1461178
  11. Sci Rep. 2024 09 17. 14(1): 21648
    Helicobacter pylori CagA mediated mitophagy to attenuate the NLRP3 inflammasome activation and enhance the survival of infected cells.
    Dingyu Chen, Lixia Wu, Xi Liu, Qinrong Wang, Shuqin Gui, Liya Bao, Zhengrong Wang, Xiaofeng He, Yan Zhao, Jianjiang Zhou, Yuan Xie.
      Helicobacter pylori (H. pylori) is one of the most common bacterial infections in the world, and its key virulence component CagA is the leading cause of gastric cancer. Mitophagy is a form of selective autophagy that eliminates damaged mitochondria and is essential for some viruses and bacteria to evade the immune system. However, the mechanisms by which CagA mediates H. pylori-induced mitophagy and NLRP3 inflammasome activation remain elusive. In this study, we reported that H. pylori primarily uses its CagA to induce mitochondrial oxidative damage, mitochondrial dysfunction, dynamic imbalance, and to block autophagic flux. Inhibition of mitophagy led to an increase in NLRP3 inflammasome activation and apoptosis and a decrease in the viability of H. pylori-infected cells. Our findings suggested that H. pylori induces mitochondrial dysfunction and mitophagy primarily via CagA. It reduces NLRP3 inflammasome activation to evade host immune surveillance and increases the survival and viability of infected cells, potentially leading to gastric cancer initiation and development. Our findings provide new insights into the pathogenesis of H. pylori-induced gastric cancer, and inhibition of mitophagy may be one of the novel techniques for the prevention and treatment of this disease.
    Keywords:   Helicobacter pylori ; Autophagy flux; Gastric cancer; Mitophagy; NLRP3 inflammasome; Survival and viability
    DOI:  https://doi.org/10.1038/s41598-024-72534-5
  12. EMBO J. 2024 Sep 16.
    ER-phagy restrains inflammatory responses through its receptor UBAC2.
    Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, Shouheng Jin.
      ER-phagy, a selective form of autophagic degradation of endoplasmic reticulum (ER) fragments, plays an essential role in governing ER homeostasis. Dysregulation of ER-phagy is associated with the unfolded protein response (UPR), which is a major clue for evoking inflammatory diseases. However, the molecular mechanism underpinning the connection between ER-phagy and disease remains poorly defined. Here, we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy, while at the same time being a negative regulator of inflammatory responses. UBAC2 harbors a canonical LC3-interacting region (LIR) in its cytoplasmic domain, which binds to autophagosomal GABARAP. Upon ER-stress or autophagy activation, microtubule affinity-regulating kinase 2 (MARK2) phosphorylates UBAC2 at serine (S) 223, promoting its dimerization. Dimerized UBAC2 interacts more strongly with GABARAP, thus facilitating selective degradation of the ER. Moreover, by affecting ER-phagy, UBAC2 restrains inflammatory responses and acute ulcerative colitis (UC) in mice. Our findings indicate that ER-phagy directed by a MARK2-UBAC2 axis may provide targets for the treatment of inflammatory disease.
    Keywords:  Colitis; ER-phagy; Inflammatory Responses; MARK2; UBAC2
    DOI:  https://doi.org/10.1038/s44318-024-00232-z
  13. Adv Exp Med Biol. 2024 ;1461 229-243
    Mitophagy Responds to the Environmental Temperature and Regulates Mitochondrial Mass in Adipose Tissues.
    Shun-Ichi Yamashita, Tomotake Kanki.
      There are at least two types of adipose tissues in the body, defined as brown adipose tissues (BATs) and white adipose tissues (WATs). These tissues comprise brown and white adipocytes, respectively. The adipocytes are commonly endowed with mitochondria, but they have diverse characteristics and roles. Brown adipocytes have abundant mitochondria that contribute to the β-oxidation of fatty acids to produce chemical energy and the production of heat via uncoupling of the mitochondrial membrane potential from ATP synthesis. Alternatively, white adipocytes have fewer mitochondria that contribute to the generation of free fatty acids via lipogenesis by providing key intermediates. Besides the described types of adipocytes, brown-like adipocytes, termed beige adipocytes, are developed in WAT depots during cold exposure. Beige adipocytes also contribute to thermogenesis. Notably, beige adipocytes may transform into white-like adipocytes after the withdrawal of cold exposure. This process is marked by the elimination of mitochondria through the activation of mitochondria autophagy (mitophagy). This review aims to describe the mitophagy that occurs during the beige-to-white transition and discuss recent insights into the molecular mechanisms of this transformation. Additionally, we describe the mitophagy monitoring strategy in adipose tissues using three independent reporter systems and discuss the availabilities and limitations of the method.
    Keywords:  Autophagy; Beige adipocytes; Beige-to-white transition; Cold exposure; Mitochondria; Mitophagy; Thermogenesis
    DOI:  https://doi.org/10.1007/978-981-97-4584-5_16
  14. Livers. 2024 Sep;4(3): 377-387
    Targeting Autophagy for Acetaminophen-Induced Liver Injury: An Update.
    Kaitlyn Hinz, Mengwei Niu, Hong-Min Ni, Wen-Xing Ding.
      Acetaminophen (APAP) overdose can induce hepatocyte necrosis and acute liver failure in experimental rodents and humans. APAP is mainly metabolized via hepatic cytochrome P450 enzymes to generate the highly reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which forms acetaminophen protein adducts (APAP-adducts) and damages mitochondria, triggering necrosis. APAP-adducts and damaged mitochondria can be selectively removed by autophagy. Increasing evidence implies that the activation of autophagy may be beneficial for APAP-induced liver injury (AILI). In this minireview, we briefly summarize recent progress on autophagy, in particular, the pharmacological targeting of SQSTM1/p62 and TFEB in AILI.
    Keywords:  NRF2; TFEB; mitophagy; p62/SQSTM1
    DOI:  https://doi.org/10.3390/livers4030027
  15. bioRxiv. 2024 Sep 03. pii: 2024.08.30.610524. [Epub ahead of print]
    Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways.
    Kelsey L Hickey, Alexandra Panov, Enya Miguel Whelan, Tillman Schäfer, Arda Mizrak, Ron R Kopito, Wolfgang Baumeister, Rubén Fernández-Busnadiego, J Wade Harper.
