bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–05–05
forty-two papers selected by
Viktor Korolchuk, Newcastle University
  1. Illuminating intercellular autophagy: A comprehensive review of cell non-autonomous autophagy.
  2. CORVET-specific subunit levels determine the balance between HOPS/CORVET endosomal tethering complexes.
  3. A RabGAP negatively regulates plant autophagy and immune trafficking.
  4. The multifaceted role of autophagy in skin autoimmune disorders: a guardian or culprit?
  5. NBR1-mediated selective autophagy of ARF7 modulates root branching.
  6. The underlying mechanism of calcium toxicity-induced autophagic cell death and lysosomal degradation in early stage of cerebral ischemia.
  7. Drosophila Nhe2 Over-expression Induces Autophagic Cell Death.
  8. The two autophagy-related proteins 8a and 8b play distinct physiological roles in Drosophila.
  9. TIGAR exacerbates obesity by triggering LRRK2-mediated defects in macroautophagy and chaperone-mediated autophagy in adipocytes.
  10. Turnover of EDEM1, an ERAD-enhancing factor, is mediated by multiple degradation routes.
  11. Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease.
  12. Harnessing Nanochaperone-Mediated Autophagy for Selective Clearance of Pathogenic Tau Protein in Alzheimer's Disease.
  13. The link between autophagy and psoriasis.
  14. Targeted degradation of NDUFS1 by agrimol B promotes mitochondrial ROS accumulation and cytotoxic autophagy arrest in hepatocellular carcinoma.
  15. Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids.
  16. AdipoRon promotes amyloid-β clearance through enhancing autophagy via nuclear GAPDH-induced sirtuin 1 activation in Alzheimer's disease.
  17. A "dual-key-and-lock" platform for distinguishing autophagy during neuroinflammation.
  18. Age-dependent dynamics of neuronal VAPBALS inclusions in the adult brain.
  19. The interaction of ER stress and autophagy in trophoblasts: navigating pregnancy outcome.
  20. The Phytophthora parasitica effector AVH195 interacts with ATG8, attenuates host autophagy, and promotes biotrophic infection.
  21. Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner.
  22. The role of labile iron on brain proteostasis; could it be an early event of neurodegenerative disease?
  23. Lysosomal dysfunction by inactivation of V-ATPase drives innate immune response in C. elegans.
  24. Cinnamaldehyde ameliorates STZ-induced diabetes through modulation of autophagic process in adipocyte and hepatic tissues on rats.
  25. Curcumin and its anti-colorectal cancer potential: From mechanisms of action to autophagy.
  26. The role of mitophagy in the development of chronic kidney disease.
  27. p37 regulates VCP/p97 shuttling and functions in the nucleus and cytosol.
  28. GDF11 inhibits the malignant progression of hepatocellular carcinoma via regulation of the mTORC1‑autophagy axis.
  29. Transcription factors Pbr3RAV2 and PbrTTG1 regulate pear resistance to Botryosphaeria dothidea via the autophagy pathway.
  30. The emerging roles of miRNA-mediated autophagy in ovarian cancer.
  31. Clathrin Light Chains negatively regulate plant immunity by hijacking the autophagy pathway.
  32. The interaction of endorepellin and neurexin triggers neuroepithelial autophagy and maintains neural tube development.
  33. Protein degrons and degradation: Exploring substrate recognition and pathway selection in plants.
  34. RIPK3 signaling and its role in regulated cell death and diseases.
  35. Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition.
  36. NBR1-mediated autophagic degradation of caspase 8 protects vascular endothelial cells against arsenite-induced apoptotic cell death.
  37. Low-Dose Colchicine Ameliorates Doxorubicin Cardiotoxicity Via Promoting Autolysosome Degradation.
  38. PARKIN is not required to sustain OXPHOS function in adult mammalian tissues.
  39. Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.
  40. The crosstalk between mitochondrial quality control and metal-dependent cell death.
  41. Interplay between α-synuclein and parkin genes: Insights of Parkinson's disease.
  42. Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice.
  1. Biochem Biophys Res Commun. 2024 Apr 27. pii: S0006-291X(24)00560-6. [Epub ahead of print]716 150024
    Illuminating intercellular autophagy: A comprehensive review of cell non-autonomous autophagy.
    Karan Selarka, Bhupendra V Shravage.
      Macro-autophagy (autophagy hereafter) is an evolutionarily conserved cellular process that has long been recognized as an intracellular mechanism for maintaining cellular homeostasis. It involves the formation of a membraned structure called the autophagosome, which carries cargo that includes toxic protein aggregates and dysfunctional organelles to the lysosome for degradation and recycling. Autophagy is primarily considered and studied as a cell-autonomous mechanism. However, recent studies have illuminated an underappreciated facet of autophagy, i.e., non-autonomously regulated autophagy. Non-autonomously regulated autophagy involves the degradation of autophagic components, including organelles, cargo, and signaling molecules, and is induced in neighboring cells by signals from primary adjacent or distant cells/tissues/organs. This review provides insight into the complex molecular mechanisms governing non-autonomously regulated autophagy, highlighting the dynamic interplay between cells within tissue/organ or distinct cell types in different tissues/organs. Emphasis is placed on modes of intercellular communication that include secreted molecules, including microRNAs, and their regulatory roles in orchestrating this phenomenon. Furthermore, we explore the multidimensional roles of non-autonomously regulated autophagy in various physiological contexts, spanning tissue development and aging, as well as its importance in diverse pathological conditions, including cancer and neurodegeneration. By studying the complexities of non-autonomously regulated autophagy, we hope to gain insights into the sophisticated intercellular dynamics within multicellular organisms, including mammals. These studies will uncover novel avenues for therapeutic intervention to modulate intercellular autophagic pathways in altered human physiology.
    Keywords:  Autophagy; Cell non-autonomous; Cell-autonomous; Disease; Inter-cellular/organ; Regulation
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150024
  2. Sci Rep. 2024 May 02. 14(1): 10146
    CORVET-specific subunit levels determine the balance between HOPS/CORVET endosomal tethering complexes.
    Ármin Sőth, Márton Molnár, Péter Lőrincz, Zsófia Simon-Vecsei, Gábor Juhász.
      The closely related endolysosomal tethering complexes HOPS and CORVET play pivotal roles in the homo- and heterotypic fusion of early and late endosomes, respectively, and HOPS also mediates the fusion of lysosomes with incoming vesicles including late endosomes and autophagosomes. These heterohexameric complexes share their four core subunits that assemble with additional two, complex-specific subunits. These features and the similar structure of the complexes could allow the formation of hybrid complexes, and the complex specific subunits may compete for binding to the core. Indeed, our biochemical analyses revealed the overlap of binding sites for HOPS-specific VPS41 and CORVET-specific VPS8 on the shared core subunit VPS18. We found that the overexpression of CORVET-specific VPS8 or Tgfbrap1 decreased the amount of core proteins VPS11 and VPS18 that are assembled with HOPS-specific subunits VPS41 or VPS39, indicating reduced amount of assembled HOPS. In line with this, we observed the elevation of both lipidated, autophagosome-associated LC3 protein and the autophagic cargo p62 in these cells, suggesting impaired autophagosome-lysosome fusion. In contrast, overexpression of HOPS-specific VPS39 or VPS41 did not affect the level of assembled CORVET or autophagy. VPS8 or Tgfbrap1 overexpression also induced Cathepsin D accumulation, suggesting that HOPS-dependent biosynthetic delivery of lysosomal hydrolases is perturbed, too. These indicate that CORVET-specific subunit levels fine-tune HOPS assembly and activity in vivo.
    DOI:  https://doi.org/10.1038/s41598-024-59775-0
  3. Curr Biol. 2024 Apr 22. pii: S0960-9822(24)00442-1. [Epub ahead of print]
    A RabGAP negatively regulates plant autophagy and immune trafficking.
    Enoch Lok Him Yuen, Alexandre Y Leary, Marion Clavel, Yasin Tumtas, Azadeh Mohseni, Jierui Zhao, Lorenzo Picchianti, Mostafa Jamshidiha, Pooja Pandey, Cian Duggan, Ernesto Cota, Yasin Dagdas, Tolga O Bozkurt.
      Plants rely on autophagy and membrane trafficking to tolerate stress, combat infections, and maintain cellular homeostasis. However, the molecular interplay between autophagy and membrane trafficking is poorly understood. Using an AI-assisted approach, we identified Rab3GAP-like (Rab3GAPL) as a key membrane trafficking node that controls plant autophagy negatively. Rab3GAPL suppresses autophagy by binding to ATG8, the core autophagy adaptor, and deactivating Rab8a, a small GTPase essential for autophagosome formation and defense-related secretion. Rab3GAPL reduces autophagic flux in three model plant species, suggesting that its negative regulatory role in autophagy is conserved in land plants. Beyond autophagy regulation, Rab3GAPL modulates focal immunity against the oomycete pathogen Phytophthora infestans by preventing defense-related secretion. Altogether, our results suggest that Rab3GAPL acts as a molecular rheostat to coordinate autophagic flux and defense-related secretion by restraining Rab8a-mediated trafficking. This unprecedented interplay between a RabGAP-Rab pair and ATG8 sheds new light on the intricate membrane transport mechanisms underlying plant autophagy and immunity.
