bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024‒03‒03
67 papers selected by
Viktor Korolchuk, Newcastle University
  1. FBXL4: safeguarding against mitochondrial depletion through suppression of mitophagy.
  2. Interplay between autophagy and CncC regulates dendrite pruning in Drosophila.
  3. Pparα activation stimulates autophagic flux through lipid catabolism-independent route.
  4. Neuronal waste management: new roles for autophagy genes in the extrusion of protein aggregates and in longevity.
  5. The HSP90 chaperone code regulates the crosstalk between proteostasis and autophagy.
  6. General autophagy-dependent and -independent lipophagic processes collaborate to regulate the overall level of lipophagy in yeast.
  7. The impact of VPS35 D620N mutation on alternative autophagy and its reversal by estrogen in Parkinson's disease.
  8. Mitochondrial bioenergetics stimulates autophagy for pathological tau clearance in tauopathy neurons.
  9. Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress.
  10. Insights into Autophagic Machinery and Lysosomal Function in Cells Involved in the Psoriatic Immune-Mediated Inflammatory Cascade.
  11. PtdIns4p is required for the autophagosomal recruitment of STX17 (syntaxin 17) to promote lysosomal fusion.
  12. Aging STINGs: mitophagy at the crossroads of neuroinflammation.
  13. The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function.
  14. Chronic arsenic exposure suppresses proteasomal and autophagic protein degradation.
  15. mTOR signaling regulates aberrant epithelial cell proliferative and migratory behaviors characteristic of airway mucous metaplasia in asthma.
  16. Autophagy differentially regulates tissue tolerance of distinct target organs in graft-versus-host disease models.
  17. Real-Time Visualization of Cholesterol Trafficking in Human Granulosa Cells Using Confocal Live Cell Microscopy as a Tool to Study the Novel Role of Autophagy in Sex Steroid Synthesis.
  18. Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system.
  19. Functional significance of O-linked N-acetylglucosamine protein modification in regulating autophagy.
  20. Single Fluorescent Probe for Multiple Tasks: Illuminating Lipid Droplets and Lysosomes in Dual Channels and Distinguishing Autophagy and Apoptosis.
  21. Combinatorial selective ER-phagy remodels the ER during neurogenesis.
  22. Focusing on the role of protein kinase mTOR in endometrial physiology and pathology: insights for therapeutic interventions.
  23. UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.
  24. Interactions Between Extracellular Vesicles and Autophagy in Neuroimmune Disorders.
  25. BMSC-Exosomes attenuate ALP dysfunction by restoring lysosomal function via the mTOR/TFEB Axis to reduce cerebral ischemia-reperfusion injury.
  26. Mitochondrial derived vesicles- Quo Vadis?
  27. Autophagy and UPS pathway contribute to nicotine-induced protection effect in Parkinson's disease.
  28. Chronic Rapamycin administration via drinking water mitigates the pathological phenotype in a Krabbe disease mouse model through autophagy activation.
  29. Attenuation of phytofungal pathogenicity of Ascomycota by autophagy modulators.
  30. α-Synuclein: Multiple pathogenic roles in trafficking and proteostasis pathways in Parkinson's disease.
  31. Betulinic acid induces apoptosis of HeLa cells via ROS-dependent ER stress and autophagy in vitro and in vivo.
  32. The size-dependence and reversibility of polystyrene nanoplastics-induced lipid accumulation in mice: Possible roles of lysosomes.
  33. The in vitro and in vivo depigmentation activity of coenzyme Q0, a major quinone derivative from Antrodia camphorata, through autophagy induction in human melanocytes and keratinocytes.
  34. Allelic heterogeneity of TTNtv cardiomyopathy can be modeled in adult zebrafish.
  35. Autophagy promotes efficient T cell responses to restrict high-dose Mycobacterium tuberculosis infection in mice.
  36. Structure-based engineering of Tor complexes reveals that two types of yeast TORC1 produce distinct phenotypes.
  37. Dimethyl Fumarate Exerts a Neuroprotective Effect by Enhancing Mitophagy via the NRF2/BNIP3/PINK1 Axis in the MPP+ Iodide-Induced Parkinson's Disease Mice Model.
  38. Diabetes mellitus and Alzheimer's disease: Vacuolar adenosine triphosphatase as a potential link.
  39. The interplay of mitophagy, autophagy, and apoptosis in cisplatin-induced kidney injury: involvement of ERK signaling pathway.
  40. Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice.
  41. Visualizing Lipophagy as a New Mechanism of the Synthesis of Sex Steroids in Human Ovary and Testis Using Immunofluorescence Staining Method.
  42. In Vivo Analysis of ER-Associated Protein Degradation and Ubiquitination in Arabidopsis thaliana.
  43. Mitochondrial DNA leakage triggers inflammation in age-related cardiovascular diseases.
  44. Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk.
  45. Dysregulation of CREB5 Impairs Decidualization and Maternal-Fetal Interactions by Inhibiting Autophagy in Recurrent Spontaneous Abortion.
  46. The Janus face of mitophagy in myocardial ischemia/reperfusion injury and recovery.
  47. Advanced glycation end products promote meniscal calcification by activating the mTOR-ATF4 positive feedback loop.
  48. Role of BcSfb3, the subunit of COPII vesicles, in fungal development and pathogenicity, ER-phagy and autophagy in the gray mold fungus Botrytis cinerea.
  49. Sodium butyrate ameliorates high glucose-suppressed neuronal mitophagy by restoring PRKN expression via inhibiting the RELA-HDAC8 complex.
  50. Impact of Suramin on Key Pathological Features of Sporadic Alzheimer's Disease-Derived Forebrain Neurons.
  51. A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.
  52. Circadian clock genes REV-ERBα regulates the secretion of IL-1β in deciduous tooth pulp stem cells by regulating autophagy in the process of physiological root resorption of deciduous teeth.
  53. A leucine-macrophage mTORC1 connection drives increased risk of atherosclerosis with high-protein diets.
  54. LC3B drives transcription-associated homologous recombination via direct interaction with R-loops.
  55. A quantitative ultrastructural timeline of nuclear autophagy reveals a role for dynamin-like protein 1 at the nuclear envelope.
  56. New autophagy-modulating lanostane-type triterpenoids from a hallucinogenic poisonous mushroom Gymnopilus orientispectabilis.
  57. Sodium butyrate exerts a neuroprotective effect in rats with acute carbon monoxide poisoning by activating autophagy through the mTOR signaling pathway.
  58. Crosstalk between ALK3(BMPR1A) deficiency and autophagy signaling mitigates pathological bone loss in osteoporosis.
  59. Cross-talk between Vimentin and autophagy regulates blood-testis barrier disruption induced by cadmium.
  60. DDIT3 deficiency accelerates bone remodeling during bone healing by enhancing osteoblast and osteoclast differentiation through ULK1-mediated autophagy.
  61. A novel synthesized cyclohexane-hydroxytyrosol derivative suppresses ovarian cancer cell growth through inducing ROS and blocking autophagic flux.