      A hallmark of neurodegenerative diseases is the progressive loss of proteostasis, leading to the accumulation of misfolded proteins or protein aggregates, with subsequent cytotoxicity. To combat this toxicity, cells have evolved degradation pathways (ubiquitin-proteasome system and autophagy) that detect and degrade misfolded proteins. However, studying the underlying cellular pathways and mechanisms has remained a challenge, as formation of many types of protein aggregates is asynchronous, with individual cells displaying distinct kinetics, thereby hindering rigorous time-course studies. Here, we merge a kinetically tractable and synchronous agDD-GFP system for aggregate formation with targeted gene knockdowns, to uncover degradation mechanisms used in response to acute aggregate formation. We find that agDD-GFP forms amorphous aggregates by cryo-electron tomography at both early and late stages of aggregate formation. Aggregate turnover occurs in a proteasome-dependent mechanism in a manner that is dictated by cellular aggregate burden, with no evidence of the involvement of autophagy. Lower levels of misfolded agDD-GFP, enriched in oligomers, utilizes UBE3C-dependent proteasomal degradation in a pathway that is independent of RPN13 ubiquitylation by UBE3C. Higher aggregate burden activates the NRF1 transcription factor to increase proteasome subunit transcription, and subsequent degradation capacity of cells. Loss or gain of NRF1 function alters the turnover of agDD-GFP under conditions of high aggregate burden. Together, these results define the role of UBE3C in degradation of this class of misfolded aggregation-prone proteins and reveals a role for NRF1 in proteostasis control in response to widespread protein aggregation.
    Keywords:  Biological Sciences; Cell Biology; NRF1; Protein aggregates; Protein quality control; Protein turnover; UBE3C; Ubiquitin-proteasome system
    DOI:  https://doi.org/10.1101/2024.08.30.610524
  16. J Cell Biol. 2024 Nov 04. pii: e202312119. [Epub ahead of print]223(11):
    Migfilin promotes autophagic flux through direct interaction with SNAP29 and Vamp8.
    Renwei Cai, Panzhu Bai, Meiling Quan, Yanyan Ding, Wenjie Wei, Chengmin Liu, Aihua Yang, Zailin Xiong, Guizhen Li, Binbin Li, Yi Deng, Ruijun Tian, Yan G Zhao, Chuanyue Wu, Ying Sun.
      Autophagy plays a crucial role in cancer cell survival by facilitating the elimination of detrimental cellular components and the recycling of nutrients. Understanding the molecular regulation of autophagy is critical for developing interventional approaches for cancer therapy. In this study, we report that migfilin, a focal adhesion protein, plays a novel role in promoting autophagy by increasing autophagosome-lysosome fusion. We found that migfilin is associated with SNAP29 and Vamp8, thereby facilitating Stx17-SNAP29-Vamp8 SNARE complex assembly. Depletion of migfilin disrupted the formation of the SNAP29-mediated SNARE complex, which consequently blocked the autophagosome-lysosome fusion, ultimately suppressing cancer cell growth. Restoration of the SNARE complex formation rescued migfilin-deficiency-induced autophagic flux defects. Finally, we found depletion of migfilin inhibited cancer cell proliferation. SNARE complex reassembly successfully reversed migfilin-deficiency-induced inhibition of cancer cell growth. Taken together, our study uncovers a new function of migfilin as an autophagy-regulatory protein and suggests that targeting the migfilin-SNARE assembly could provide a promising therapeutic approach to alleviate cancer progression.
    DOI:  https://doi.org/10.1083/jcb.202312119
  17. iScience. 2024 Sep 20. 27(9): 110814
    FYVE1/FREE1 is involved in glutamine-responsive TORC1 activation in plants.
    Mirai Tanigawa, Tatsuya Maeda, Erika Isono.
      Target of rapamycin complex 1 (TORC1) integrates nutrient availability, growth factors, and stress signals to regulate cellular metabolism according to its environment. Similar to mammals, amino acids have been shown to activate TORC1 in plants. However, as the Rag complex that controls amino acid-responsive TORC1 activation mechanisms in many eukaryotes is not conserved in plants, the amino acid-sensing mechanisms upstream of TORC1 in plants remain unknown. In this study, we report that Arabidopsis FYVE1/FREE1 is involved in glutamine-induced TORC1 activation, independent of its previously reported function in ESCRT-dependent processes. FYVE1/FREE1 has a domain structure similar to that of the yeast glutamine sensor Pib2 that directly activates TORC1. Similar to Pib2, FYVE1/FREE1 interacts with TORC1 in response to glutamine. Furthermore, overexpression of a FYVE1/FREE1 variant lacking the presumptive TORC1 activation motif hindered the glutamine-responsive activation of TORC1. Overall, these observations suggest that FYVE1/FREE1 acts as an intracellular amino acid sensor that triggers TORC1 activation in plants.
    Keywords:  Biological sciences; Molecular biology; Plant biology;
    DOI:  https://doi.org/10.1016/j.isci.2024.110814
  18. Nat Commun. 2024 Sep 19. 15(1): 7707
    Activation of parkin by a molecular glue.
    Véronique Sauvé, Eric Stefan, Nathalie Croteau, Thomas Goiran, Rayan Fakih, Nupur Bansal, Adelajda Hadzipasic, Jing Fang, Paramasivam Murugan, Shimin Chen, Edward A Fon, Warren D Hirst, Laura F Silvian, Jean-François Trempe, Kalle Gehring.
      Mutations in parkin and PINK1 cause early-onset Parkinson's disease (EOPD). The ubiquitin ligase parkin is recruited to damaged mitochondria and activated by PINK1, a kinase that phosphorylates ubiquitin and the ubiquitin-like domain of parkin. Activated phospho-parkin then ubiquitinates mitochondrial proteins to target the damaged organelle for degradation. Here, we present the mechanism of activation of a new class of small molecule allosteric modulators that enhance parkin activity. The compounds act as molecular glues to enhance the ability of phospho-ubiquitin (pUb) to activate parkin. Ubiquitination assays and isothermal titration calorimetry with the most active compound (BIO-2007817) identify the mechanism of action. We present the crystal structure of a closely related compound (BIO-1975900) bound to a complex of parkin and two pUb molecules. The compound binds next to pUb on RING0 and contacts both proteins. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) experiments confirm that activation occurs through release of the catalytic Rcat domain. In organello and mitophagy assays demonstrate that BIO-2007817 partially rescues the activity of parkin EOPD mutants, R42P and V56E, offering a basis for the design of activators as therapeutics for Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41467-024-51889-3
  19. ACS Pharmacol Transl Sci. 2024 Sep 13. 7(9): 2637-2649
    Bidirectional Effect of Long-Term Δ9-Tetrahydrocannabinol Treatment on mTOR Activity and Metabolome.