    Keywords:  ATG8; ATG8-interacting motif (AIM); AlphaFold2; PR1 secretion; RXLR effectors; RabGAP; autophagy; callose deposition; plant immunity; vesicle trafficking
    DOI:  https://doi.org/10.1016/j.cub.2024.04.002
  4. Front Immunol. 2024 ;15 1343987
    The multifaceted role of autophagy in skin autoimmune disorders: a guardian or culprit?
    Yi Lin, Xiuyi Wu, Yiwen Yang, Yue Wu, Leihong Xiang, Chengfeng Zhang.
      Autophagy is a cellular process that functions to maintain intracellular homeostasis via the degradation and recycling of defective organelles or damaged proteins. This dynamic mechanism participates in various biological processes, such as the regulation of cellular differentiation, proliferation, survival, and the modulation of inflammation and immune responses. Recent evidence has demonstrated the involvement of polymorphisms in autophagy-related genes in various skin autoimmune diseases. In addition, autophagy, along with autophagy-related proteins, also contributes to homeostasis maintenance and immune regulation in the skin, which is associated with skin autoimmune disorders. This review aims to provide an overview of the multifaceted role of autophagy in skin autoimmune diseases and shed light on the potential of autophagy-targeting therapeutic strategies in dermatology.
    Keywords:  alopecia areata; atopic dermatitis; autophagy; psoriasis; skin autoimmune disorder; systemic lupus erythematosus; systemic sclerosis; vitiligo
    DOI:  https://doi.org/10.3389/fimmu.2024.1343987
  5. EMBO Rep. 2024 Apr 29.
    NBR1-mediated selective autophagy of ARF7 modulates root branching.
    Elise Ebstrup, Jeppe Ansbøl, Ana Paez-Garcia, Henry Culp, Jonathan Chevalier, Pauline Clemmens, Núria S Coll, Miguel A Moreno-Risueno, Eleazar Rodriguez.
      Auxin dictates root architecture via the Auxin Response Factor (ARF) family of transcription factors, which control lateral root (LR) formation. In Arabidopsis, ARF7 regulates the specification of prebranch sites (PBS) generating LRs through gene expression oscillations and plays a pivotal role during LR initiation. Despite the importance of ARF7 in this process, there is a surprising lack of knowledge about how ARF7 turnover is regulated and how this impacts root architecture. Here, we show that ARF7 accumulates in autophagy mutants and is degraded through NBR1-dependent selective autophagy. We demonstrate that the previously reported rhythmic changes to ARF7 abundance in roots are modulated via autophagy and might occur in other tissues. In addition, we show that the level of co-localization between ARF7 and autophagy markers oscillates and can be modulated by auxin to trigger ARF7 turnover. Furthermore, we observe that autophagy impairment prevents ARF7 oscillation and reduces both PBS establishment and LR formation. In conclusion, we report a novel role for autophagy during development, namely by enacting auxin-induced selective degradation of ARF7 to optimize periodic root branching.
    Keywords:  ARF7; Autophagy; Auxin; Lateral Root; NBR1
    DOI:  https://doi.org/10.1038/s44319-024-00142-5
  6. Anat Cell Biol. 2024 Apr 29.
    The underlying mechanism of calcium toxicity-induced autophagic cell death and lysosomal degradation in early stage of cerebral ischemia.
    Jirakhamon Sengking, Pasuk Mahakkanukrauh.
      Cerebral ischemia is the important cause of worldwide disability and mortality, that is one of the obstruction of blood vessels supplying to the brain. In early stage, glutamate excitotoxicity and high level of intracellular calcium (Ca2+) are the major processes which can promote many downstream signaling involving in neuronal death and brain tissue damaging. Moreover, autophagy, the reusing of damaged cell organelles, is affected in early ischemia. Under ischemic conditions, autophagy plays an important role to maintain energy of the brain and its function. In the other hand, over intracellular Ca2+ accumulation triggers excessive autophagic process and lysosomal degradation leading to autophagic process impairment which finally induce neuronal death. This article reviews the association between intracellular Ca2+ and autophagic process in acute stage of ischemic stroke.
    Keywords:  Autophagy; Calcium toxicity; Cerebral ischemia; Lysosomal degradation; Neuronal cell death
    DOI:  https://doi.org/10.5115/acb.24.003
  7. Mol Biol Cell. 2024 May 02. mbcE24020058
    Drosophila Nhe2 Over-expression Induces Autophagic Cell Death.
    Jobelle Peralta, Blake DuPriest, Daniel Orozco, Juan Reyna Pacheco, Laura Martins, Rachel Ann Soriano, Alan Wong, Ramy Wong, Bree Grillo-Hill.
      Autophagy is a conserved catabolic process where double membrane-bound structures form around macromolecules or organelles targeted for degradation. Autophagosomes fuse with lysosomes to facilitate degradation and macromolecule recycling for homeostasis or growth in a cell autonomous fashion. In cancer cells, autophagy is often upregulated and helps cancer cells survive nutrient deprivation and stressful growth conditions. Here, we propose that the increased intracellular pH (pHi) common to cancer cells is sufficient to induce autophagic cell death. We previously developed tools to increase pHi in the Drosophila eye via over-expression of DNhe2, resulting in aberrant patterning and reduced tissue size. We examined fly eyes at earlier stages of development and found fewer interommatidial cells. We next tested whether this decrease in cell number was due to increased cell death. We found that the DNhe2-induced cell death was caspase-independent, which is inconsistent with apoptosis. However, this cell death required autophagy genes, which supports autophagy as the mode of cell death. We also found that expression of molecular markers supports increased autophagy. Together, our findings suggest new roles for ion transport proteins in regulating conserved, critical developmental processes and provide evidence for new paradigms in growth control.
    DOI:  https://doi.org/10.1091/mbc.E24-02-0058
  8. Genomics. 2024 May 01. pii: S0888-7543(24)00074-0. [Epub ahead of print] 110853
    The two autophagy-related proteins 8a and 8b play distinct physiological roles in Drosophila.
    Yuchen Xu, Wei Liu, Zhaolin Sun, Yurun Yu, Tianhao Yang, Xirui Lu, Guiqiang Zhang, Jianwei Jiao, Xiuying Duan.
      Atg8 family proteins play crucial roles in autophagy to maintain cellular homeostasis. However, the physiological roles of Atg8 family proteins have not been systematically determined. In this study, we generated Atg8a and Atg8b (homologs of Atg8 in Drosophila melanogaster) knockout flies. We found that the loss of Atg8a affected autophagy and resulted in partial lethality, abnormal wings, decreased lifespan, and decreased climbing ability in flies. Furthermore, the loss of Atg8a resulted in reduced muscle integrity and the progressive degeneration of the neuron system. We also found that the phosphorylation at Ser88 of Atg8a is important for autophagy and neuronal integrity. The loss of Atg8b did not affect autophagy but induced male sterility in flies. Here, we take full advantage of the fly system to elucidate the physiological function of Atg8a and Atg8b in Drosophila.
    Keywords:  Atg8; Autophagy; Developmental defects; Drosophila; Male sterility; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.ygeno.2024.110853
  9. Autophagy. 2024 Apr 30. 1-21
    TIGAR exacerbates obesity by triggering LRRK2-mediated defects in macroautophagy and chaperone-mediated autophagy in adipocytes.
    Tian Zhang, Ke-Gang Linghu, Jia Tan, Mingming Wang, Diao Chen, Yan Shen, Junchao Wu, Mingjun Shi, Yuxia Zhou, Lei Tang, Lirong Liu, Zheng-Hong Qin, Bing Guo.
      Obesity is one of the most common metabolic diseases around the world, which is distinguished by the abnormal buildup of triglycerides within adipose cells. Recent research has revealed that autophagy regulates lipid mobilization to maintain energy balance. TIGAR (Trp53 induced glycolysis regulatory phosphatase) has been identified as a glycolysis inhibitor, whether it plays a role in the metabolism of lipids is unknown. Here, we found that TIGAR transgenic (TIGAR+/+) mice exhibited increased fat mass and trended to obesity phenotype. Non-target metabolomics showed that TIGAR caused the dysregulation of the metabolism profile. The quantitative transcriptome sequencing identified an increased levels of LRRK2 and RAB7B in the adipose tissue of TIGAR+/+ mice. It was confirmed in vitro that TIGAR overexpression increased the levels of LRRK2 by inhibiting polyubiquitination degradation, thereby suppressing macroautophagy and chaperone-mediated autophagy (CMA) while increasing lipid accumulation which were reversed by the LRRK2 inhibitor DNL201. Furthermore, TIGAR drove LRRK2 to interact with RAB7B for suppressing lysosomal degradation of lipid droplets, while the increased lipid droplets in adipocytes were blocked by the RAB7B inhibitor ML282. Additionally, fat-specific TIGAR knockdown of TIGAR+/+ mice alleviated the symptoms of obesity, and adipose tissues-targeting superiority DNL201 nano-emulsion counteracted the obesity phenotype in TIGAR+/+ mice. In summary, the current results indicated that TIGAR performed a vital function in the lipid metabolism through LRRK2-mediated negative regulation of macroautophagy and CMA in adipocyte. The findings suggest that TIGAR has the potential to serve as a viable therapeutic target for treating obesity and its associated metabolic dysfunction.