  62. Cathelicidin LL-37 promotes wound healing in diabetic mice by regulating TFEB-dependent autophagy.
  63. BOP1 contributes to the activation of autophagy in polycystic ovary syndrome via nucleolar stress response.
  64. AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner.
  65. ER remodelling by ER-phagy in neurogenesis.
  66. mTOR pathway occupies a central role in the emergence of latent cancer cells.
  67. Lessons from inducible pluripotent stem cell models on neuronal senescence in aging and neurodegeneration.
  1. Autophagy. 2024 Feb 29. 1-3
    FBXL4: safeguarding against mitochondrial depletion through suppression of mitophagy.
    Prajakta Kulkarni, Giang Thanh Nguyen-Dien, Keri-Lyn Kozul, Julia K Pagan.
      Mitophagy is a critical mitochondrial quality control process that selectively removes dysfunctional or excess mitochondria through the autophagy-lysosome system. The process is tightly controlled to ensure cellular and physiological homeostasis. Insufficient mitophagy can result in failure to remove damaged mitochondria and consequent cellular degeneration, but it is equally important to appropriately restrain mitophagy to prevent excessive mitochondrial depletion. Here, we discuss our recent discovery that the SKP1-CUL1-F-box (SCF)-FBXL4 (F-box and leucine-rich repeat protein 4) E3 ubiquitin ligase localizes to the mitochondrial outer membrane, where it constitutively mediates the ubiquitination and degradation of BNIP3L/NIX and BNIP3 mitophagy receptors to suppress mitophagy. The post-translational regulation of BNIP3L and BNIP3 is disrupted in mitochondrial DNA depletion syndrome 13 (MTDPS13), a multi-systemic disorder caused by mutations in the FBXL4 gene and characterized by elevated mitophagy and mitochondrial DNA/mtDNA depletion in patient fibroblasts. Our results demonstrate that mitophagy is not solely stimulated in response to specific conditions but is instead also actively suppressed through the continuous degradation of BNIP3L and BNIP3 mediated by the SCF-FBXL4 ubiquitin ligase. Thus, cellular conditions or signaling events that prevent the FBXL4-mediated turnover of BNIP3L and BNIP3 on specific mitochondria are expected to facilitate their selective removal.
    Keywords:  BNIP3; BNIP3L/NIX; FBXL4; MTDPS13; mitophagy; ubiquitin ligase
    DOI:  https://doi.org/10.1080/15548627.2024.2318077
  2. Proc Natl Acad Sci U S A. 2024 Mar 05. 121(10): e2310740121
    Interplay between autophagy and CncC regulates dendrite pruning in Drosophila.
    Jue Yu Kelly Tan, Liang Yuh Chew, Gábor Juhász, Fengwei Yu.
      Autophagy is essential for the turnover of damaged organelles and long-lived proteins. It is responsible for many biological processes such as maintaining brain functions and aging. Impaired autophagy is often linked to neurodevelopmental and neurodegenerative diseases in humans. However, the role of autophagy in neuronal pruning during development remains poorly understood. Here, we report that autophagy regulates dendrite-specific pruning of ddaC sensory neurons in parallel to local caspase activation. Impaired autophagy causes the formation of ubiquitinated protein aggregates in ddaC neurons, dependent on the autophagic receptor Ref(2)P. Furthermore, the metabolic regulator AMP-activated protein kinase and the insulin-target of rapamycin pathway act upstream to regulate autophagy during dendrite pruning. Importantly, autophagy is required to activate the transcription factor CncC (Cap "n" collar isoform C), thereby promoting dendrite pruning. Conversely, CncC also indirectly affects autophagic activity via proteasomal degradation, as impaired CncC results in the inhibition of autophagy through sequestration of Atg8a into ubiquitinated protein aggregates. Thus, this study demonstrates the important role of autophagy in activating CncC prior to dendrite pruning, and further reveals an interplay between autophagy and CncC in neuronal pruning.
    Keywords:  Atg8a; CncC; autophagy; dendrite pruning; metamorphosis
    DOI:  https://doi.org/10.1073/pnas.2310740121
  3. Fish Physiol Biochem. 2024 Feb 24.
    Pparα activation stimulates autophagic flux through lipid catabolism-independent route.
    Yan-Yu Zhang, Jun-Xian Wang, Fang Qiao, Mei-Ling Zhang, Yuan Luo, Zhen-Yu Du.
      Autophagy is a cellular process that involves the fusion of autophagosomes and lysosomes to degrade damaged proteins or organelles. Triglycerides are hydrolyzed by autophagy, releasing fatty acids for energy through mitochondrial fatty acid oxidation (FAO). Inhibited mitochondrial FAO induces autophagy, establishing a crosstalk between lipid catabolism and autophagy. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, stimulates lipid catabolism genes, including fatty acid transport and mitochondrial FAO, while also inducing autophagy through transcriptional regulation of transcription factor EB (TFEB). Therefore, the study explores whether PPARα regulates autophagy through TFEB transcriptional control or mitochondrial FAO. In aquaculture, addressing liver lipid accumulation in fish is crucial. Investigating the link between lipid catabolism and autophagy is significant for devising lipid-lowering strategies and maintaining fish health. The present study investigated the impact of dietary fenofibrate and L-carnitine on autophagy by activating Pparα and enhancing FAO in Nile tilapia (Oreochromis niloticus), respectively. The dietary fenofibrate and L-carnitine reduced liver lipid content and enhanced ATP production, particularly fenofibrate. FAO enhancement by L-carnitine showed no changes in autophagic protein levels and autophagic flux. Moreover, fenofibrate-activated Pparα promoted the expression and nuclear translocation of Tfeb, upregulating autophagic initiation and lysosomal biogenesis genes. Pparα activation exhibited an increasing trend of LC3II protein at the basal autophagy and cumulative p62 protein trends after autophagy inhibition in zebrafish liver cells. These data show that Pparα activation-induced autophagic flux should be independent of lipid catabolism.
    Keywords:  Autophagy; Fatty acid oxidation; Lipid catabolism; PPARα activation; Transcription factor EB
    DOI:  https://doi.org/10.1007/s10695-024-01327-4
  4. Autophagy. 2024 Feb 27.
    Neuronal waste management: new roles for autophagy genes in the extrusion of protein aggregates and in longevity.
    Ling-Hsuan Sun, Caitlin Lange, Malene Hansen, Caroline Kumsta.
      A decline in macroautophagic/autophagic activity with age contributes to the accumulation of damaged molecules and is associated with the impairment of neuronal functions and the onset of age-related diseases, particularly neurodegenerative disorders. To learn about the neuronal-specific roles of autophagy genes in aging, we specifically inhibited autophagy genes pan-neuronally in C. elegans, which leads to unexpected positive impacts on neuronal homeostasis including polyQ aggregate load and organismal lifespan. These improvements are independent of canonical, degradative autophagy in neurons and instead correlated with an increase in the secretion of large, extracellular vesicles, known as exophers. We found that the ATG-16.2 WD40 domain, a conserved domain critical for at least some noncanonical autophagy functions of ATG16L1 in mammalian cells, is required for the increased exopher biogenesis, reduction in polyQ aggregate load, and lifespan extension induced by neuronal inhibition of early-acting autophagy genes. Our study suggests that noncanonical functions of ATG-16.2, and potentially other early-acting autophagy genes, may play a role in neuronal exopher formation and in C. elegans aging, extending beyond their canonical degradative functions in the autophagy process.