    Andras Bilkei-Gorzo, Britta Schurmann, Marion Schneider, Michael Kraemer, Prakash Nidadavolu, Eva C Beins, Christa E Müller, Mona Dvir-Ginzberg, Andreas Zimmer.
      Brain aging is associated with cognitive decline, reduced synaptic plasticity, and altered metabolism. The activity of mechanistic target of rapamycin (mTOR) has a major impact on aging by regulating cellular metabolism. Although reduced mTOR signaling has a general antiaging effect, it can negatively affect the aging brain by reducing synaptogenesis and thus cognitive functions. Increased mTOR activity facilitates aging and is responsible for the amnestic effect of the cannabinoid receptor 1 agonist Δ9-tetrahydrocannabinol (THC) in higher doses. Long-term low-dose Δ9-THC had an antiaging effect on the brain by restoring cognitive abilities and synapse densities in old mice. Whether changes in mTOR signaling and metabolome are associated with its positive effects on the aging brain is an open question. Here, we show that Δ9-THC treatment has a tissue-dependent and dual effect on mTOR signaling and the metabolome. In the brain, Δ9-THC treatment induced a transient increase in mTOR activity and in the levels of amino acids and metabolites involved in energy production, followed by an increased synthesis of synaptic proteins. Unexpectedly, we found a similar reduction in the mTOR activity in adipose tissue and in the level of amino acids and carbohydrate metabolites in blood plasma as in animals on a low-calorie diet. Thus, long-term Δ9-THC treatment first increases the level of energy and synaptic protein production in the brain, followed by a reduction in mTOR activity and metabolic processes in the periphery. Our study suggests that a dual effect on mTOR activity and the metabolome could be the basis for an effective antiaging and pro-cognitive medication.
    DOI:  https://doi.org/10.1021/acsptsci.4c00002
  20. Front Oncol. 2024 ;14 1393670
    Biologic activity and treatment resistance to gastrointestinal cancer: the role of circular RNA in autophagy regulation.
    Bo Zhang, Zhe Li, Guoliang Ye, Kefeng Hu.
      Circular RNAs (circRNAs) lack the 5'-end methylated guanine cap structure and 3' polyadenylate tail structure, classifying it as a non-coding RNA. With the extensive investigation of circRNA, its role in regulating cell death has garnered significant attention in recent years, establishing it as a recognized participant in cancer's biological processes. Autophagy, an essential pathway in programmed cell death (PCD), involves the formation of autophagosomes using lysosomes to degrade cellular contents under the regulation of various autophagy-related (ATG) genes. Numerous studies have demonstrated that circRNA can modulate the biological activity of cancer cells by influencing the autophagy pathway, exhibiting a dualistic role in suppressing or promoting carcinogenesis. In this review, we comprehensively analyze how autophagy-related circRNA impacts the progression of gastrointestinal cancer (GIC). Additionally, we discuss drug resistance phenomena associated with autophagy regulation in GIC. This review offers valuable insights into exploring potential biological targets for prognosis and treatment strategies related to GIC.
    Keywords:  autophagy; biological activity; circular RNA; drug resistance; gastrointestinal cancer
    DOI:  https://doi.org/10.3389/fonc.2024.1393670
  21. FEBS Open Bio. 2024 Sep 16.
    Transcriptional changes impact hepatic proteome in autophagy-impaired liver.
    Kamal Baral, Spandan Joshi, Adriana Lopez, Gavisha Mugon, Aroma Chanda, Arya A Chandrasheker, Cameron Hinton, Kapil Thapa, Arissa Mercer, Leah Spade, Gang Liu, Bhupal Prasad Bhetwal, Jia Fang, Bilon Khambu.
      Hepatic proteomes are intricately controlled through biosynthesis, extracellular secretion, and intrahepatic degradation. Autophagy governs lysosome-mediated intrahepatic degradation and the hepatic proteome. When autophagy is impaired, it leads to the accumulation of intrahepatic proteins, causing proteinopathy. This study investigates whether autophagy can modulate the hepatic proteome non-degradatively. Utilizing conditional, inducible, and hepatotoxin models of hepatic autophagy impairment, we assessed the overall hepatic proteome expression using Coomassie brilliant blue (CBB) staining and liquid chromatography-tandem mass spectrometry (LC/MS). We pinpointed and confirmed four specific hepatic proteins-Cps1, Ahcy, Ca3, and Gstm1-that were selectively modified in autophagy-deficient livers. Expression of Cps1, Ahcy, and Ca3 were significantly reduced, while Gstm1 expression increased in livers with autophagy impairment. Interestingly, these changes in hepatic protein levels were not due to defective autophagic degradation but were associated with alterations in mRNA transcript levels. Moreover, as a result of autophagic dysfunction, sustained activation of the nuclear erythroid-derived 2-like 2 (Nrf2) transcription factor, transcriptionally regulated the mRNA levels of these proteins. Our findings indicate that autophagy can influence hepatic proteins not solely via traditional degradative routes but also through non-degradative transcriptional processes by modulating Nrf2.
    Keywords:  Nrf2; autophagy; hepatic proteome; liver; non‐degradative; transcriptional repression
    DOI:  https://doi.org/10.1002/2211-5463.13898
  22. Talanta. 2024 Sep 14. pii: S0039-9140(24)01264-5. [Epub ahead of print]281 126885
    A FRET biosensor constructed using pH sensitive G-quadruplex DNA for detecting mitochondrial autophagy.
    Dawei Yang, Ranran Sun, Hongxia Sun, Qian Li, Hong Zhang, Xiufeng Zhang, Lei Shi, Li Yao, Yalin Tang.
      Mitochondria are crucial powerhouses and central organelles for maintaining normal physiological activities in eukaryotic cells. The use of highly specific optical biosensors to monitor mitochondrial autophagy (mitophagy) is an important way for detecting mitochondrial abnormalities. Herein, we report a pH responsive G-quadruplex (G4) structure folded by the oligonucleotide named P24. P24 is composed of four GGCCTG repeating units, and the high guanine content allows it to form an antiparallel G4 topology at pH 4.5 (lysosomal pH). However, when pH increases to around 7.4 (mitochondrial pH), P24 further transforms into a double-stranded structure. Unlike most oligonucleotides that enter lysosomes, P24 highly targets mitochondria in live cells. These characteristics enable P24 to construct a pH responsive optical biosensor by linking a pair of fluorescence resonance energy transfer (FRET) fluorophores. The P24 based biosensor demonstrates reliable applications in detecting mitophagy in live cells.