    Keywords:  Chaperone-mediated autophagy; TIGAR; lipid metabolism; macroautophagy; obesity
    DOI:  https://doi.org/10.1080/15548627.2024.2338576
  10. Genes Cells. 2024 Apr 29.
    Turnover of EDEM1, an ERAD-enhancing factor, is mediated by multiple degradation routes.
    Riko Katsuki, Mai Kanuka, Ren Ohta, Shusei Yoshida, Taku Tamura.
      Quality-based protein production and degradation in the endoplasmic reticulum (ER) are essential for eukaryotic cell survival. During protein maturation in the ER, misfolded or unassembled proteins are destined for disposal through a process known as ER-associated degradation (ERAD). EDEM1 is an ERAD-accelerating factor whose gene expression is upregulated by the accumulation of aberrant proteins in the ER, known as ER stress. Although the role of EDEM1 in ERAD has been studied in detail, the turnover of EDEM1 by intracellular degradation machinery, including the proteasome and autophagy, is not well understood. To clarify EDEM1 regulation in the protein level, degradation mechanism of EDEM1 was examined. Our results indicate that both ERAD and autophagy degrade EDEM1 alike misfolded degradation substrates, although each degradation machinery targets EDEM1 in different folded states of proteins. We also found that ERAD factors, including the SEL1L/Hrd1 complex, YOD1, XTP3B, ERdj3, VIMP, BAG6, and JB12, but not OS9, are involved in EDEM1 degradation in a mannose-trimming-dependent and -independent manner. Our results suggest that the ERAD accelerating factor, EDEM1, is turned over by the ERAD itself, similar to ERAD clients.
    Keywords:  EDEM1; ER quality control; ER stress; ERAD; autophagy; proteasome; protein degradation; protein turnover; unfolded protein response
    DOI:  https://doi.org/10.1111/gtc.13117
  11. Autophagy. 2024 May 02. 1-11
    Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease.
    Kateřina Veverová, Jan Laczó, Alžběta Katonová, Hana Horáková, Veronika Matušková, Francesco Angelucci, Martina Laczó, Zuzana Nedelská, Jakub Hort, He-Ling Wang, Jianying Zhang, Liu Shi, Evandro Fei Fang, Martin Vyhnálek.
      Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aβ: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.
    Keywords:  Autophagy; BNIP3L; PINK1; TFEB; mild cognitive impairment; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2340408
  12. Adv Mater. 2024 Apr 30. e2313869
    Harnessing Nanochaperone-Mediated Autophagy for Selective Clearance of Pathogenic Tau Protein in Alzheimer's Disease.
    Linlin Xu, Xiaohui Wu, Shuyue Zhao, Haodong Hu, Silei Wang, Yongxin Zhang, Jiajing Chen, Xiaochen Zhang, Yu Zhao, Rujiang Ma, Fan Huang, Linqi Shi.
      Accumulation of pathological tau is a hallmark of Alzheimer's disease (AD), which correlates more closely with cognitive impairment than does the amyloid-β (Aβ) burden. Autophagy is a powerful process for the clearance of toxic proteins including aberrant tau. However, compromised autophagy has been demonstrated in neurodegeneration including AD and current autophagy inducers remain enormously challenging due to inability of restoring autophagy pathway and lack of targeting specificity. Here, pathogenic tau-specific autophagy based on customized nanochaperone is developed for AD treatment. In this strategy, the nanochaperone can selectively bind to pathogenic tau and maintain tau homeostasis, thereby ensuring microtubule stability which is important for autophagy pathway. Meanwhile, the bound pathogenic tau can be sequestered in autophagosomes by in situ autophagy activation of nanochaperone. Consequently, autophagosomes wrapping with pathogenic tau are able to be trafficked along the stabilized microtubule to achieve successful fusion with lysosomes, resulting in the enhancement of autophagic flux and pathologic tau clearance. After treatment with this nanochaperone-mediated autophagy strategy, the tau burden, neuron damages and cognitive deficits of AD mice are significantly alleviated in the brain. Therefore, this work represents a promising candidate for AD-targeted therapy and provides new insights into future design of anti-neurodegeneration drugs. This article is protected by copyright. All rights reserved.
    Keywords:  alzheimer's disease; autophagy; microtubule; nanochaperone; tau protein
    DOI:  https://doi.org/10.1002/adma.202313869
  13. Acta Histochem. 2024 Apr 29. pii: S0065-1281(24)00034-5. [Epub ahead of print]126(4): 152166
    The link between autophagy and psoriasis.
    Nannan Liang, Kaiming Zhang.
      Autophagy is a lysosome-dependent, self-renewal mechanism that degrades and recycles cellular components in eukaryotic cells to maintain the homeostasis of the intracellular environment. Psoriasis is featured by increased inflammatory response, epidermal hyperproliferation and abnormal differentiation, infiltration of immune cells and increased expression levels of both endothelial adhesion molecules and angiogenic mediators. Evidence indicates that autophagy has important roles in many different types of cells, such as lymphocytes, keratinocytes, monocytes and mesenchymal stem cells (MSCs). This paper will review the role of autophagy in the pathogenesis of psoriasis and strategies for therapeutic modulation. Key Message Autophagy regulates the functions of cutaneous cells (MSCs, KCs, T cells and endothelial cells). Since reduced autophagy contributes in part to the pathogenesis of psoriasis, enhancement of autophagy can be an alternative approach to mitigate psoriasis.
    Keywords:  Autophagy; Keratinocyte; Mesenchymal stem cell; Psoriasis; T cell
    DOI:  https://doi.org/10.1016/j.acthis.2024.152166
  14. Free Radic Biol Med. 2024 Apr 30. pii: S0891-5849(24)00429-5. [Epub ahead of print]
    Targeted degradation of NDUFS1 by agrimol B promotes mitochondrial ROS accumulation and cytotoxic autophagy arrest in hepatocellular carcinoma.
    Lixia Dong, Li Luo, Zihao Wang, Shan Lian, Mao Wang, Xingyun Wu, Jiawu Fan, Yan Zeng, Sijia Li, Sinan Lv, Yurong Yang, Rong Chen, Enhao Shen, Wenyong Yang, Changlong Li, Kui Wang.
      Hepatocellular carcinoma (HCC) is a global public health problem with increased morbidity and mortality. Agrimol B, a natural polyphenol, has been proved to be a potential anticancer drug. Our recent report showed a favorable anticancer effect of agrimol B in HCC, however, the mechanism of action remains unclear. Here, we found agrimol B inhibits the growth and proliferation of HCC cells in vitro as well as in an HCC patient-derived xenograft (PDX) model. Notably, agrimol B drives autophagy initiation and blocks autophagosome-lysosome fusion, resulting in autophagosome accumulation and autophagy arrest in HCC cells. Mechanistically, agrimol B downregulates the protein level of NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1) through caspase 3-mediated degradation, leading to mitochondrial reactive oxygen species (mROS) accumulation and autophagy arrest. NDUFS1 overexpression partially restores mROS overproduction, autophagosome accumulation, and growth inhibition induced by agrimol B, suggesting a cytotoxic role of agrimol B-induced autophagy arrest in HCC cells. Notably, agrimol B significantly enhances the sensitivity of HCC cells to sorafenib in vitro and in vivo. In conclusion, our study uncovers the anticancer mechanism of agrimol B in HCC involving the regulation of oxidative stress and autophagy, and suggests agrimol B as a potential therapeutic drug for HCC treatment.
    Keywords:  Agrimol B; NDUFS1; autophagy; hepatocellular carcinoma; mROS; sorafenib
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.04.242
  15. Cell Rep. 2024 May 02. pii: S2211-1247(24)00501-1. [Epub ahead of print]43(5): 114173
    Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids.
    Navroop K Dhaliwal, Octavia Yifang Weng, Xiaoxue Dong, Afrin Bhattacharya, Mai Ahmed, Haruka Nishimura, Wendy W Y Choi, Aditi Aggarwal, Bryan W Luikart, Qiang Shu, Xuekun Li, Michael D Wilson, Jason Moffat, Lu-Yang Wang, Julien Muffat, Yun Li.
      Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.
    Keywords:  CP: Cell biology; CP: Neuroscience; PTEN; autism; brain organoids; epilepsy; mTOR; neurodevelopmental disorders; neurons
    DOI:  https://doi.org/10.1016/j.celrep.2024.114173
  16. Br J Pharmacol. 2024 Apr 28.
    AdipoRon promotes amyloid-β clearance through enhancing autophagy via nuclear GAPDH-induced sirtuin 1 activation in Alzheimer's disease.
    Fengjiao Sun, Jiangong Wang, Lingbin Meng, Zhenyu Zhou, Yong Xu, Meizi Yang, Yixin Li, Tianrui Jiang, Bin Liu, Haijing Yan.