    Keywords:  ATG-16.2/ATG16L1; Aging; c. elegans; exophers; non-canonical autophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2322420
  5. Autophagy. 2024 Feb 27.
    The HSP90 chaperone code regulates the crosstalk between proteostasis and autophagy.
    Sarah J Backe, Jennifer A Heritz, Mehdi Mollapour.
      Proteostasis, the maintenance of proper protein folding, stability, and degradation within cells, is fundamental for cellular function. Two key players in this intricate cellular process are macroautophagy/autophagy and chaperoning of nascent proteins. Here, we explore the crosstalk between autophagy and the HSP90 chaperone in maintaining proteostasis, highlighting their interplay and significance in cellular homeostasis.
    Keywords:  Atg1; ULK1; chaperone; chaperone code; co-chaperone; phosphorylation
    DOI:  https://doi.org/10.1080/15548627.2024.2323259
  6. Autophagy. 2024 Feb 29.
    General autophagy-dependent and -independent lipophagic processes collaborate to regulate the overall level of lipophagy in yeast.
    Na Kang, Jinling Tan, Sisi Yan, Leiying Lin, Qiang Gao.
      Lipophagy in the yeast Saccharomyces cerevisiae is a microautophagic process in which lipid droplets (LDs) are directly engulfed into the vacuole, despite the fact that multiple core ATG (autophagy related) genes related to general autophagy have been reported to be essential for this process for unknown reasons. In this study, we report new findings about the regulation of lipophagy by analyzing, under different culture conditions, both the engulfment of LDs into the vacuole and the degradation of LD surface proteins. We find that the degradation of LD surface proteins relies on autophagy and can occur independently of lipophagy. Furthermore, glucose restriction can trigger an ATG1-independent lipophagic process, depending on the glucose concentration in the mediums. In summary, we describe an ATG-independent lipophagic process in yeast, such that the overall level of lipophagy in cells is governed by a dynamic balance between the ATG-dependent and -independent lipophagic processes.
    Keywords:  Autophagy; autophagy related genes; lipid droplet surface proteins; lipid droplets; lipophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2325297
  7. Cell Mol Life Sci. 2024 Feb 27. 81(1): 103
    The impact of VPS35 D620N mutation on alternative autophagy and its reversal by estrogen in Parkinson's disease.
    Tomotaka Shiraishi, Keiko Bono, Hiromi Hiraki, Yoko Manome, Hisayoshi Oka, Yasuyuki Iguchi, Hirotaka James Okano.
      VPS35 plays a key role in neurodegenerative processes in Alzheimer's disease and Parkinson's disease (PD). Many genetic studies have shown a close relationship between autophagy and PD pathophysiology, and specifically, the PD-causing D620N mutation in VPS35 has been shown to impair autophagy. However, the molecular mechanisms underlying neuronal cell death and impaired autophagy in PD are debated. Notably, increasing evidence suggests that Rab9-dependent "alternative" autophagy, which is driven by a different molecular mechanism that driving ATG5-dependent "conventional" autophagy, also contributes to neurodegenerative process. In this study, we investigated the relationship between alternative autophagy and VPS35 D620N mutant-related PD pathogenesis. We isolated iPSCs from the blood mononuclear cell population of two PD patients carrying the VPS35 D620N mutant. In addition, we used CRISPR-Cas9 to generate SH-SY5Y cells carrying the D620N variant of VPS35. We first revealed that the number of autophagic vacuoles was significantly decreased in ATG5-knockout Mouse Embryonic Fibroblast or ATG5-knockdown patient-derived dopaminergic neurons carrying the VPS35 D620N mutant compared with that of the wild type VPS35 control cells. Furthermore, estrogen, which activates alternative autophagy pathways, increased the number of autophagic vacuoles in ATG5-knockdown VPS35 D620N mutant dopaminergic neurons. Estrogen induces Rab9 phosphorylation, mediated through Ulk1 phosphorylation, ultimately regulating alternative autophagy. Moreover, estrogen reduced the apoptosis rate of VPS35 D620N neurons, and this effect of estrogen was diminished under alternative autophagy knockdown conditions. In conclusion, alternative autophagy might be important for maintaining neuronal homeostasis and may be associated with the neuroprotective effect of estrogen in PD with VPS35 D620N.
    Keywords:  Alternative autophagy; Estrogen; Parkinson’s disease; Rab9; Retromer; VPS35
    DOI:  https://doi.org/10.1007/s00018-024-05123-4
  8. bioRxiv. 2024 Feb 13. pii: 2024.02.12.579959. [Epub ahead of print]
    Mitochondrial bioenergetics stimulates autophagy for pathological tau clearance in tauopathy neurons.
    Nuo Jia, Dhasarathan Ganesan, Hongyuan Guan, Yu Young Jeong, Sinsuk Han, Marialaina Nissenbaum, Alexander W Kusnecov, Qian Cai.
      Hyperphosphorylation and aggregation of microtubule-associated tau is a pathogenic hallmark of tauopathies and a defining feature of Alzheimer's disease (AD). Pathological tau is targeted by autophagy for clearance, but autophagy dysfunction is indicated in tauopathy. While mitochondrial bioenergetic failure has been shown to precede the development of tau pathology, it is unclear whether energy metabolism deficiency is involved in tauopathy-related autophagy defects. Here, we reveal that stimulation of anaplerotic metabolism restores defective oxidative phosphorylation (OXPHOS) in tauopathy which, strikingly, leads to enhanced autophagy and pronounced tau clearance. OXPHOS-induced autophagy is attributed to increased ATP-dependent phosphatidylethanolamine biosynthesis in mitochondria. Excitingly, early bioenergetic stimulation boosts autophagy activity and reduces tau pathology, thereby counteracting memory impairment in tauopathy mice. Taken together, our study sheds light on a pivotal role of bioenergetic dysfunction in tauopathy-linked autophagy defects and suggests a new therapeutic strategy to prevent toxic tau buildup in AD and other tauopathies.
    DOI:  https://doi.org/10.1101/2024.02.12.579959
  9. Proc Natl Acad Sci U S A. 2024 Mar 05. 121(10): e2313540121
    Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress.
    Mohamed A Eldeeb, Andrew N Bayne, Armaan Fallahi, Thomas Goiran, Emma J MacDougall, Andrea Soumbasis, Cornelia E Zorca, Jace-Jones Tabah, Rhalena A Thomas, Nathan Karpilovsky, Meghna Mathur, Thomas M Durcan, Jean-François Trempe, Edward A Fon.
      Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive early-onset Parkinson's disease (PD). PINK1 is a Ser/Thr kinase that regulates mitochondrial quality control by triggering mitophagy mediated by the ubiquitin (Ub) ligase Parkin. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane forming a high-molecular-weight complex with the translocase of the outer membrane (TOM). PINK1 then phosphorylates Ub, which enables recruitment and activation of Parkin followed by autophagic clearance of the damaged mitochondrion. Thus, Parkin-dependent mitophagy hinges on the stable accumulation of PINK1 on the TOM complex. Yet, the mechanism linking mitochondrial stressors to PINK1 accumulation and whether the translocases of the inner membrane (TIMs) are also involved remain unclear. Herein, we demonstrate that mitochondrial stress induces the formation of a PINK1-TOM-TIM23 supercomplex in human cultured cell lines, dopamine neurons, and midbrain organoids. Moreover, we show that PINK1 is required to stably tether the TOM to TIM23 complexes in response to stress such that the supercomplex fails to accumulate in cells lacking PINK1. This tethering is dependent on an interaction between the PINK1 N-terminal-C-terminal extension module and the cytosolic domain of the Tom20 subunit of the TOM complex, the disruption of which, by either designer or PD-associated PINK1 mutations, inhibits downstream mitophagy. Together, the findings provide key insight into how PINK1 interfaces with the mitochondrial import machinery, with important implications for the mechanisms of mitochondrial quality control and PD pathogenesis.
    Keywords:  PINK1; mitochondrial import; mitochondrial quality control; mitophagy; proteolysis
    DOI:  https://doi.org/10.1073/pnas.2313540121
  10. Arch Immunol Ther Exp (Warsz). 2024 Jan 01. 72(1):
    Insights into Autophagic Machinery and Lysosomal Function in Cells Involved in the Psoriatic Immune-Mediated Inflammatory Cascade.
    Martyna Kuczyńska, Marta Moskot, Magdalena Gabig-Cimińska.
      Impaired autophagy, due to the dysfunction of lysosomal organelles, contributes to maladaptive responses by pathways central to the immune system. Deciphering the immune-inflammatory ecosystem is essential, but remains a major challenge in terms of understanding the mechanisms responsible for autoimmune diseases. Accumulating evidence implicates a role that is played by a dysfunctional autophagy-lysosomal pathway (ALP) and an immune niche in psoriasis (Ps), one of the most common chronic skin diseases, characterized by the co-existence of autoimmune and autoinflammatory responses. The dysregulated autophagy associated with the defective lysosomal system is only one aspect of Ps pathogenesis. It probably cannot fully explain the pathomechanism involved in Ps, but it is likely important and should be seriously considered in Ps research. This review provides a recent update on discoveries in the field. Also, it sheds light on how the dysregulation of intracellular pathways, coming from modulated autophagy and endolysosomal trafficking, characteristic of key players of the disease, i.e., skin-resident cells, as well as circulating immune cells, may be responsible for immune impairment and the development of Ps.
    Keywords:  Autoimmune; Autophagy–lysosomal pathway; Circulating immune cells; Psoriasis; Skin-resident cells
    DOI:  https://doi.org/10.2478/aite-2024-0005
  11. Autophagy. 2024 Feb 27.
    PtdIns4p is required for the autophagosomal recruitment of STX17 (syntaxin 17) to promote lysosomal fusion.
    Hajnalka Laczkó-Dobos, Arindam Bhattacharjee, Asha Kiran Maddali, András Kincses, Hussein Abuammar, Krisztina Sebők-Nagy, Tibor Páli, András Dér, Tamás Hegedűs, Gábor Csordás, Gábor Juhász.
      The autophagosomal SNARE STX17 (syntaxin 17) promotes lysosomal fusion and degradation, but its autophagosomal recruitment is incompletely understood. Notably, PtdIns4P is generated on autophagosomes and promotes fusion through an unknown mechanism. Here we show that soluble recombinant STX17 is spontaneously recruited to negatively charged liposomes and adding PtdIns4P to liposomes containing neutral lipids is sufficient for its recruitment. Consistently, STX17 colocalizes with PtdIns4P-positive autophagosomes in cells, and specific inhibition of PtdIns4P synthesis on autophagosomes prevents its loading. Molecular dynamics simulations indicate that C-terminal positively charged amino acids establish contact with membrane bilayers containing negatively charged PtdIns4P. Accordingly, Ala substitution of Lys and Arg residues in the C terminus of STX17 abolishes membrane binding and impairs its autophagosomal recruitment. Finally, only wild type but not Ala substituted STX17 expression rescues the autophagosome-lysosome fusion defect of STX17 loss-of-function cells. We thus identify a key step of autophagosome maturation that promotes lysosomal fusion.
    Keywords:  Autophagosome; PI4K2A; autophagy; coincidence detection; electrostatic interaction; phosphoinositide
    DOI:  https://doi.org/10.1080/15548627.2024.2322493
  12. Autophagy. 2024 Feb 27.
    Aging STINGs: mitophagy at the crossroads of neuroinflammation.
    Juan Ignacio Jiménez-Loygorri, Patricia Boya.
      Loss of proteostasis and dysregulated mitochondrial function are part of the traditional hallmarks of aging, and in their last revision impaired macroautophagy and chronic inflammation are also included. Mitophagy is at the intersection of all these processes but whether it undergoes age-associated perturbations was not known. In our recent work, we performed a systematic and systemic analysis of mitolysosome levels in mice and found that, despite the already-known decrease in non-selective macroautophagy, mitophagy remains stable or increases upon aging in all tissues analyzed and is mediated by the PINK1-PRKN-dependent pathway. Further analyses revealed a concomitant increase in mtDNA leakage into the cytosol and activation of the CGAS-STING1 inflammation axis. Notably, both phenomena are also observed in primary fibroblasts from aged human donors. We hypothesized that mitophagy might be selectively upregulated during aging to improve mitochondrial fitness and reduce mtDNA-induced inflammation. Treatment with the mitophagy inducer urolithin A alleviates age-associated neurological decline, including improved synaptic connectivity, cognitive memory and visual function. Supporting our initial hypothesis, urolithin A reduces the levels of cytosolic mtDNA, CGAS-STING1 activation and neuroinflammation. Finally, using an in vitro model of mitochondrial membrane permeabilization we validated that PINK1-PRKN-mediated mitophagy is essential to resolve cytosolic mtDNA-triggered inflammation. These findings open up an integrative approach to tackle aging and increase healthspan via mitophagy induction.
    Keywords:  Inflammation; PINK1; Parkin; mitochondria; mtDNA; retina
    DOI:  https://doi.org/10.1080/15548627.2024.2322421
  13. Elife. 2024 Feb 27. pii: RP91010. [Epub ahead of print]12
    The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function.
    Lena H Nguyen, Youfen Xu, Maanasi Nair, Angelique Bordey.
      Brain somatic mutations in various components of the mTOR complex 1 (mTORC1) pathway have emerged as major causes of focal malformations of cortical development and intractable epilepsy. While these distinct gene mutations converge on excessive mTORC1 signaling and lead to common clinical manifestations, it remains unclear whether they cause similar cellular and synaptic disruptions underlying cortical network hyperexcitability. Here, we show that in utero activation of the mTORC1 activator genes, Rheb or MTOR, or biallelic inactivation of the mTORC1 repressor genes, Depdc5, Tsc1, or Pten in the mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability but different changes in excitatory synaptic transmission. Our findings suggest that, despite converging on mTORC1 signaling, mutations in different mTORC1 pathway genes differentially impact cortical excitatory synaptic activity, which may confer gene-specific mechanisms of hyperexcitability and responses to therapeutic intervention.