    Keywords:  Autophagy; Biosensor; G-quadruplex; Mitochondrion; pH responsive
    DOI:  https://doi.org/10.1016/j.talanta.2024.126885
  23. Adv Sci (Weinh). 2024 Sep 17. e2308823
    VPS34 Governs Oocyte Developmental Competence by Regulating Mito/Autophagy: A Novel Insight into the Significance of RAB7 Activity and Its Subcellular Location.
    Wenwen Liu, Kehan Wang, Yuting Lin, Lu Wang, Xin Jin, Yuexin Qiu, Wenya Sun, Ling Zhang, Yan Sun, Xiaowei Dou, Shiming Luo, Youqiang Su, Qingyuan Sun, Wenpei Xiang, Feiyang Diao, Jing Li.
      Asynchronous nuclear and cytoplasmic maturation in human oocytes is believed to cause morphological anomalies after controlled ovarian hyperstimulation. Vacuolar protein sorting 34 (VPS34) is renowned for its pivotal role in regulating autophagy and endocytic trafficking. To investigate its impact on oocyte development, oocyte-specific knockout mice (ZcKO) are generated, and these mice are completely found infertile, with embryonic development halted at 2- to 4-cell stage. This infertility is related with a disruption on autophagic/mitophagic flux in ZcKO oocytes, leading to subsequent failure of zygotic genome activation (ZGA) in derived 2-cell embryos. The findings further elucidated the regulation of VPS34 on the activity and subcellular translocation of RAS-related GTP-binding protein 7 (RAB7), which is critical not only for the maturation of late endosomes and lysosomes, but also for initiating mitophagy via retrograde trafficking. VPS34 binds directly with RAB7 and facilitates its activity conversion through TBC1 domain family member 5 (TBC1D5). Consistent with the cytoplasmic vacuolation observed in ZcKO oocytes, defects in multiple vesicle trafficking systems are also identified in vacuolated human oocytes. Furthermore, activating VPS34 with corynoxin B (CB) treatment improved oocyte quality in aged mice. Hence, VPS34 activation may represent a novel approach to enhance oocyte quality in human artificial reproduction.
    Keywords:  VPS34; autophagy; mitophagy; oocyte; retromer
    DOI:  https://doi.org/10.1002/advs.202308823
  24. Talanta. 2024 Sep 12. pii: S0039-9140(24)01228-1. [Epub ahead of print]281 126849
    An intelligent NIR fluorescent dye with dual response to pH and viscosity for investigating the interactions between LDs and mitochondria.
    Wei Zhang, Xing Tian, Yanxi Zhu, Lei Yang, Zhanxian Li, Mingming Yu.
      The interaction between lipid droplets and mitochondria plays a pivotal role in biological processes including cellular stress, metabolic homeostasis, cellular autophagy and apoptosis. Deciphering the complex interplay between lipid droplets and mitochondria is essential for gaining insights into the fundamental workings of the cell and can have broad implications for the development of therapeutic strategies for various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. In this study, we develop a pH and viscosity-responsive near-infrared (NIR) fluorescent probe PTOH to investigate the interaction between lipid droplets and mitochondria. This probe demonstrates a significant enhancement in fluorescence intensity at 470 nm when the pH increases, while under acidic conditions, its fluorescence intensity at 730 nm intensifies by a factor of 35 with rising system viscosity. Cell imaging experiments revealed that PTOH can effectively discriminate between normal and cancerous cells, as well as detect intracellular pH and viscosity alterations induced by drugs. Additionally, PTOH is utilized to visualize the interaction between lipid droplets and mitochondria and to differentiate between cellular autophagy and apoptosis phenomena, providing a valuable tool for elucidating the mechanisms underlying lipid droplet-mitochondria interactions and their associated diseases.
    Keywords:  Apoptosis; Autophagy; Lipid droplets; Mitochondria; Viscosity; pH
    DOI:  https://doi.org/10.1016/j.talanta.2024.126849
  25. Autophagy. 2024 Sep 18.
    Serine ubiquitination of SQSTM1 regulates NFE2L2-dependent redox homeostasis.
    Rukmini Mukherjee, Anshu Bhattacharya, João Mello-Vieira, Santosh Kumar Kuncha, Marina Hoffmann, Alexis Gonzalez, Rajeshwari Rathore, Attinder Chadha, Donghyuk Shin, Thomas Colby, Ivan Matic, Shaeri Mukherjee, Mohit Misra, Ivan Dikic.
      The KEAP1-NFE2L2 axis is essential for the cellular response against metabolic and oxidative stress. KEAP1 is an adaptor protein of CUL3 (cullin 3) ubiquitin ligase that controls the cellular levels of NFE2L2, a critical transcription factor of several cytoprotective genes. Oxidative stress, defective autophagy and pathogenic infections activate NFE2L2 signaling through phosphorylation of the autophagy receptor protein SQSTM1, which competes with NFE2L2 for binding to KEAP1. Here we show that phosphoribosyl-linked serine ubiquitination of SQSTM1 catalyzed by SidE effectors of Legionella pneumophila controls NFE2L2 signaling and cell metabolism upon Legionella infection. Serine ubiquitination of SQSTM1 sterically blocks its binding to KEAP1, resulting in NFE2L2 ubiquitination and degradation. This reduces NFE2L2-dependent antioxidant synthesis in the early phase of infection. Levels of serine ubiquitinated SQSTM1 diminish in the later stage of infection allowing the expression of NFE2L2-target genes; causing a differential regulation of the host metabolome and proteome in a NFE2L2-dependent manner.
    Keywords:  Antioxidants; KEAP1; bacterial infection; legionella pneumophila; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1080/15548627.2024.2404375
  26. Am J Physiol Renal Physiol. 2024 Sep 19.
    COMMD5 counteracts cisplatin-induced nephrotoxicity by maintaining tubular epithelial integrity and autophagy flux.
    Maiko Ogasawara-Nosoko, Hiroyuki Matsuda, Jin Ikeda, Masanaori Abe, Yoshikazu Masuhiro, Morito Endo, Pavel Hamet, Johanne Tremblay.