       BACKGROUND AND PURPOSE: Amyloid-β (Aβ) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development of AD impairs autophagy, which results in an imbalanced clearance of Aβ. Our previous research demonstrated that AdipoRon, an agonist of adiponectin receptors, decreased the deposition of Aβ and enhanced cognitive function in AD. However, the exact mechanisms by which AdipoRon affects Aβ clearance remain unclear.
    EXPERIMENTAL APPROACH: We studied how AdipoRon affects autophagy in HT22 cells and APP/PS1 transgenic mice. We also investigated the signalling pathway involved and used pharmacological inhibitors to examine the role of autophagy in this process.
    KEY RESULTS: AdipoRon promotes Aβ clearance by activating neuronal autophagy in the APP/PS1 transgenic mice. Interestingly, we found that AdipoRon induces the nuclear translocation of GAPDH, where it interacts with the SIRT1/DBC1 complex. This interaction then leads to the release of DBC1 and the activation of SIRT1, which in turn activates autophagy. Importantly, we found that inhibiting either GAPDH or SIRT1 to suppress the activity of SIRT1 counteracts the elevated autophagy and decreased Aβ deposition caused by AdipoRon. This suggests that SIRT1 plays a critical role in the effect of AdipoRon on autophagic induction in AD.
    CONCLUSION AND IMPLICATIONS: AdipoRon promotes the clearance of Aβ by enhancing autophagy through the AdipoR1/AMPK-dependent nuclear translocation of GAPDH and subsequent activation of SIRT1. This novel molecular pathway sheds light on the modulation of autophagy in AD and may lead to the development of new therapeutic strategies targeting this pathway.
    Keywords:  AMPK; AdipoR1; AdipoRon; Alzheimer's disease; Aβ; DBC1; GAPDH; SIRT1; autophagy
    DOI:  https://doi.org/10.1111/bph.16400
  17. Biosens Bioelectron. 2024 Apr 27. pii: S0956-5663(24)00349-X. [Epub ahead of print]258 116344
    A "dual-key-and-lock" platform for distinguishing autophagy during neuroinflammation.
    Shuyang Zhai, Wei Hu, Zhihong Liu, Yingbin Liu.
      Autophagy is an essential degradative process that governs the renewal of organelle and maintains the homeostasis of cellular microenvironment. Its dysregulation has been demonstrated to be an indicator for neuroinflammation. To elucidate the interrelationship between neuroinflammation and autophagy, optical probes are ideal tools as they offer a number of advantages such as high spatiotemporal resolution and non-invasive sensing, which help to visualize the physiological and pathological functions of interested analytes. However, single autophagy parameter-response probes may generate false-positive results since they cannot distinguish between neuroinflammation and other autophagic stimuli. In contrast, chemosensors that respond to two (or more) targets can improve selectivity by qualifying response conditions. Herein, a "dual-key-and-lock" strategy was applied to construct probe (Vis-NO) to selectively recognize autophagy under inflammation out of other stimuli. The red fluorescence of Vis-NO was lit up only in the simultaneously presence of high viscosity and nitric oxide (NO) in lysosome. Due to the characteristics of high viscosity and overexpressed NO within lysosomes, Vis-NO could be used to selectively identify autophagy during neuroinflammation, providing expanding insights into the interrelationship between autophagy, neuroinflammation and stroke in pathology, and informing about the mechanisms through which autophagy regulates inflammation.
    Keywords:  Autophagy; Neuroninflammation; Optical probe; Stroke; “Dual-key-and-lock” mechanism
    DOI:  https://doi.org/10.1016/j.bios.2024.116344
  18. Neurobiol Dis. 2024 Apr 26. pii: S0969-9961(24)00116-5. [Epub ahead of print] 106517
    Age-dependent dynamics of neuronal VAPBALS inclusions in the adult brain.
    Aparna Thulasidharan, Lovleen Garg, Shweta Tendulkar, Girish S Ratnaparkhi.
      Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive and fatal disease, caused by the degeneration of upper and lower motor neurons within the brain and spinal cord in the ageing human. The dying neurons contain cytoplasmic inclusions linked to the onset and progression of the disease. Here, we use a Drosophila model of ALS8 (VAPP58S) to understand the modulation of these inclusions in the ageing adult brain. The adult VAPP58S fly shows progressive deterioration in motor function till its demise 25 days post-eclosion. The density of VAPP58S-positive brain inclusions is stable for 5-15 days of age. In contrast, adding a single copy of VAPWT to the VAPP58S animal leads to a large decrease in inclusion density with concomitant rescue of motor function and lifespan. ER stress, a contributing factor in disease, shows reduction with ageing for the disease model. Autophagy, rather than the Ubiquitin Proteasome system, is the dominant mechanism for aggregate clearance. We explored the ability of Drosophila Valosin-containing protein (VCP/TER94), the ALS14 locus, which is involved in cellular protein clearance, to regulate age-dependent aggregation. Contrary to expectation, TER94 overexpression increased VAPP58S punctae density, while its knockdown led to enhanced clearance. Expression of a dominant positive allele, TER94R152H, further stabilised VAPP58S puncta, cementing roles for an ALS8-ALS14 axis. Our results are explained by a mechanism where autophagy is modulated by TER94 knockdown. Our study sheds light on the complex regulatory events involved in the neuronal maintenance of ALS8 aggregates, suggesting a context-dependent switch between proteasomal and autophagy-based mechanisms as the larvae develop into an adult. A deeper understanding of the nucleation and clearance of the inclusions, which affect cellular stress and function, is essential for understanding the initiation and progression of ALS.
    Keywords:  ALS14; ALS8; Ageing; Autophagy; FAF1; Neuroaggregate; TER94; VCP; Valosin; p97
    DOI:  https://doi.org/10.1016/j.nbd.2024.106517
  19. Biol Reprod. 2024 Apr 28. pii: ioae066. [Epub ahead of print]
    The interaction of ER stress and autophagy in trophoblasts: navigating pregnancy outcome.
    Yi Zheng, Xia Zha, Bei Zhang, Mabrouk Elsabagh, Hongrong Wang, Mengzhi Wang, Hao Zhang.
      The endoplasmic reticulum (ER) is a complex and dynamic organelle that initiates unfolded protein response (UPR) and endoplasmic reticulum stress (ER Stress) in response to the accumulation of unfolded or misfolded proteins within its lumen. Autophagy is a paramount intracellular degradation system that facilitates the transportation of proteins, cytoplasmic components, and organelles to lysosomes for degradation and recycling. Preeclampsia (PE) and intrauterine growth retardation (IUGR) are two common complications of pregnancy associated with abnormal trophoblast differentiation and placental dysfunctions and have a major impact on fetal development and maternal health. The intricate interplay between ER Stress, and autophagy and their impact on pregnancy outcomes, through mediating trophoblast differentiation and placental development, has been highlighted in various reports. Autophagy controls trophoblast regulation through a variety of gene expressions and signalling pathways while excessive ER Stress triggers downstream apoptotic signalling, culminating in trophoblast apoptosis. This comprehensive review delves into the intricacies of placental development and explores the underlying mechanisms of PE and IUGR. In addition, this review will elucidate the molecular mechanisms of ER Stress and autophagy, both individually and in their interplay, in mediating placental development and trophoblast differentiation, particularly highlighting their roles in PE and IUGR development. This research seeks to the interplay between ER Stress and impaired autophagy in the placental trophoderm, offering novel insights into their contribution to pregnancy complications.
    Keywords:  autophagy; endoplasmic reticulum stress; intrauterine growth retardation; preeclampsia; trophoblast
    DOI:  https://doi.org/10.1093/biolre/ioae066
  20. BMC Biol. 2024 Apr 29. 22(1): 100
    The Phytophthora parasitica effector AVH195 interacts with ATG8, attenuates host autophagy, and promotes biotrophic infection.
    Serena Testi, Marie-Line Kuhn, Valérie Allasia, Pascaline Auroy, Fantao Kong, Gilles Peltier, Sophie Pagnotta, Julie Cazareth, Harald Keller, Franck Panabières.
       BACKGROUND: Plant pathogens secrete effector proteins into host cells to suppress immune responses and manipulate fundamental cellular processes. One of these processes is autophagy, an essential recycling mechanism in eukaryotic cells that coordinates the turnover of cellular components and contributes to the decision on cell death or survival.
    RESULTS: We report the characterization of AVH195, an effector from the broad-spectrum oomycete plant pathogen, Phytophthora parasitica. We show that P. parasitica expresses AVH195 during the biotrophic phase of plant infection, i.e., the initial phase in which host cells are maintained alive. In tobacco, the effector prevents the initiation of cell death, which is caused by two pathogen-derived effectors and the proapoptotic BAX protein. AVH195 associates with the plant vacuolar membrane system and interacts with Autophagy-related protein 8 (ATG8) isoforms/paralogs. When expressed in cells from the green alga, Chlamydomonas reinhardtii, the effector delays vacuolar fusion and cargo turnover upon stimulation of autophagy, but does not affect algal viability. In Arabidopsis thaliana, AVH195 delays the turnover of ATG8 from endomembranes and promotes plant susceptibility to P. parasitica and the obligate biotrophic oomycete pathogen Hyaloperonospora arabidopsidis.