    Keywords:  HCN channels; Ih current; action potential; epilepsy; malformation of cortical development; mouse; neuroscience; seizures
    DOI:  https://doi.org/10.7554/eLife.91010
  14. Environ Toxicol Pharmacol. 2024 Feb 23. pii: S1382-6689(24)00038-3. [Epub ahead of print]107 104398
    Chronic arsenic exposure suppresses proteasomal and autophagic protein degradation.
    Isabell I Augenstein, Alexandra N Nail, Ana P Ferragut Cardoso, J Christopher States, Mayukh Banerjee.
      Ubiquitin Proteasomal System (UPS) and autophagy dysregulation initiate cancer. These pathways are regulated by zinc finger proteins. Trivalent inorganic arsenic (iAs) displaces zinc from zinc finger proteins disrupting functions of important cellular proteins. The effect of chronic environmental iAs exposure (100 nM) on UPS has not been studied. We tested the hypothesis that environmental iAs exposure suppresses UPS, activating autophagy as a compensatory mechanism. We exposed skin (HaCaT and Ker-CT; independent quadruplicates) and lung (BEAS-2B; independent triplicates) cell cultures to 0 or 100 nM iAs for 7 or 8 weeks. We quantified ER stress (XBP1 splicing employing Reverse Transcriptase -Polymerase Chain Reaction), proteasomal degradation (immunoblots), and initiation and completion of autophagy (immunoblots). We demonstrate that chronic iAs exposure suppresses UPS, initiates autophagy, but suppresses autophagic protein degradation in skin and lung cell lines. Our data suggest that chronic iAs exposure inhibits autophagy which subsequently suppresses UPS.
    Keywords:  Arsenic; Autophagy; Environmental exposure; Ubiquitin proteasomal system
    DOI:  https://doi.org/10.1016/j.etap.2024.104398
  15. bioRxiv. 2024 Feb 14. pii: 2024.02.12.579905. [Epub ahead of print]
    mTOR signaling regulates aberrant epithelial cell proliferative and migratory behaviors characteristic of airway mucous metaplasia in asthma.
    Katrina Kudrna, Elizabeth B Staab, Evan Eilers, Paul Thomes, Shailendra Maurya, Steven L Brody, Todd A Wyatt, Kristina L Bailey, John D Dickinson.
      In asthma, the airway epithelium is hyperplastic, hypertrophied, and lined with numerous large MUC5AC-containing goblet cells (GC). Furthermore, the normal epithelial architecture is disorganized with numerous, what we here describe as, ectopic goblet cells (eGC) deep within the thickened epithelial layer disconnected from the lumenal surface. mTOR is a highly conserved pathway that regulates cell size and proliferation. We hypothesized that the balance between mTOR and autophagy signaling regulates key features of the asthma epithelial layer. Airway histological sections from subjects with asthma had increased frequency of eGC and increased levels of mTOR phosphorylation target-Ribosomal S6. Using human airway epithelial cells (hAECs) with IL-13 stimulation and timed withdrawal to stimulate resolution, we found that multiple key downstream phosphorylation targets downstream from the mTOR complex were increased during early IL-13-mediated mucous metaplasia, and then significantly declined during resolution. The IL-13-mediated changes in mTOR signaling were paralleled by morphologic changes with airway epithelial hypertrophy, hyperplasia, and frequency of eGC. We then examined the relationship between mTOR and autophagy using mice deficient in autophagy protein Atg16L1. Despite having increased cytoplasmic mucins, mouse AECs from Atg16L1 deficient mice had no significant difference in mTOR downstream signaling. mTOR inhibition with rapamycin led to a loss of IL-13-mediated epithelial hypertrophy, hyperplasia, ectopic GC distribution, and reduction in cytoplasmic MUC5AC levels. mTOR inhibition was also associated with a reduction in aberrant IL-13-mediated hAEC proliferation and migration. Our findings demonstrate that mTOR signaling is associated with mucous metaplasia and is crucial to the disorganized airway epithelial structure and function characteristic of muco-obstructive airway diseases such as asthma.Graphical Abstract Key Concepts: The airway epithelium in asthma is disorganized and characterized by cellular proliferation, aberrant migration, and goblet cell mucous metaplasia.mTOR signaling is a dynamic process during IL-13-mediated mucous metaplasia, increasing with IL-13 stimulation and declining during resolution.mTOR signaling is strongly increased in the asthmatic airway epithelium.mTOR signaling is associated with the development of key features of the metaplastic airway epithelium including cell proliferation and ectopic distribution of goblet cells and aberrant cellular migration.Inhibition of mTOR leads to decreased epithelial hypertrophy, reduced ectopic goblet cells, and cellular migration.
    DOI:  https://doi.org/10.1101/2024.02.12.579905
  16. J Clin Invest. 2024 Mar 01. pii: e167369. [Epub ahead of print]134(5):
    Autophagy differentially regulates tissue tolerance of distinct target organs in graft-versus-host disease models.
    Katherine Oravecz-Wilson, Emma Lauder, Austin Taylor, Laure Maneix, Jeanine L Van Nostrand, Yaping Sun, Lu Li, Dongchang Zhao, Chen Liu, Pavan Reddy.
      Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, animals that lacked ATG5 in the gastrointestinal tract or liver showed significantly greater tissue injury and mortality, while autophagy deficiency in the skin, kidneys, or heart did not affect mortality. Treatment with the systemic autophagy inducer sirolimus only partially mitigated GVHD mortality in intestine-specific autophagy-deficient hosts. Deficiency of autophagy increased MHC class I on the target intestinal epithelial cells, resulting in greater susceptibility to damage by alloreactive T cells. Thus, autophagy is a critical cell-intrinsic protective response that promotes tissue tolerance and regulates GVHD severity.
    Keywords:  Autophagy; Immunology; Transplantation
    DOI:  https://doi.org/10.1172/JCI167369
  17. Methods Mol Biol. 2024 Feb 28.
    Real-Time Visualization of Cholesterol Trafficking in Human Granulosa Cells Using Confocal Live Cell Microscopy as a Tool to Study the Novel Role of Autophagy in Sex Steroid Synthesis.
    Yashar Esmaeilian, Ozgur Oktem.
      Autophagy is an evolutionarily conserved process that aims to maintain the energy homeostasis of the cell by recycling long-lived proteins and organelles. We have very recently demonstrated that lipophagy, a special form of autophagy, mediates the association of the lipid droplets (LDs) with lysosomes to deliver the lipid cargo within the LDs to lysosomes for degradation in order to release free cholesterol required for steroid synthesis in human ovary and testis. In this chapter, we describe live cell confocal microscopy technique that allows us to monitor real-time cholesterol trafficking and the association of cholesterol-laden LDs with lysosome (lipophagy) in human granulosa cells.
    Keywords:  Autophagy; Cholesterol; Confocal microscopy; ImageJ; Lipid droplet; Live cell imaging; Luteinized granulosa cell
    DOI:  https://doi.org/10.1007/7651_2024_521
  18. Nat Aging. 2024 Feb 27.
    Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system.
    Pingze Zhang, James H Catterson, Sebastian Grönke, Linda Partridge.