      Oxidative stress mediated by reactive oxygen species (ROS) contributes to apoptosis of tubular epithelial cells (TECs) and renal inflammation during acute kidney injury (AKI). Copper Metabolism MURR1 domain-containing 5 (COMMD5/HCaRG) shows strong cytoprotective properties. COMMD5 is highly expressed in proximal tubules (PTs), where it controls cell differentiation. We assessed its role in cisplatin-induced AKI using transgenic mice in which COMMD5 is overexpressed in the PTs. Cisplatin caused the accumulation of damaged mitochondria and cellular waste in PTs, thus increasing the apoptosis of TECs. COMMD5 overexpression effectively protected TECs from cisplatin nephrotoxicity by decreasing intracellular ROS levels, mitochondrial dysfunction, and apoptosis through the preservation of tubular epithelial integrity, thus alleviating morphological and functional kidney damage. Excessive ROS production by hydrogen peroxide led to long-term autophagy activation through an increased burden on the autophagy/lysosome degradation system in TECs, and autophagic elimination of damaged mitochondria and cellular waste was compromised. COMMD5 attenuated oxidative injury by increasing autophagy flux, possibly due to a reduction of intracellular ROS levels through maintained tubular epithelial integrity, which decreased JNK/caspase-3-dependent apoptosis. Meanwhile, COMMD5 inhibition by small interfering RNA reduced the resistance of TECs to cisplatin cytotoxicity, as shown by disrupted tubular epithelial integrity and cell viability. These data indicated that COMMD5 protects TECs from drug-induced oxidative stress and toxicity by maintaining tubular epithelial integrity and autophagy flux and ultimately decreases mitochondrial dysfunction and apoptosis. Increasing COMMD5 content in PTs is proposed as a new protective and therapeutic strategy against AKI.
    Keywords:  acute kidney injury; autophagy flux; copper metabolism MURR1 domain-containing 5; mitochondria; tubular epithelial integrity
    DOI:  https://doi.org/10.1152/ajprenal.00026.2024
  27. Stem Cell Res Ther. 2024 Sep 15. 15(1): 305
    Adipose stem cell exosomes promote mitochondrial autophagy through the PI3K/AKT/mTOR pathway to alleviate keloids.
    Chang Liu, Liliia Khairullina, Youyou Qin, Yingbo Zhang, Zhibo Xiao.
      BACKGROUND: Fibrosis with unrelieved chronic inflammation is an important pathological change in keloids. Mitochondrial autophagy plays a crucial role in reducing inflammation and inhibiting fibrosis. Adipose stem cell-derived exosomes, a product of adipose stem cell paracrine secretion, have pharmacological effects, such as anti-inflammatory and antiapoptotic effects, and mediate autophagy. Therefore, this study aims to investigate the function and mechanism of adipose stem cell exosomes in the treatment of keloids.METHOD: We isolated adipose stem cell exosomes under normoxic and hypoxic condition to detect their effects on keloid fibroblast proliferation, migration, and collagen synthesis. Meanwhile, 740YPDGFR (PI3K/AKT activator) was applied to detect the changes in autophagic flow levels and mitochondrial morphology and function in keloid fibroblasts. We constructed a human keloid mouse model by transplanting human keloid tissues into six-week-old (20-22 g; female) BALB/c nude mice, meanwhile, we applied adipose stem cell exosomes to treat the mouse model and observed the retention and effect of ADSC exosomes in vivo.
    RESULTS: ADSC exosomes can inhibit the PI3K/AKT/mTOR signaling pathway. The exosomes of ADSCs decreased the inflammatory level of KFs, enhanced the interaction between P62 and LC3, and restored the mitochondrial membrane potential. In the human keloid mouse model, ADSC exosomes can exist stably, promote mitochondrial autophagy in keloid tissue, improve mitochondrial morphology, reduce inflammatory reaction and fibrosis. Meanwhile, At the same time, the exosomes derived from hypoxic adipose stem cells have played a more effective role in both in vitro and in vivo experiments.
    CONCLUSIONS: Adipose stem cell exosomes inhibited the PI3K/AKT/mTOR pathway, activated mitochondrial autophagy, and alleviated keloid scars.
    Keywords:  ADSCs; Exosomes; Keloids; Mitophagy; PI3K/AKT/mTOR
    DOI:  https://doi.org/10.1186/s13287-024-03928-5
  28. Genes Dis. 2024 Nov;11(6): 101266
    VPS13D affects epileptic seizures by regulating mitochondrial fission and autophagy in epileptic rats.
    Jian Wang, Fan Zhang, Zhong Luo, Haiqing Zhang, Changyin Yu, Zucai Xu.
      Abnormal mitochondrial dynamics can lead to seizures, and improved mitochondrial dynamics can alleviate seizures. Vacuolar protein sorting 13D (VPS13D) is closely associated with regulating mitochondrial homeostasis and autophagy. However, further investigation is required to determine whether VPS13D affects seizures by influencing mitochondrial dynamics and autophagy. We aimed to investigate the influence of VPS13D on behavior in a rat model of acute epileptic seizures. Hence, we established an acute epileptic seizure rat model and employed the CRISPR/CAS9 technology to construct a lentivirus to silence the Vps13d gene. Furthermore, we used the HT22 mouse hippocampal neuron cell line to establish a stable strain with suppressed expression of Vps13d in vitro. Then, we performed quantitative proteomic and bioinformatics analyses to confirm the mechanism by which VPS13D influences mitochondrial dynamics and autophagy, both in vitro and in vivo using the experimental acute epileptic seizure model. We found that knockdown of Vps13d resulted in reduced seizure latency and increased seizure frequency in the experimental rats. Immunofluorescence staining and western blot analysis revealed a significant increase in mitochondrial dynamin-related protein 1 expression following Vps13d knockdown. Moreover, we observed a significant reduction in LC3II protein expression levels and the LC3II/LC3I ratio (indicators for autophagy) accompanied by a significant increase in P62 expression (an autophagy adaptor protein). The proteomic analysis confirmed the up-regulation of P62 protein expression. Therefore, we propose that VPS13D plays a role in modulating seizures by influencing mitochondrial dynamics and autophagy.
    Keywords:  Autophagy; Mitochondrial dynamics; Mitochondrial fission; Seizures; VPS13D
    DOI:  https://doi.org/10.1016/j.gendis.2024.101266
  29. Open Life Sci. 2024 ;19(1): 20220958
    The role of rapamycin in the PINK1/Parkin signaling pathway in mitophagy in podocytes.
    Shengyou Yu, Weixue Zhu, Li Yu.