    CONCLUSIONS: Taken together, our observations suggest that AVH195 targets ATG8 to attenuate autophagy and prevent associated host cell death, thereby favoring biotrophy during the early stages of the infection process.
    Keywords:  Autophagy; Biotrophy; Effector; Oomycete; Vacuoles
    DOI:  https://doi.org/10.1186/s12915-024-01899-w
  21. Cell Rep. 2024 Apr 26. pii: S2211-1247(24)00477-7. [Epub ahead of print]43(5): 114149
    Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner.
    Davy Vanhoutte, Tobias G Schips, Rachel A Minerath, Jiuzhou Huo, Naga Swathi Sree Kavuri, Vikram Prasad, Suh-Chin Lin, Michael J Bround, Michelle A Sargent, Christopher M Adams, Jeffery D Molkentin.
      Loss of muscle mass is a feature of chronic illness and aging. Here, we report that skeletal muscle-specific thrombospondin-1 transgenic mice (Thbs1 Tg) have profound muscle atrophy with age-dependent decreases in exercise capacity and premature lethality. Mechanistically, Thbs1 activates transforming growth factor β (TGFβ)-Smad2/3 signaling, which also induces activating transcription factor 4 (ATF4) expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to facilitate muscle atrophy. Indeed, myofiber-specific inhibition of TGFβ-receptor signaling represses the induction of ATF4, normalizes ALP and UPS, and partially restores muscle mass in Thbs1 Tg mice. Similarly, myofiber-specific deletion of Smad2 and Smad3 or the Atf4 gene antagonizes Thbs1-induced muscle atrophy. More importantly, Thbs1-/- mice show significantly reduced levels of denervation- and caloric restriction-mediated muscle atrophy, along with blunted TGFβ-Smad3-ATF4 signaling. Thus, Thbs1-mediated TGFβ-Smad3-ATF4 signaling in skeletal muscle regulates tissue rarefaction, suggesting a target for atrophy-based muscle diseases and sarcopenia with aging.
    Keywords:  ATF4; CP: Metabolism; TGFβ; atrophy; autophagy; extracellular matrix; proteasome; skeletal muscle; thrombospondin
    DOI:  https://doi.org/10.1016/j.celrep.2024.114149
  22. Arch Biochem Biophys. 2024 Apr 30. pii: S0003-9861(24)00139-5. [Epub ahead of print]756 110020
    The role of labile iron on brain proteostasis; could it be an early event of neurodegenerative disease?
    Aiyarin Kittilukkana, Jannarong Intakhad, Chalermchai Pilapong.
      Iron deposits in the brain are a natural consequence of aging. Iron accumulation, especially in the form of labile iron, can trigger a cascade of adverse effects, eventually leading to neurodegeneration and cognitive decline. Aging also increases the dysfunction of cellular proteostasis. The question of whether iron alters proteostasis is now being pondered. Herein, we investigated the effect of ferric citrate, considered as labile iron, on various aspects of proteostasis of neuronal cell lines, and also established an animal model having a labile iron diet in order to evaluate proteostasis alteration in the brain along with behavioral effects. According to an in vitro study, labile iron was found to activate lysosome formation but inhibits lysosomal clearance function. Furthermore, the presence of labile iron can alter autophagic flux and can also induce the accumulation of protein aggregates. RNA-sequencing analysis further reveals the upregulation of various terms related to proteostasis along with neurodegenerative disease-related terms. According to an in vivo study, a labile iron-rich diet does not induce iron overload conditions and was not detrimental to the behavior of male Wistar rats. However, an iron-rich diet can promote iron accumulation in a region-dependent manner. By staining for autophagic markers and misfolding proteins in the cerebral cortex and hippocampus, an iron-rich diet was actually found to alter autophagy and induce an accumulation of misfolding proteins. These findings emphasize the importance of labile iron on brain cell proteostasis, which could be implicated in developing of neurological diseases.
    Keywords:  Autophagy; Labile iron; Lysosome; Misfolding peptide; Proteostasis
    DOI:  https://doi.org/10.1016/j.abb.2024.110020
  23. Cell Rep. 2024 Apr 26. pii: S2211-1247(24)00466-2. [Epub ahead of print]43(5): 114138
    Lysosomal dysfunction by inactivation of V-ATPase drives innate immune response in C. elegans.
    Xuepiao Pu, Bin Qi.
      Pathogens target vacuolar ATPase (V-ATPase) to inhibit lysosomal acidification or lysosomal fusion, causing lysosomal dysfunction. However, it remains unknown whether cells can detect dysfunctional lysosomes and initiate an immune response. In this study, we discover that dysfunction of lysosomes caused by inactivation of V-ATPase enhances innate immunity against bacterial infections. We find that lysosomal V-ATPase interacts with DVE-1, whose nuclear localization serves as a proxy for the induction of mitochondrial unfolded protein response (UPRmt). The inactivation of V-ATPase promotes the nuclear localization of DVE-1, activating UPRmt and inducing downstream immune response genes. Furthermore, pathogen resistance conferred by inactivation of V-ATPase requires dve-1 and its downstream immune effectors. Interestingly, animals grow slower after vha RNAi, suggesting that the vha-RNAi-induced immune response costs the most energy through activation of DVE-1, which trades off with growth. This study reveals how dysfunctional lysosomes can trigger an immune response, emphasizing the importance of conserving energy during immune defense.
    Keywords:  C. elegans; CP: Immunology; UPR(mt); V-ATPase; immunity; lysosomes; mitochondria; mitochondrial surveillance; pathogen
    DOI:  https://doi.org/10.1016/j.celrep.2024.114138
  24. Sci Rep. 2024 May 02. 14(1): 10053
    Cinnamaldehyde ameliorates STZ-induced diabetes through modulation of autophagic process in adipocyte and hepatic tissues on rats.
    Nesma A Ghazal, Yara T Agamia, Basant K Meky, Nagwa M Assem, Wafaa M Abdel-Rehim, Sara A Shaker.
      Type 2 diabetes mellitus is a worldwide public health issue. In the globe, Egypt has the ninth-highest incidence of diabetes. Due to its crucial role in preserving cellular homeostasis, the autophagy process has drawn a lot of attention in recent years, Therefore, the purpose of this study was to evaluate the traditional medication metformin with the novel therapeutic effects of cinnamondehyde on adipocyte and hepatic autophagy in a model of high-fat diet/streptozotocin-diabetic rats. The study was conducted on 40 male albino rats, classified into 2 main groups, the control group and the diabetic group, which was subdivided into 4 subgroups (8 rats each): untreated diabetic rats, diabetic rats received oral cinnamaldehyde 40 mg/kg/day, diabetic rats received oral metformin 200 mg/kg/day and diabetic rats received a combination of both cinnamaldehyde and metformin daily for 4 weeks. The outcomes demonstrated that cinnamaldehyde enhanced the lipid profile and glucose homeostasis. Moreover, Cinnamaldehyde had the opposite effects on autophagy in both tissues; by altering the expression of genes that control autophagy, such as miRNA 30a and mammalian target of rapamycin (mTOR), it reduced autophagy in adipocytes and stimulated it in hepatic tissues. It may be inferred that by increasing the treatment efficacy of metformin and lowering its side effects, cinnamaldehyde could be utilized as an adjuvant therapy with metformin for the treatment of type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41598-024-60150-2
  25. Phytother Res. 2024 May 03.
    Curcumin and its anti-colorectal cancer potential: From mechanisms of action to autophagy.
    Aranka Brockmueller, Vicenç Ruiz de Porras, Mehdi Shakibaei.
      Colorectal cancer (CRC) development and progression, one of the most common cancers globally, is supported by specific mechanisms to escape cell death despite chemotherapy, including cellular autophagy. Autophagy is an evolutionarily highly conserved degradation pathway involved in a variety of cellular processes, such as the maintenance of cellular homeostasis and clearance of foreign bodies, and its imbalance is associated with many diseases. However, the role of autophagy in CRC progression remains controversial, as it has a dual function, affecting either cell death or survival, and is associated with cellular senescence in tumor therapy. Indeed, numerous data have been presented that autophagy in cancers serves as an alternative to cell apoptosis when the latter is ineffective or in apoptosis-resistant cells, which is why it is also referred to as programmed cell death type II. Curcumin, one of the active constituents of Curcuma longa, has great potential to combat CRC by influencing various cellular signaling pathways and epigenetic regulation in a safe and cost-effective approach. This review discusses the efficacy of curcumin against CRC in vitro and in vivo, particularly its modulation of autophagy and apoptosis in various cellular pathways. While clinical studies have assessed the potential of curcumin in cancer prevention and treatment, none have specifically examined its role in autophagy. Nonetheless, we offer an overview of potential correlations to support the use of this polyphenol as a prophylactic or co-therapeutic agent in CRC.
    Keywords:  apoptosis; autophagy; colorectal cancer; curcumin; senescence
    DOI:  https://doi.org/10.1002/ptr.8220
  26. PeerJ. 2024 ;12 e17260
    The role of mitophagy in the development of chronic kidney disease.