      Suppression of target of rapamycin complex 1 (TORC1) by rapamycin ameliorates aging in diverse species. S6 kinase (S6K) is an essential mediator, but the mechanisms involved are unclear. Here we show that activation of S6K specifically in Drosophila fat-body blocked extension of lifespan by rapamycin, induced accumulation of multilamellar lysosomes and blocked age-associated hyperactivation of the NF-κB-like immune deficiency (IMD) pathway, indicative of reduced inflammaging. Syntaxin 13 mediated the effects of TORC1-S6K signaling on lysosome morphology and inflammaging, suggesting they may be linked. Inflammaging depended on the IMD receptor regulatory isoform PGRP-LC, and repression of the IMD pathway from midlife extended lifespan. Age-related inflammaging was higher in females than in males and was not lowered in males by rapamycin treatment or lowered S6K. Rapamycin treatment also elevated Syntaxin 12/13 levels in mouse liver and prevented age-related increase in noncanonical NF-κB signaling, suggesting that the effect of TORC1 on inflammaging is conserved from flies to mammals.
    DOI:  https://doi.org/10.1038/s43587-024-00578-3
  19. Pharmacol Res. 2024 Feb 28. pii: S1043-6618(24)00064-1. [Epub ahead of print]202 107120
    Functional significance of O-linked N-acetylglucosamine protein modification in regulating autophagy.
    Zhuang Zhu, Wenhao Ren, Shaoming Li, Ling Gao, Keqian Zhi.
      Autophagy is a core molecular pathway that preserves cellular and organismal homeostasis. Being susceptible to nutrient availability and stress, eukaryotic cells recycle or degrade internal components via membrane transport pathways to provide sustainable biological molecules and energy sources. The dysregulation of this highly conserved physiological process has been strongly linked to human disease. Post-translational modification, a mechanism that regulates protein function, plays a crucial role in autophagy regulation. O-linked N-acetylglucosamine protein modification (O-GlcNAcylation), a monosaccharide post-translational modification of intracellular proteins, is essential in nutritional and stress regulatory mechanisms. O-GlcNAcylation has emerged as an essential regulatory mechanism of autophagy. It regulates autophagy throughout its lifetime by targeting the core components of the autophagy regulatory network. This review provides an overview of the O-GlcNAcylation of autophagy-associated proteins and their regulation and function in the autophagy pathway. Therefore, this article may contribute to further understanding of the role of O-GlcNAc-regulated autophagy and provide new perspectives for the treatment of human diseases.
    Keywords:  AMP-activated protein kinase (PubChem SID: 379980424); Autophagy; D-Glucose (PubChem CID: 5793); O-GlcNAc transferase (PubChem CID: 405228932); O-GlcNAcase (PubChem CID: 405229538); O-GlcNAcylation; Post-translational modification; Serine/threonine-protein kinase mTOR (PubChem SID: 472409785); UDP-GlcNAc (PubChem CID:445675)
    DOI:  https://doi.org/10.1016/j.phrs.2024.107120
  20. Anal Chem. 2024 Mar 01.
    Single Fluorescent Probe for Multiple Tasks: Illuminating Lipid Droplets and Lysosomes in Dual Channels and Distinguishing Autophagy and Apoptosis.
    Chun Dai, Wei Ge, Tianyu Li, Xiuqi Kong, Minggang Tian, Jie Niu.
      Lipid droplets (LDs) and lysosomes play key roles in autophagy and cell apoptosis, and the discriminative visualization of the two organelles and simultaneously of autophagy and apoptosis is very helpful to understand their internal relationships. However, fluorescent probes that can concurrently achieve these tasks are not available currently. Herein, we delicately fabricate a robust probe CAQ2 for multiple tasks: illumination of LDs and lysosomes in dual emission colors as well as discriminative visualization of cell apoptosis and autophagy. The probe exhibited both lipophilic and basic properties and displayed different emission colors in neutral and protonated forms; thus, LDs and lysosomes emitted blue and red fluorescence colors, respectively. Because of the lysosomal acidification during autophagy, CAQ2 detected autophagy with evidently enhanced red emission. Because of the lysosomal alkalization during apoptosis, CAQ2 imaged apoptosis with a drastically decreased red fluorescence intensity. With the robust probe, the autophagy under starvation and lipidless conditions was visualized, and the apoptosis induced by H2O2, ultraviolet (UV) irradiation, and rotenone treatment was successfully observed. The efficient detoxification of Na2S against rotenone treatment was successfully revealed.
    DOI:  https://doi.org/10.1021/acs.analchem.3c03653
  21. Nat Cell Biol. 2024 Mar 01.
    Combinatorial selective ER-phagy remodels the ER during neurogenesis.
    Melissa J Hoyer, Cristina Capitanio, Ian R Smith, Julia C Paoli, Anna Bieber, Yizhi Jiang, Joao A Paulo, Miguel A Gonzalez-Lozano, Wolfgang Baumeister, Florian Wilfling, Brenda A Schulman, J Wade Harper.
      The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis to calcium ion flux and inter-organelle communication. A case in point concerns the process of neurogenesis, where a refined tubular ER network is assembled via ER shaping proteins into the newly formed neuronal projections to create highly polarized dendrites and axons. Previous studies have suggested a role for autophagy in ER remodelling, as autophagy-deficient neurons in vivo display axonal ER accumulation within synaptic boutons, and the membrane-embedded ER-phagy receptor FAM134B has been genetically linked with human sensory and autonomic neuropathy. However, our understanding of the mechanisms underlying selective removal of the ER and the role of individual ER-phagy receptors is limited. Here we combine a genetically tractable induced neuron (iNeuron) system for monitoring ER remodelling during in vitro differentiation with proteomic and computational tools to create a quantitative landscape of ER proteome remodelling via selective autophagy. Through analysis of single and combinatorial ER-phagy receptor mutants, we delineate the extent to which each receptor contributes to both the magnitude and selectivity of ER protein clearance. We define specific subsets of ER membrane or lumenal proteins as preferred clients for distinct receptors. Using spatial sensors and flux reporters, we demonstrate receptor-specific autophagic capture of ER in axons, and directly visualize tubular ER membranes within autophagosomes in neuronal projections by cryo-electron tomography. This molecular inventory of ER proteome remodelling and versatile genetic toolkit provide a quantitative framework for understanding the contributions of individual ER-phagy receptors for reshaping ER during cell state transitions.
    DOI:  https://doi.org/10.1038/s41556-024-01356-4
  22. Mol Biol Rep. 2024 Feb 24. 51(1): 359
    Focusing on the role of protein kinase mTOR in endometrial physiology and pathology: insights for therapeutic interventions.
    Bin Wang, Mingxia Gao, Ying Yao, Hongwei Li, Xuehong Zhang.
      The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase crucial for cellular differentiation, proliferation, and autophagy. It shows a complex role in the endometrium, influencing both normal and pathogenic conditions. mTOR promotes the growth and maturation of endometrial cells, enhancing endometrial receptivity and decidualization. However, it also contributes to the development of endometriosis (EMs) and endometrial cancer (EC), thus emerging as a therapeutic target for these conditions. In this review, we summarize recent research progress on the mTOR signalling pathway in the endometrium. This provides insights into female endometrial structure and function and guides the prevention and treatment of related diseases.