      This study aimed to clarify the role of rapamycin in the PINK1/Parkin signaling pathway in mitophagy in podocytes and the role of voltage-dependent anion channel 1 (VDAC1) in the PINK1/Parkin signaling pathway in mouse glomerular podocytes. For this purpose, podocytes were cultured with rapamycin and observed using microscopy. The apoptosis rate of podocytes was detected by flow cytometry. Changes in the mitochondrial membrane potential were measured. The autophagy-related proteins VDAC1, PINK1, Parkin, and LC3 were detected, and mitochondrial autophagosomes were observed via transmission electron microscopy. In the present study, we demonstrated that the number of podocytes treated with rapamycin was significantly reduced. Compared with those in the control group, the apoptosis rate of podocytes and the degree of mitochondrial membrane potential depolarization were significantly higher. We also found the expression levels of VDAC1, PINK1, Parkin, and LC3 were significantly increased. In the rapamycin-treated group, the numbers of swollen mitochondria and mitochondrial autophagosomes were significantly higher. Finally, we showed that rapamycin can upregulate the expression of VDAC1, PINK1, Parkin, and LC3 in glomerular podocytes, which is correlated with mitophagy. VDAC1 is involved in mitophagy and is related to the PINK1/Parkin signaling pathway, serving as an indicator of mitophagy in podocytes.
    Keywords:  VDAC1; mitophagy; podocyte; rapamycin; signaling pathway
    DOI:  https://doi.org/10.1515/biol-2022-0958
  30. Cell Res. 2024 Sep 19.
    α-Synuclein amyloid fibril directly binds to LC3B and suppresses SQSTM1/p62-mediated selective autophagy.
    Qianhui Xu, Huilan Wang, Ruonan Yang, Youqi Tao, Ziying Wang, Shengnan Zhang, Bo Sun, Dan Li, Boxun Lu, Cong Liu.
      
    DOI:  https://doi.org/10.1038/s41422-024-01022-2
  31. J Neuroinflammation. 2024 Sep 18. 21(1): 228
    iPLA2β loss leads to age-related cognitive decline and neuroinflammation by disrupting neuronal mitophagy.
    Li Jiao, Wenxin Shao, Wenqi Quan, Longjiang Xu, Penghui Liu, Jinling Yang, Xiaozhong Peng.
      BACKGROUND: During brain aging, disturbances in neuronal phospholipid metabolism result in impaired cognitive function and dysregulation of neurological processes. Mutations in iPLA2β are associated with neurodegenerative conditions that significantly impact brain phospholipids. iPLA2β deficiency exacerbates mitochondrial dysfunction and abnormal mitochondrial accumulation. We hypothesized that iPLA2β contributes to age-related cognitive decline by disrupting neuronal mitophagy.METHODOLOGY: We used aged wild-type (WT) mice and iPLA2β-/- mice as natural aging models to assess cognitive performance, iPLA2β expression in the cortex, levels of chemokines and inflammatory cytokines, and mitochondrial dysfunction, with a specific focus on mitophagy and the mitochondrial phospholipid profile. To further elucidate the role of iPLA2β, we employed adeno-associated virus (AAV)-mediated iPLA2β overexpression in aged mice and re-evaluated these parameters.
    RESULTS: Our findings revealed a significant reduction in iPLA2β levels in the prefrontal cortex of aged brains. Notably, iPLA2β-deficient mice exhibited impaired learning and memory. Loss of iPLA2β in the PFC of aged mice led to increased levels of chemokines and inflammatory cytokines. This damage was associated with altered mitochondrial morphology, reduced ATP levels due to dysregulation of the parkin-independent mitophagy pathway, and changes in the mitochondrial phospholipid profile. AAV-mediated overexpression of iPLA2β alleviated age-related parkin-independent mitophagy pathway dysregulation in primary neurons and the PFC of aged mice, reduced inflammation, and improved cognitive function.
    CONCLUSIONS: Our study suggests that age-related iPLA2β loss in the PFC leads to cognitive decline through the disruption of mitophagy. These findings highlight the potential of targeting iPLA2β to ameliorate age-related neurocognitive disorders.
    DOI:  https://doi.org/10.1186/s12974-024-03219-z
  32. Curr Mol Med. 2024 ;24(10): 1269-1281
    The Roles of Autophagy-related miRNAs in Gynecologic Tumors: A Review of Current Knowledge for Possible Targeted Therapy.
    Mahya Mobinikhaledi, Arezoo Faridzadeh, Tahereh Farkhondeh, Mohammad Hossein Pourhanifeh, Saeed Samarghandian.
      Gynecological cancers are the leading cause of malignancy-related death and disability in the world. These cancers are diagnosed at end stages, and unfortunately, the standard therapeutic strategies available for the treatment of affected women [including chemotherapy, radiotherapy and surgery] are not safe and effective enough. Moreover, the unwanted side-effects lowering the patients' life quality is another problem for these therapies. Therefore, researchers should search for better alternative/complementary treatments. The involvement of autophagy in the pathogenesis of various cancers has been demonstrated. Recently, a novel crosstalk between microRNAs, small non-coding RNAs with important regulatory functions, and autophagy machinery has been highlighted. In this review, we indicate the importance of this interaction for targeted therapy in the treatment of cancers including gynecological cancers, with a focus on underlying mechanisms.
    Keywords:  autophagy; cervical cancer; chemotherapy.; endometrial cancer; microRNA; ovarian cancer
    DOI:  https://doi.org/10.2174/0115665240263059231002093454
  33. Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01025-8. [Epub ahead of print] 114674
    Lysosome-related organelle integrity suppresses TIR-1 aggregation to restrain toxic propagation of p38 innate immunity.
    Samantha Y Tse-Kang, Read Pukkila-Worley.
      Innate immunity in bacteria, plants, and animals requires the specialized subset of Toll/interleukin-1/resistance gene (TIR) domain proteins that are nicotinamide adenine dinucleotide (NAD+) hydrolases. Aggregation of these TIR proteins engages their enzymatic activity, but it is unknown how this protein multimerization is regulated. Here, we discover that TIR oligomerization is controlled to prevent immune toxicity. We find that p38 propagates its own activation in a positive feedback loop, which promotes the aggregation of the lone enzymatic TIR protein in the nematode C. elegans (TIR-1, homologous to human sterile alpha and TIR motif-containing 1 [SARM1]). We perform a forward genetic screen to determine how the p38 positive feedback loop is regulated. We discover that the integrity of the specific lysosomal subcompartment that expresses TIR-1 is actively maintained to limit inappropriate TIR-1 aggregation on the membranes of these organelles, which restrains toxic propagation of p38 innate immunity. Thus, innate immunity in C. elegans intestinal epithelial cells is regulated by specific control of TIR-1 multimerization.