    Kexin Yang, Ting Li, Yingpu Geng, Xiangyu Zou, Fujun Peng, Wei Gao.
      Chronic kidney disease (CKD) represents a significant global health concern, with renal fibrosis emerging as a prevalent and ultimate manifestation of this condition. The absence of targeted therapies presents an ongoing and substantial challenge. Accumulating evidence suggests that the integrity and functionality of mitochondria within renal tubular epithelial cells (RTECs) often become compromised during CKD development, playing a pivotal role in the progression of renal fibrosis. Mitophagy, a specific form of autophagy, assumes responsibility for eliminating damaged mitochondria to uphold mitochondrial equilibrium. Dysregulated mitophagy not only correlates with disrupted mitochondrial dynamics but also contributes to the advancement of renal fibrosis in CKD. While numerous studies have examined mitochondrial metabolism, ROS (reactive oxygen species) production, inflammation, and apoptosis in kidney diseases, the precise pathogenic mechanisms underlying mitophagy in CKD remain elusive. The exact mechanisms through which modulating mitophagy mitigates renal fibrosis, as well as its influence on CKD progression and prognosis, have not undergone systematic investigation. The role of mitophagy in AKI has been relatively clear, but the role of mitophagy in CKD is still rare. This article presents a comprehensive review of the current state of research on regulating mitophagy as a potential treatment for CKD. The objective is to provide fresh perspectives, viable strategies, and practical insights into CKD therapy, thereby contributing to the enhancement of human living conditions and patient well-being.
    Keywords:  Chronic kidney disease; Mitochondria; Mitophagy; Renal fibrosis
    DOI:  https://doi.org/10.7717/peerj.17260
  27. Sci Adv. 2024 May 03. 10(18): eadl6082
    p37 regulates VCP/p97 shuttling and functions in the nucleus and cytosol.
    Lidia Wrobel, Johanna L Hoffmann, Xinyi Li, David C Rubinsztein.
      The AAA+-ATPase valosin-containing protein (VCP; also called p97 or Cdc48), a major protein unfolding machinery with a variety of essential functions, localizes to different subcellular compartments where it has different functions. However, the processes regulating the distribution of VCP between the cytosol and nucleus are not understood. Here, we identified p37 (also called UBXN2B) as a major factor regulating VCP nucleocytoplasmic shuttling. p37-dependent VCP localization was crucial for local cytosolic VCP functions, such as autophagy, and nuclear functions in DNA damage repair. Mutations in VCP causing multisystem proteinopathy enhanced its association with p37, leading to decreased nuclear localization of VCP, which enhanced susceptibility to DNA damage accumulation. Both VCP localization and DNA damage susceptibility in cells with such mutations were normalized by lowering p37 levels. Thus, we uncovered a mechanism by which VCP nucleocytoplasmic distribution is fine-tuned, providing a means for VCP to respond appropriately to local needs.
    DOI:  https://doi.org/10.1126/sciadv.adl6082
  28. Exp Ther Med. 2024 Jun;27(6): 252
    GDF11 inhibits the malignant progression of hepatocellular carcinoma via regulation of the mTORC1‑autophagy axis.
    Qingyi Wu, Chan Fan, Kebo Liu, Jiefu Tang.
      Hepatocellular carcinoma (HCC) is a common malignant tumor, which is associated with a poor prognosis and high mortality rate. It is well known that growth differentiation factor 11 (GDF11) acts as a tumor suppressor in various types of cancer, including HCC. The present study aimed to determine the tumor-suppressive properties of GDF11 in HCC and to assess the intrinsic mechanisms. In the present study, the human hepatoma cell line Huh-7 was transfected with the GDF11 overexpression plasmid (Oe-GDF11) for gain-of-function experiments to investigate the effects of GDF11 on the biological behaviors of HCC cells, including proliferation, colony formation, apoptosis, cell cycle arrest, migration, invasion, epithelial-mesenchymal transition (EMT) and angiogenesis. The proliferation, colony formation, apoptosis, cell cycle, migration, invasion and angiogenesis of HCC cells were assessed by CCK-8, EdU staining, colony formation, flow cytometry, wound healing, Transwell and tube formation assays, respectively. Apoptosis-, cell cycle-, EMT-related key factors were also determined by western blot assay. Furthermore, Oe-GDF11-transfected Huh-7 cells were treated with the mammalian target of rapamycin (mTOR) activator MHY1485 for rescue experiments to explore whether GDF11 could exert antitumor effects against HCC via mediating the mTOR complex 1 (mTORC1)-autophagy axis. In the present study, GDF11 was verified to be lowly expressed in HCC cells. Overexpression of GDF11 inhibited the proliferation, colony formation, migration, invasion, EMT and angiogenesis of HCC cells, and facilitated the apoptosis and cell cycle arrest of HCC cells. Additionally, it was verified that overexpression of GDF11 inactivated the mTORC1 signaling pathway to enhance autophagy in HCC cells. Treatment with the mTOR activator MHY1485 partially reversed the tumor-suppressive effects of GDF11 overexpression on HCC. In conclusion, GDF11 may exert tumor-suppressive properties in HCC cells through inactivating the mTORC1 signaling pathway to strengthen autophagy.
    Keywords:  growth differentiation factor 11; hepatocellular carcinoma; mammalian target of rapamycin complex 1-autophagy axis
    DOI:  https://doi.org/10.3892/etm.2024.12540
  29. Plant Physiol. 2024 May 02. pii: kiae252. [Epub ahead of print]
    Transcription factors Pbr3RAV2 and PbrTTG1 regulate pear resistance to Botryosphaeria dothidea via the autophagy pathway.
    Xun Sun, Fei Wang, Yun Wang, Ye Zhang, Yue Zhang, Yuting Liu, Xiaolei Sun, Kaijie Qi, Zhihua Xie, Shaoling Zhang.
      Pear ring rot, caused by Botryosphaeria dothidea, is the most serious disease of pear (Pyrus spp.) trees. However, the molecular mechanisms underlying pear resistance to B. dothidea remain elusive. Herein, we demonstrated that the pear AuTophagy-related Gene 1a (PbrATG1a) plays a key role in autophagic activity and resistance to B. dothidea. Stable overexpression of PbrATG1a enhanced resistance to B. dothidea in pear calli. Autophagy activity was greater in PbrATG1a overexpressing calli than in WT calli. We used yeast one-hybrid screening to identify a transcription factor, Related to ABI3 and VP1 (Pbr3RAV2), that binds the promoter of PbrATG1a and enhances pear resistance to B. dothidea by regulating autophagic activity. Specifically, overexpression of Pbr3RAV2 enhanced resistance to B. dothidea in pear calli, while transient silencing of Pbr3RAV2 resulted in compromised resistance to B. dothidea in Pyrus betulaefolia. In addition, we identified Transparent Testa Glabra 1 (PbrTTG1), which interacts with Pbr3RAV2. Pathogen infection enhanced the interaction between Pbr3RAV2 and PbrTTG1. The Pbr3RAV2-PbrTTG1 complex increased the binding capacity of Pbr3RAV2 and transcription of PbrATG1a. In addition to providing insights into the molecular mechanisms underlying pear disease resistance, these findings suggest potential genetic targets for enhancing disease resistance in pear.
    Keywords:   Botryosphaeria dothidea ; autophagy; interaction; pear; transcription factor
    DOI:  https://doi.org/10.1093/plphys/kiae252
  30. Cell Death Dis. 2024 May 03. 15(5): 314
    The emerging roles of miRNA-mediated autophagy in ovarian cancer.
    Yamin Ding, Xuan Huang, Tuo Ji, Cong Qi, Xuzhu Gao, Rongbin Wei.
      Ovarian cancer is one of the common tumors of the female reproductive organs. It has a high mortality rate, is highly heterogeneous, and early detection and primary prevention are very complex. Autophagy is a cellular process in which cytoplasmic substrates are targeted for degradation in lysosomes through membrane structures called autophagosomes. The periodic elimination of damaged, aged, and redundant cellular molecules or organelles through the sequential translation between amino acids and proteins by two biological processes, protein synthesis, and autophagic protein degradation, helps maintain cellular homeostasis. A growing number of studies have found that autophagy plays a key regulatory role in ovarian cancer. Interestingly, microRNAs regulate gene expression at the posttranscriptional level and thus can regulate the development and progression of ovarian cancer through the regulation of autophagy in ovarian cancer. Certain miRNAs have recently emerged as important regulators of autophagy-related gene expression in cancer cells. Moreover, miRNA analysis studies have now identified a sea of aberrantly expressed miRNAs in ovarian cancer tissues that can affect autophagy in ovarian cancer cells. In addition, miRNAs in plasma and stromal cells in tumor patients can affect the expression of autophagy-related genes and can be used as biomarkers of ovarian cancer progression. This review focuses on the potential significance of miRNA-regulated autophagy in the diagnosis and treatment of ovarian cancer.
    DOI:  https://doi.org/10.1038/s41419-024-06677-8
  31. Plant Commun. 2024 Apr 30. pii: S2590-3462(24)00207-4. [Epub ahead of print] 100937
    Clathrin Light Chains negatively regulate plant immunity by hijacking the autophagy pathway.