    Keywords:  Decidualization; Endometrial cancer; Endometrial receptivity; Endometriosis; Endometrium; mTOR
    DOI:  https://doi.org/10.1007/s11033-023-08937-w
  23. bioRxiv. 2024 Feb 16. pii: 2024.02.15.580526. [Epub ahead of print]
    UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.
    Cody J Drozd, Tamjid A Chowdhury, Christopher C Quinn.
      MAPK8IP3 (unc-16/JIP3) is a neurodevelopmental-disorder associated gene that can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1(LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, two genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.
    DOI:  https://doi.org/10.1101/2024.02.15.580526
  24. Neurosci Bull. 2024 Feb 29.
    Interactions Between Extracellular Vesicles and Autophagy in Neuroimmune Disorders.
    Xiwen Ai, Haojun Yu, Yu Cai, Yangtai Guan.
      Neuroimmune disorders, such as multiple sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis, and Guillain-Barré syndrome, are characterized by the dysfunction of both the immune system and the nervous system. Increasing evidence suggests that extracellular vesicles and autophagy are closely associated with the pathogenesis of these disorders. In this review, we summarize the current understanding of the interactions between extracellular vesicles and autophagy in neuroimmune disorders and discuss their potential diagnostic and therapeutic applications. Here we highlight the need for further research to fully understand the mechanisms underlying these disorders, and to develop new diagnostic and therapeutic strategies.
    Keywords:  Autophagy; Extracellular vesicles; Guillain–Barré syndrome; Multiple sclerosis; Myasthenia gravis; Neuroimmune disorders; Neuromyelitis optica spectrum disorder
    DOI:  https://doi.org/10.1007/s12264-024-01183-5
  25. Exp Neurol. 2024 Feb 23. pii: S0014-4886(24)00052-9. [Epub ahead of print] 114726
    BMSC-Exosomes attenuate ALP dysfunction by restoring lysosomal function via the mTOR/TFEB Axis to reduce cerebral ischemia-reperfusion injury.
    Haining Liu, Chen Li, Xiaofeng Zhang, Hui Chen, Qi Zhang, Yuting Zeng, Shuqi Zheng, Jihua Zou, Yijin Zhao, Xiaoyan Zheng, Guozhi Huang, Qing Zeng.
      BACKGROUND: The complex pathophysiological changes following cerebral ischemia-reperfusion injury (CIRI) include the accumulation of defective proteins and damaged organelles, which cause massive neuron demise. To preserve cellular homeostasis, the autophagy-lysosomal pathway (ALP) is crucial for neurons to dispose of these substances. Many studies have shown that bone mesenchymal stem cell exosomes (BMSC-Exos) can reduce CIRI. However, the specific mechanisms have not been well elucidated, a fact that limits its widespread clinical use. This study aimed to clarify whether BMSC-Exos could attenuate ALP dysfunction by restoring lysosomal function after CIRI via inhibiting mTOR and then activating TFEB nucleus translocation.METHODS: In this study, Flow cytometry, Nanoparticle tracking analysis (NTA), Transmission electron microscope (TEM), and Western blot were used to identify the BMSCs and BMSC-Exos used in this experiment as conforming to the requirements. In vivo experiments, SD rats were modeled with temporary middle cerebral artery occlusion (tMCAO), and BMSC-Exos was injected into the tail vein 2 h after modeling. Triphenyl tetrazolium chloride (TTC) staining, modified neurological severity scores (mNSS), corner turn test, and rotating rod test were used to detect neurological deficits in rats after BMSC-Exos intervention. Western blot and Immunofluorescence were used to detect ALP, transcription factor EB(TFEB) nucleus translocation, and mammalian target of rapamycin (mTOR) change at different time points after modeling and after BMSC-Exos intervention. In vitro experiments, pheochromocytoma cells (PC12) cells were subjected to oxygen-glucose deprivation and reperfusion (OGD/R) modeling to mimic CIRI, and were respectively intervened BMSC-Exos, BMSC-Exos + MHY 1485 (the mTOR agonist), Rapamycin (the mTOR inhibitor). CCK8, Western blot, and Immunofluorescence were used to detect PC12 cell survival, TFEB nucleus translocation, and cathepsin B(CTSB) Immunofluorescence intensity.
    RESULTS: We found that ALP dysfunction occurred 72 h after tMCAO, and BMSC-Exos can attenuate ALP dysfunction by restoring lysosomal function. Next, we examined TFEB nucleus translocation and the expression of mTOR, a key regulator of translocation. We found that BMSC-Exos could inhibit mTOR and activate TFEB nucleus translocation. Additional in vitro tests revealed that BMSC-Exos could increase PC12 cell survival after OGD/R, activating TFEB nucleus translocation and enhancing the fluorescence intensity of CTSB, which in turn could be reversed by the mTOR agonist, MHY1485. This effect was similar to another mTOR inhibitor, Rapamycin.
    CONCLUSION: BMSC-Exos could attenuate ALP dysfunction by restoring lysosomal function after CIRI by inhibiting mTOR and then promoting TFEB nucleus translocation.
    Keywords:  Autophagy lysosomal pathway; Bone mesenchymal stem cell; Cerebral ischemia-reperfusion injury; TFEB; exosomes; mTOR
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114726
  26. FEBS J. 2024 Feb 27.
    Mitochondrial derived vesicles- Quo Vadis?
    Reut Hazan Ben-Menachem, Ophry Pines, Ann Saada.
      Mitochondria are dynamic, intracellular organelles with a separate genome originating from prokaryotes. They perform numerous functions essential for cellular metabolism and energy production. Mitochondrial-derived vesicles (MDVs) are single or double membrane-enclosed vesicles, formed and released from the mitochondrial sub-compartments into the cytosol, in response to various triggers. MDVs interact with other organelles such as lysosomes and peroxisomes or may be incorporated and excreted via extracellular vesicles (EVs). MDVs selectively incorporate diverse protein and lipid cargoes and are involved in various functions such as mitochondrial quality control, immunomodulation, energy complementation, and compartmentalization and transport. This review aims to provide a summary of the current knowledge of MDVs biogenesis, release, cargoes, and roles.
    Keywords:  membrane; mitochondria; mitochondrial-derived vesicles
    DOI:  https://doi.org/10.1111/febs.17103
  27. Exp Brain Res. 2024 Mar 02.
    Autophagy and UPS pathway contribute to nicotine-induced protection effect in Parkinson's disease.
    Inam Ullah, Shahab Uddin, Longhe Zhao, Xin Wang, Hongyu Li.