    Keywords:  CP: Immunology; Caenorhabditis elegans; Pseudomonas aeruginosa; SARM1; TIR-1; intestinal immunity; lysosome-related organelles; p38
    DOI:  https://doi.org/10.1016/j.celrep.2024.114674
  34. Cell Cycle. 2024 Sep 19. 1-21
    Autophagy unrelated transcriptional mechanisms of hydroxychloroquine resistance revealed by integrated multi-omics of evolved cancer cells.
    Silvia G Vaena, Martin J Romeo, Mirna Mina-Abouda, Emma C Funk, George Fullbright, David T Long, Joe R Delaney.
      Hydroxychloroquine (HCQ) and chloroquine are repurposed drugs known to disrupt autophagy, a molecular recycling pathway essential for tumor cell survival, chemotherapeutic resistance, and stemness. We pursued a multi-omic strategy in OVCAR3 ovarian cancer and CCL218 colorectal cancer cells. Two genome-scale screens were performed. In the forward genetic screen, cell populations were passaged for 15 drug pulse-chases with HCQ or vehicle control. Evolved cells were collected and processed for bulk RNA-seq, exome-seq, and single-cell RNA-seq (scRNA-seq). In the reverse genetic screen, a pooled CRISPR-Cas9 library was used in cells over three pulse-chases of HCQ or vehicle control treatments. HCQ evolved cells displayed remarkably few mutational differences, but substantial transcriptional differences. Transcriptomes revealed multiple pathways associated with resistance to HCQ, including upregulation of glycolysis, exocytosis, and chromosome condensation/segregation, or downregulation of translation and apoptosis. The Cas9 screen identified only one autophagy gene. Chromosome condensation and segregation were confirmed to be disrupted by HCQ in live cells and organelle-free in vitro extracts. Transcriptional plasticity was the primary mechanism by which cells evolved resistance to HCQ. Neither autophagy nor the lysosome were substantive hits. Our analysis may serve as a model for how to better position repurposed drugs in oncology.
    Keywords:  Autophagy; colon cancer; drug resistance; hydroxychloroquine; ovarian cancer
    DOI:  https://doi.org/10.1080/15384101.2024.2402191
  35. iScience. 2024 Sep 20. 27(9): 110741
    The role of mitochondrial autophagy in osteoarthritis.
    Genchun Wang, Xiong Zhang, Jingting Xu, Liangcai Hou, Zhou Guo, Kai Sun, Fengjing Guo.
      Osteoarthritis (OA) is a progressive degenerative joint disease, and the underlying molecular mechanisms of OA remain poorly understood. This study aimed to elucidate the relationship between mitochondrial autophagy and OA by identifying key regulatory genes and their biological functions. Utilizing bioinformatics analyses of RNA expression profiles from the GSE55235 dataset, we identified 2,136 differentially expressed genes, leading to the discovery of hub genes associated with mitochondrial autophagy and OA. Gene set enrichment analysis (GSEA) revealed their involvement in critical pathways, highlighting their potential roles in OA pathogenesis. Furthermore, our study explored the immunological landscape of OA, identifying distinct immune cell infiltration patterns that contribute to the disease's inflammatory profile. We also evaluated the therapeutic potential of drugs targeting these hub genes, suggesting potential approaches for OA treatment. Collectively, this study advances our knowledge of mitochondrial autophagy in OA and proposes promising biomarkers and therapeutic targets.
    Keywords:  Bioinformatics; Cell biology; Physiology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.110741
  36. J Colloid Interface Sci. 2024 Sep 11. pii: S0021-9797(24)02158-1. [Epub ahead of print]678(Pt C): 13-23
    Autophagic cell death induced by pH modulation for enhanced iron-based chemodynamic therapy.
    Fengfeng Xue, Huifeng Zhao, Hui Liu, Jingjing Lou, Kailin Li, Zikang Wang, Lu An, Qiwei Tian.
      Iron-based chemodynamic therapy (CDT) exhibits commendable biocompatibility and selectivity, but its efficacy is constrained by the intracellular pH of tumors. To overcome this obstacle, we constructed a silica delivery platform loaded with autophagy-inducing reagents (rapamycin, RAPA) and iron-based Fenton reagents (Fe3O4). This platform was utilized to explore a novel strategy that leverages autophagy to decrease tumor acidity, consequently boosting the effectiveness of CDT. Both in vitro and in vivo experiments revealed that RAPA prompted the generation of acidic organelles (e.g., autophagic vacuoles and autophagosomes), effectively changing the intracellular pH in the tumor microenvironment. Furthermore, RAPA-induced tumor acidification significantly amplified the efficacy of Fe3O4-based Fenton reactions, consequently increasing the effectiveness of Fe3O4-based CDT. This innovative approach, which leverages the interplay between autophagy induction and iron-based CDT, shows promise in overcoming the limitations posed by tumor pH, thus offering a more efficient approach to tumor treatments.
    Keywords:  Autophagic cell death; Autophagy-inducing reagents; Chemodynamic therapy; Intracellular pH; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.jcis.2024.09.093
  37. Genes Dis. 2024 Nov;11(6): 101074
    Mitophagy deficiency activates stimulator of interferon genes activation and aggravates pathogenetic cardiac remodeling.
    Guoxiang Zhou, Xiaowen Wang, Mingyu Guo, Can Qu, Lei Gao, Jiang Yu, Yuanjing Li, Suxin Luo, Qiong Shi, Yongzheng Guo.
      Stimulator of interferon genes (STING) has recently been found to play a crucial role in cardiac sterile inflammation and dysfunction. The role of stimulator of interferon genes (STING) in cardiac sterile inflammation and dysfunction has been recently discovered. This study aims to examine the involvement of STING in pathological cardiac remodeling and the mechanisms that govern the activation of the STING pathway. To investigate this, transverse aortic constriction (TAC) was performed on STING knockout mice to induce pressure overload-induced cardiac remodeling. Subsequently, cardiac function, remodeling, and inflammation levels were evaluated. The STING pathway was found to be activated in the pressure overload-stressed heart and angiotensin II (Ang II)-stimulated cardiac fibroblasts. Loss of STING expression led to a significant reduction in inflammatory responses, mitochondrial fragmentation, and oxidative stress in the heart, resulting in attenuated cardiac remodeling and dysfunction. Furthermore, the exacerbation of pressure overload-induced STING-mediated inflammation and pathological cardiac remodeling was observed when mitophagy was suppressed through the silencing of Parkin, an E3 ubiquitin ligase. Taken together, these findings indicate that STING represents a newly identified and significant molecule implicated in the process of pathological cardiac remodeling and that mitophagy is an upstream mechanism that regulates STING activation. Targeting STING may therefore provide a novel therapeutic strategy for pathological cardiac remodeling and heart failure.