    Hu-Jiao Lan, Jie Ran, Wen-Xu Wang, Lei Zhang, Ni-Ni Wu, Ya-Ting Zhao, Min-Jun Huang, Min Ni, Feng Liu, Ninghui Cheng, Paul A Nakata, Jianwei Pan, Steven A Whitham, Barbara J Baker, Jian-Zhong Liu.
      The crosstalk between clathrin-mediated endocytosis (CME) and autophagy pathway has been reported in mammals. However, the interconnection of CME with autophagy has not been established in plants. In this report, we showed that Arabidopsis CLATHRIN LIGHT CHAIN (CLC) subunit 2 and 3 double mutant, clc2-1 clc3-1, phenocopied the Arabidopsis AUTOPHAGY-RELATED GENE (ATG) mutants both in auto-immunity and nutrient sensitivity. Accordingly, the autophagy pathway was significantly compromised in the clc2-1 clc3-1 mutant. Interestingly, we demonstrated with multiple assays that CLC2 directly interacted with ATG8h/ATG8i in a domain-specific manner. As expected, both GFP-ATG8h/GFP-ATG8i and CLC2-GFP were subjected to autophagic degradation and the degradation of GFP-ATG8h was significantly reduced in the clc2-1 clc3-1 mutant. Notably, simultaneously knocking out ATG8h and ATG8i by the CRISPR/CAS9 resulted in an enhanced resistance against Golovinomyces cichoracearum, supporting the functional relevance of the CLC2-ATG8h/8i interactions. In conclusion, our results uncovered a link between the function of CLCs and the autophagy pathway in Arabidopsis.
    Keywords:  autophagy; cell death; clathrin light chain; clathrin-mediated endocytosis; immunity; senescence
    DOI:  https://doi.org/10.1016/j.xplc.2024.100937
  32. Sci Bull (Beijing). 2024 Mar 15. pii: S2095-9273(24)00182-8. [Epub ahead of print]
    The interaction of endorepellin and neurexin triggers neuroepithelial autophagy and maintains neural tube development.
    Lei Lu, Meizhu Bai, Yufang Zheng, Xiukun Wang, Zhongzhong Chen, Rui Peng, Richard H Finnell, Tongjin Zhao, Chengtao Li, Bo Wu, Yunping Lei, Jinsong Li, Hongyan Wang.
      Heparan sulfate proteoglycan 2 (HSPG2) gene encodes the matrix protein Perlecan, and genetic inactivation of this gene creates mice that are embryonic lethal with severe neural tube defects (NTDs). We discovered rare genetic variants of HSPG2 in 10% cases compared to only 4% in controls among a cohort of 369 NTDs. Endorepellin, a peptide cleaved from the domain V of Perlecan, is known to promote angiogenesis and autophagy in endothelial cells. The roles of enderepellin in neurodevelopment remain unclear so far. Our study revealed that endorepellin can migrate to the neuroepithelial cells and then be recognized and bind with the neuroepithelia receptor neurexin in vivo. Through the endocytic pathway, the interaction of endorepellin and neurexin physiologically triggers autophagy and appropriately modulates the differentiation of neural stem cells into neurons as a blocker, which is necessary for normal neural tube closure. We created knock-in (KI) mouse models with human-derived HSPG2 variants, using sperm-like stem cells that had been genetically edited by CRISPR/Cas9. We realized that any HSPG2 variants that affected the function of endorepellin were considered pathogenic causal variants for human NTDs given that the severe NTD phenotypes exhibited by these KI embryos occurred in a significantly higher response frequency compared to wildtype embryos. Our study provides a paradigm for effectively confirming pathogenic mutations in other genetic diseases. Furthermore, we demonstrated that using autophagy inhibitors at a cellular level can repress neuronal differentiation. Therefore, autophagy agonists may prevent NTDs resulting from failed autophagy maintenance and neuronal over-differentiation caused by deleterious endorepellin variants.
    DOI:  https://doi.org/10.1016/j.scib.2024.03.026
  33. Plant Cell. 2024 May 03. pii: koae141. [Epub ahead of print]
    Protein degrons and degradation: Exploring substrate recognition and pathway selection in plants.
    Erika Isono, Jianming Li, Pablo Pulido, Wei Siao, Steven H Spoel, Zhishuo Wang, Xiaohong Zhuang, Marco Trujillo.
      Proteome composition is dynamic and influenced by many internal and external cues, including developmental signals, light availability, or environmental stresses. Protein degradation, in synergy with protein biosynthesis, allows cells to respond to various stimuli and adapt by reshaping the proteome. Protein degradation mediates the final and irreversible disassembly of proteins, which is important for protein quality control and to eliminate misfolded or damaged proteins, as well as entire organelles. Consequently, it contributes to cell resilience by buffering against protein or organellar damage caused by stresses. Moreover, protein degradation plays important roles in cell signaling, as well as transcriptional and translational events. The intricate task of recognizing specific proteins for degradation is achieved by specialized systems that are tailored to the substrate's physicochemical properties and subcellular localization. These systems recognize diverse substrate cues collectively referred to as "degrons", which can assume a range of structural configurations. They are molecular surfaces recognized by E3 ligases of the ubiquitin-proteasome system, but can also be considered as general features recognized by other degradation systems, including autophagy or even organellar proteases. Here we provide an overview of the newest developments in the field, delving into the intricate processes of protein recognition and elucidating the pathways through which they are recruited for degradation.
    DOI:  https://doi.org/10.1093/plcell/koae141
  34. Cell Death Discov. 2024 Apr 29. 10(1): 200
    RIPK3 signaling and its role in regulated cell death and diseases.
    Yaqi Zhou, Yaxuan Xiang, Sijie Liu, Chenyao Li, Jiaheng Dong, Xiangrui Kong, Xinying Ji, Xiaoxia Cheng, Lei Zhang.
      Receptor-interacting protein kinase 3 (RIPK3), a member of the receptor-interacting protein kinase (RIPK) family with serine/threonine protein kinase activity, interacts with RIPK1 to generate necrosomes, which trigger caspase-independent programmed necrosis. As a vital component of necrosomes, RIPK3 plays an indispensable role in necroptosis, which is crucial for human life and health. In addition, RIPK3 participates in the pathological process of several infections, aseptic inflammatory diseases, and tumors (including tumor-promoting and -suppressive activities) by regulating autophagy, cell proliferation, and the metabolism and production of chemokines/cytokines. This review summarizes the recent research progress of the regulators of the RIPK3 signaling pathway and discusses the potential role of RIPK3/necroptosis in the aetiopathogenesis of various diseases. An in-depth understanding of the mechanisms and functions of RIPK3 may facilitate the development of novel therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41420-024-01957-w
  35. J Inorg Biochem. 2024 Apr 23. pii: S0162-0134(24)00097-7. [Epub ahead of print]256 112574
    Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition.
    Guan-Dong Zhang, Meng-Meng Wang, Yan Su, Hongbao Fang, Xu-Ling Xue, Hong-Ke Liu, Zhi Su.
      Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh3, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh3 exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC50 value of 4.0 μM. Ru-TPE-PPh3 could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh3 also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation.
    Keywords:  Anti-cancer; Autophagy; CuAAC; Ru-arene complex; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.jinorgbio.2024.112574
  36. Biochem Biophys Res Commun. 2024 Apr 25. pii: S0006-291X(24)00542-4. [Epub ahead of print]715 150006
    NBR1-mediated autophagic degradation of caspase 8 protects vascular endothelial cells against arsenite-induced apoptotic cell death.
    Siyao Hu, Fu Wang, Lejiao Mao, Xuejun Jiang, Yilin Luo, Xia Qin, Zhen Zou, Chengzhi Chen, Chao Yu, Jun Zhang.
      Vascular endothelial cells play a critical role in maintaining the health of blood vessels, but dysfunction can lead to cardiovascular diseases. The impact of arsenite exposure on cardiovascular health is a significant concern due to its potential adverse effects. This study aims to explore how NBR1-mediated autophagy in vascular endothelial cells can protect against oxidative stress and apoptosis induced by arsenite. Initially, our observations revealed that arsenite exposure increased oxidative stress and triggered apoptotic cell death in human umbilical vein endothelial cells (HUVECs). However, treatment with the apoptosis inhibitor Z-VAD-FMK notably reduced arsenite-induced apoptosis. Additionally, arsenite activated the autophagy pathway and enhanced autophagic flux in HUVECs. Interestingly, inhibition of autophagy exacerbated arsenite-induced apoptotic cell death. Our findings also demonstrated the importance of autophagy receptor NBR1 in arsenite-induced cytotoxicity, as it facilitated the recruitment of caspase 8 to autophagosomes for degradation. The protective effect of NBR1 against arsenite-induced apoptosis was compromised when autophagy was inhibited using pharmacological inhibitors or through genetic knockdown of essential autophagy genes. Conversely, overexpression of NBR1 facilitated caspase 8 degradation and reduced apoptotic cell death in arsenite-treated HUVECs. In conclusion, our study highlights the vital role of NBR1-mediated autophagic degradation of caspase 8 in safeguarding vascular endothelial cells from arsenite-induced oxidative stress and apoptotic cell death. Targeting this pathway could offer a promising therapeutic approach to mitigate cardiovascular diseases associated with arsenite exposure.
    Keywords:  Apoptosis; Autophagy; Autophagy receptor; Caspase 8 degradation; NBR1
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150006
  37. J Am Heart Assoc. 2024 May 03. e033700
    Low-Dose Colchicine Ameliorates Doxorubicin Cardiotoxicity Via Promoting Autolysosome Degradation.
    Ying Peng, Zhonggen Li, Jianchao Zhang, Yunshu Dong, Chenglin Zhang, Yiming Dong, Yafei Zhai, Honglin Zheng, Mengduan Liu, Jing Zhao, Wenting Du, Yangyang Liu, Liping Sun, Xiaowei Li, Hailong Tao, Deyong Long, Xiaoyan Zhao, Xin Du, Changsheng Ma, Yaohe Wang, Jianzeng Dong.
       BACKGROUND: The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So, exploring alternative effective molecules to attenuate its cardiotoxicity is crucial. Colchicine is a safe and well-tolerated drug that helps reduce the production of reactive oxygen species. High doses of colchicine have been reported to block the fusion of autophagosomes and lysosomes in cancer cells. However, the impact of colchicine on the autophagy activity within cardiomyocytes remains inadequately elucidated. Recent studies have highlighted the beneficial effects of colchicine on patients with pericarditis, postprocedural atrial fibrillation, and coronary artery disease. It remains ambiguous how colchicine regulates autophagic flux in doxorubicin-induced heart failure.
    METHODS AND RESULTS: Doxorubicin was administered to establish models of heart failure both in vivo and in vitro. Prior studies have reported that doxorubicin impeded the breakdown of autophagic vacuoles, resulting in damaged mitochondria and the accumulation of reactive oxygen species. Following the administration of a low dose of colchicine (0.1 mg/kg, daily), significant improvements were observed in heart function (left ventricular ejection fraction: doxorubicin group versus treatment group=43.75%±3.614% versus 57.07%±2.968%, P=0.0373). In terms of mechanism, a low dose of colchicine facilitated the degradation of autolysosomes, thereby mitigating doxorubicin-induced cardiotoxicity.
    CONCLUSIONS: Our research has shown that a low dose of colchicine is pivotal in restoring the autophagy activity, thereby attenuating the cardiotoxicity induced by doxorubicin. Consequently, colchicine emerges as a promising therapeutic candidate to improve doxorubicin cardiotoxicity.
    Keywords:  autophagy; colchicine; doxorubicin cardiotoxicity; heart failure
    DOI:  https://doi.org/10.1161/JAHA.123.033700
  38. NPJ Parkinsons Dis. 2024 Apr 29. 10(1): 93
    PARKIN is not required to sustain OXPHOS function in adult mammalian tissues.
    Roberta Filograna, Jule Gerlach, Hae-Na Choi, Giovanni Rigoni, Michela Barbaro, Mikael Oscarson, Seungmin Lee, Katarina Tiklova, Markus Ringnér, Camilla Koolmeister, Rolf Wibom, Sara Riggare, Inger Nennesmo, Thomas Perlmann, Anna Wredenberg, Anna Wedell, Elisa Motori, Per Svenningsson, Nils-Göran Larsson.
      Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson's disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.
    DOI:  https://doi.org/10.1038/s41531-024-00707-0
  39. Nature. 2024 May 01.
    Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.
    Ruei-Zeng Lin, Gwang-Bum Im, Allen Chilun Luo, Yonglin Zhu, Xuechong Hong, Joseph Neumeyer, Hong-Wen Tang, Norbert Perrimon, Juan M Melero-Martin.
      Ischaemic diseases such as critical limb ischaemia and myocardial infarction affect millions of people worldwide1. Transplanting endothelial cells (ECs) is a promising therapy in vascular medicine, but engrafting ECs typically necessitates co-transplanting perivascular supporting cells such as mesenchymal stromal cells (MSCs), which makes clinical implementation complicated2,3. The mechanisms that enable MSCs to facilitate EC engraftment remain elusive. Here we show that, under cellular stress, MSCs transfer mitochondria to ECs through tunnelling nanotubes, and that blocking this transfer impairs EC engraftment. We devised a strategy to artificially transplant mitochondria, transiently enhancing EC bioenergetics and enabling them to form functional vessels in ischaemic tissues without the support of MSCs. Notably, exogenous mitochondria did not integrate into the endogenous EC mitochondrial pool, but triggered mitophagy after internalization. Transplanted mitochondria co-localized with autophagosomes, and ablation of the PINK1-Parkin pathway negated the enhanced engraftment ability of ECs. Our findings reveal a mechanism that underlies the effects of mitochondrial transfer between mesenchymal and endothelial cells, and offer potential for a new approach for vascular cell therapy.
    DOI:  https://doi.org/10.1038/s41586-024-07340-0
  40. Cell Death Dis. 2024 Apr 27. 15(4): 299
    The crosstalk between mitochondrial quality control and metal-dependent cell death.
    Qi-Yuan Zhou, Chao Ren, Jing-Yan Li, Lu Wang, Yu Duan, Ren-Qi Yao, Ying-Ping Tian, Yong-Ming Yao.
      Mitochondria are the centers of energy and material metabolism, and they also serve as the storage and dispatch hubs of metal ions. Damage to mitochondrial structure and function can cause abnormal levels and distribution of metal ions, leading to cell dysfunction and even death. For a long time, mitochondrial quality control pathways such as mitochondrial dynamics and mitophagy have been considered to inhibit metal-induced cell death. However, with the discovery of new metal-dependent cell death including ferroptosis and cuproptosis, increasing evidence shows that there is a complex relationship between mitochondrial quality control and metal-dependent cell death. This article reviews the latest research results and mechanisms of crosstalk between mitochondrial quality control and metal-dependent cell death in recent years, as well as their involvement in neurodegenerative diseases, tumors and other diseases, in order to provide new ideas for the research and treatment of related diseases.
    DOI:  https://doi.org/10.1038/s41419-024-06691-w
  41. Mol Biol Rep. 2024 Apr 29. 51(1): 586
    Interplay between α-synuclein and parkin genes: Insights of Parkinson's disease.
    Kajal Sharma, Shivani Chib, Aniket Gupta, Randhir Singh, Rishabh Chalotra.
      Parkinson's disease (PD) is a complex and debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The pathogenesis of PD is intimately linked to the roles of two key molecular players, α-synuclein (α-syn) and Parkin. Understanding the intricate interplay between α-syn and Parkin is essential for unravelling the molecular underpinnings of PD. Their roles in synaptic function and protein quality control underscore their significance in neuronal health. Dysregulation of these processes, as seen in PD, highlights the potential for targeted therapeutic strategies aimed at restoring normal protein homeostasis and mitigating neurodegeneration. Investigating the connections between α-syn, Parkin, and various pathological mechanisms provides insights into the complex web of factors contributing to PD pathogenesis and offers hope for the development of more effective treatments for this devastating neurological disorder. The present compilation provides an overview of their structures, regional and cellular locations, associations, physiological functions, and pathological roles in the context of PD.
    Keywords:  Neurodegeneration; Parkin; Parkinson’s disease; α-synuclein
    DOI:  https://doi.org/10.1007/s11033-024-09520-7
  42. Sci Signal. 2024 Apr 30. 17(834): eadn4556
    Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice.
    Xin Shi, Xiao-Zhong Zhou, Gang Chen, Wei-Feng Luo, Chengyu Zhou, Tian-Ju He, Mandar T Naik, Qin Jiang, John Marshall, Cong Cao.
      Signaling mediated by brain-derived neurotrophic factor (BDNF), which is supported by the postsynaptic scaffolding protein PSD-95, has antidepressant effects. Conversely, clinical depression is associated with reduced BDNF signaling. We found that peptidomimetic compounds that bind to PSD-95 promoted signaling by the BDNF receptor TrkB in the hippocampus and reduced depression-like behaviors in mice. The compounds CN2097 and Syn3 both bind to the PDZ3 domain of PSD-95, and Syn3 also binds to an α-helical region of the protein. Syn3 reduced depression-like behaviors in two mouse models of stress-induced depression; CN2097 had similar but less potent effects. In hippocampal neurons, application of Syn3 enhanced the formation of TrkB-Gαi1/3-PSD-95 complexes and potentiated downstream PI3K-Akt-mTOR signaling. In mice subjected to chronic mild stress (CMS), systemic administration of Syn3 reversed the CMS-induced, depression-associated changes in PI3K-Akt-mTOR signaling, dendrite complexity, spine density, and autophagy in the hippocampus and reduced depression-like behaviors. Knocking out Gαi1/3 in hippocampal neurons prevented the therapeutic effects of Syn3, indicating dependence of these effects on the TrkB pathway. The findings suggest that compounds that induce the formation of PSD-95-TrkB complexes have therapeutic potential to alleviate depression.
    DOI:  https://doi.org/10.1126/scisignal.adn4556
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