    Keywords:  Cardiac remodeling; Mitochondrial autophagy; STING; Sterile inflammation; mtDNA
    DOI:  https://doi.org/10.1016/j.gendis.2023.08.003
  38. PeerJ. 2024 ;12 e18062
    Relationship between ferroptosis and mitophagy in acute lung injury: a mini-review.
    Yunhua Cheng, Liling Zhu, Shuangxiong Xie, Binyuan Lu, Xiaoyu Du, Guanjiang Ding, Yan Wang, Linchong Ma, Qingxin Li.
      Acute lung injury (ALI) is one of the most deadly and prevalent diseases in the intensive care unit. Ferroptosis and mitophagy are pathological mechanisms of ALI. Ferroptosis aggravates ALI, whereas mitophagy regulates ALI. Ferroptosis and mitophagy are both closely related to reactive oxygen species (ROS). Mitophagy can regulate ferroptosis, but the specific relationship between ferroptosis and mitophagy is still unclear. This study summarizes previous research findings on ferroptosis and mitophagy, revealing their involvement in ALI. Examining the functions of mTOR and NLPR3 helps clarify the connection between ferroptosis and mitophagy in ALI, with the goal of establishing a theoretical foundation for potential therapeutic approaches in the future management of ALI.
    Keywords:  Acute lung injury; Ferroptosis; Mechanism; Mitochondria; Mitophagy; Relationship
    DOI:  https://doi.org/10.7717/peerj.18062
  39. J Biol Chem. 2024 Sep 12. pii: S0021-9258(24)02268-3. [Epub ahead of print] 107767
    Iron regulatory protein 2 facilitates ferritinophagy and DNA damage/repair through guiding ATG9A trafficking.
    Ting Zhang, Qian Liu, Quan Chen, Hao Wu.
      Trace elemental iron is an essential nutrient that participates in diverse metabolic processes. Dysregulation of cellular iron homeostasis, both iron deficiency and iron overload, is detrimental and tightly associated with diseases pathogenesis. IRPs-IREs system locates at the center for iron homeostasis regulation. Additionally, ferritinophagy, the autophagy-dependent ferritin catabolism for iron recycle, is emerging as a novel mechanism for iron homeostasis regulation. It is still unclear whether IRPs-IREs system and ferritinophagy are synergistic or redundant in determining iron homeostasis. Here we report that IRP2, but not IRP1, is indispensable for ferritinophagy in response to iron depletion. Mechanistically, IRP2 ablation results in compromised AMPK activation and defective ATG9A endosomal trafficking, leading to the decreased engulfment of NCOA4-ferritin complex by endosomes and the subsequent dysregulated endosomal microferritinophagy. Moreover, this defective endosomal microferritinophagy exacerbates DNA damage and reduces colony formation in IRP2 depleted cells. Collectively, this study expands the physiological function of IRP2 in endosomal microferritinophagy and highlights a potential crosstalk between IRPs-IREs and ferritinophagy in manipulating iron homeostasis.
    Keywords:  AMPK; ATG9A; Ferritinophagy; IRP2; Iron
    DOI:  https://doi.org/10.1016/j.jbc.2024.107767
  40. iScience. 2024 Sep 20. 27(9): 110757
    ZIKV induces P62-mediated autophagic degradation of TRAF6 through TRAF6-NS1 interaction.
    Shengze Zhang, Chuming Luo, Qiqi Chen, Nina Li, Xinzhong Liao, Jiani Wu, Haolu Zha, Ting Xie, Shaohui Bai, Weijian Tian, Lin Zhu, Xuan Zou, Shisong Fang, Caijun Sun, Ying Jiang, Jianhui Yuan, Yuelong Shu, Nan Wu, Huanle Luo.
      Tumor necrosis factor receptor-associated factor 6 (TRAF6) is crucial in flavivirus infections, modulating the host immune response through interactions with viral proteins. Despite its importance, the relationship between TRAF6 and Zika virus (ZIKV) remains poorly understood. Our prior proteomics analysis revealed reduced TRAF6 protein levels in ZIKV-infected human trophoblast cells compared to non-infected controls. Subsequent studies in cell models and murine tissues confirmed a significant reduction in both TRAF6 mRNA and protein levels post-ZIKV infection. Further investigations unveiled that ZIKV induces P62-mediated degradation of TRAF6, with NS1 identified as the primary contributor. Co-localization and interaction studies demonstrated that NS1 promotes the association of P62, a key autophagy mediator, with TRAF6. Notably, our findings revealed TRAF6 enhances ZIKV infection, NS1 ubiquitination, NS1 expression, and the production of inflammatory cytokines and chemokines. These insights highlight the intricate TRAF6-ZIKV relationship, offering potential for drug targeting NS1-TRAF6 interactions to manage ZIKV infections effectively.
    Keywords:  Biological sciences; Molecular biology; Natural sciences; Virology
    DOI:  https://doi.org/10.1016/j.isci.2024.110757
  41. EMBO J. 2024 Sep 16.
    Non-autophagic Golgi-LC3 lipidation facilitates TFE3 stress response against Golgi dysfunction.
    Jaemin Kang, Cathena Meiling Li, Namhoon Kim, Jongyeon Baek, Yong-Keun Jung.
      Lipidated ATG8/LC3 proteins are recruited to single membrane compartments as well as autophagosomes, supporting their functions. Although recent studies have shown that Golgi-LC3 lipidation follows Golgi damage, its molecular mechanism and function under Golgi stress remain unknown. Here, by combining DLK1 overexpression as a new strategy for induction of Golgi-specific LC3 lipidation, and the application of Golgi-damaging reagents, we unravel the mechanism and role of Golgi-LC3 lipidation. Upon DLK1 overexpression, LC3 is lipidated on the Golgi apparatus in an ATG12-ATG5-ATG16L1 complex-dependent manner; a post-Golgi trafficking blockade is the primary cause of this lipidation. During Golgi stress, ATG16L1 is recruited through its interaction with V-ATPase for Golgi-LC3 lipidation. After post-Golgi trafficking inhibition, TFE3, a key regulator of the Golgi stress response, is translocated to the nucleus. Defects in LC3 lipidation disrupt this translocation, leading to an attenuation of the Golgi stress response. Together, our results reveal the mechanism and unexplored function of Golgi-LC3 lipidation in the Golgi stress response.
    Keywords:  CASM; Golgi Apparatus; Golgi Stress Response; Post-Golgi Trafficking; V-ATPase
    DOI:  https://doi.org/10.1038/s44318-024-00233-y
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