      The gradual nature of age-related neurodegeneration causes Parkinson's disease (PD) and impairs movement, memory, intellectual ability, and social interaction. One of the most prevalent neurodegenerative conditions affecting the central nervous system (CNS) among the elderly is PD. PD affects both motor and cognitive functions. Degeneration of dopaminergic (DA) neurons and buildup of the protein α-synuclein (α-Syn) in the substantia nigra pars compacta (SNpc) are two major causes of this disorder. Both UPS and ALS systems serve to eliminate α-Syn. Autophagy and UPS deficits, shortened life duration, and lipofuscin buildup accelerate PD. This sickness has no cure. Innovative therapies are halting PD progression. Bioactive phytochemicals may provide older individuals with a natural substitute to help delay the onset of neurodegenerative illnesses. This study examines whether nicotine helps transgenic C. elegans PD models. According to numerous studies, nicotine enhances synaptic plasticity and dopaminergic neuronal survival. Upgrades UPS pathways, increases autophagy, and decreases oxidative stress and mitochondrial dysfunction. At 100, 150, and 200 µM nicotine levels, worms showed reduced α-Syn aggregation, repaired DA neurotoxicity after 6-OHDA intoxication, increased lifetime, and reduced lipofuscin accumulation. Furthermore, nicotine triggered autophagy and UPS. We revealed nicotine's potential as a UPS and autophagy activator to prevent PD and other neurodegenerative diseases.
    Keywords:   Caenorhabditis elegans ; Autophagy; Lgg-1; Longevity; Nicotine; Parkinson’s disease; Proteasome (UPS); α-Synuclein
    DOI:  https://doi.org/10.1007/s00221-023-06765-9
  28. Biomed Pharmacother. 2024 Feb 28. pii: S0753-3322(24)00235-X. [Epub ahead of print]173 116351
    Chronic Rapamycin administration via drinking water mitigates the pathological phenotype in a Krabbe disease mouse model through autophagy activation.
    Ambra Del Grosso, Sara Carpi, Miriam De Sarlo, Luca Scaccini, Laura Colagiorgio, Husam B R Alabed, Lucia Angella, Roberto Maria Pellegrino, Ilaria Tonazzini, Carla Emiliani, Marco Cecchini.
      Krabbe disease (KD) is a rare disorder arising from the deficiency of the lysosomal enzyme galactosylceramidase (GALC), leading to the accumulation of the cytotoxic metabolite psychosine (PSY) in the nervous system. This accumulation triggers demyelination and neurodegeneration, and despite ongoing research, the underlying pathogenic mechanisms remain incompletely understood, with no cure currently available. Previous studies from our lab revealed the involvement of autophagy dysfunctions in KD pathogenesis, showcasing p62-tagged protein aggregates in the brains of KD mice and heightened p62 levels in the KD sciatic nerve. We also demonstrated that the autophagy inducer Rapamycin (RAPA) can partially reinstate the wild type (WT) phenotype in KD primary cells by decreasing the number of p62 aggregates. In this study, we tested RAPA in the Twitcher (TWI) mouse, a spontaneous KD mouse model. We administered the drug ad libitum via drinking water (15 mg/L) starting from post-natal day (PND) 21-23. We longitudinally monitored the mouse motor performance through grip strength and rotarod tests, and a set of biochemical parameters related to the KD pathogenesis (i.e. autophagy markers expression, PSY accumulation, astrogliosis and myelination). Our findings demonstrate that RAPA significantly enhances motor functions at specific treatment time points and reduces astrogliosis in TWI brain, spinal cord, and sciatic nerves. Utilizing western blot and immunohistochemistry, we observed a decrease in p62 aggregates in TWI nervous tissues, corroborating our earlier in-vitro results. Moreover, RAPA treatment partially removes PSY in the spinal cord. In conclusion, our results advocate for considering RAPA as a supportive therapy for KD. Notably, as RAPA is already available in pharmaceutical formulations for clinical use, its potential for KD treatment can be rapidly evaluated in clinical trials.
    Keywords:  Globoid cell leukodystrophy; Krabbe disease; P62aggregates; Rapamycin; Twitcher mouse; autophagy induction; psychosine
    DOI:  https://doi.org/10.1016/j.biopha.2024.116351
  29. Nat Commun. 2024 Feb 29. 15(1): 1621
    Attenuation of phytofungal pathogenicity of Ascomycota by autophagy modulators.
    Jongchan Woo, Seungmee Jung, Seongbeom Kim, Yurong Li, Hyunjung Chung, Tatiana V Roubtsova, Honghong Zhang, Celine Caseys, Dan Kliebenstein, Kyung-Nam Kim, Richard M Bostock, Yong-Hwan Lee, Martin B Dickman, Doil Choi, Eunsook Park, Savithramma P Dinesh-Kumar.
      Autophagy in eukaryotes functions to maintain homeostasis by degradation and recycling of long-lived and unwanted cellular materials. Autophagy plays important roles in pathogenicity of various fungal pathogens, suggesting that autophagy is a novel target for development of antifungal compounds. Here, we describe bioluminescence resonance energy transfer (BRET)-based high-throughput screening (HTS) strategy to identify compounds that inhibit fungal ATG4 cysteine protease-mediated cleavage of ATG8 that is critical for autophagosome formation. We identified ebselen (EB) and its analogs ebselen oxide (EO) and 2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PT) as inhibitors of fungal pathogens Botrytis cinerea and Magnaporthe oryzae ATG4-mediated ATG8 processing. The EB and its analogs inhibit spore germination, hyphal development, and appressorium formation in Ascomycota pathogens, B. cinerea, M. oryzae, Sclerotinia sclerotiorum and Monilinia fructicola. Treatment with EB and its analogs significantly reduced fungal pathogenicity. Our findings provide molecular insights to develop the next generation of antifungal compounds by targeting autophagy in important fungal pathogens.
    DOI:  https://doi.org/10.1038/s41467-024-45839-2
  30. Neuroscientist. 2024 Feb 29. 10738584241232963
    α-Synuclein: Multiple pathogenic roles in trafficking and proteostasis pathways in Parkinson's disease.
    Annie J Zalon, Drew J Quiriconi, Caleb Pitcairn, Joseph R Mazzulli.
      Parkinson's disease (PD) is a common age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the midbrain. A hallmark of both familial and sporadic PD is the presence of Lewy body inclusions composed mainly of aggregated α-synuclein (α-syn), a presynaptic protein encoded by the SNCA gene. The mechanisms driving the relationship between α-syn accumulation and neurodegeneration are not completely understood, although recent evidence indicates that multiple branches of the proteostasis pathway are simultaneously perturbed when α-syn aberrantly accumulates within neurons. Studies from patient-derived midbrain cultures that develop α-syn pathology through the endogenous expression of PD-causing mutations show that proteostasis disruption occurs at the level of synthesis/folding in the endoplasmic reticulum (ER), downstream ER-Golgi trafficking, and autophagic-lysosomal clearance. Here, we review the fundamentals of protein transport, highlighting the specific steps where α-syn accumulation may intervene and the downstream effects on proteostasis. Current therapeutic efforts are focused on targeting single pathways or proteins, but the multifaceted pathogenic role of α-syn throughout the proteostasis pathway suggests that manipulating several targets simultaneously will provide more effective disease-modifying therapies for PD and other synucleinopathies.
    Keywords:  Parkinson’s disease; autophagy; protein trafficking; synuclein
    DOI:  https://doi.org/10.1177/10738584241232963
  31. J Nat Med. 2024 Feb 25.
    Betulinic acid induces apoptosis of HeLa cells via ROS-dependent ER stress and autophagy in vitro and in vivo.
    Ping Chen, Xueer Zhang, Qiaomiao Fang, Zhongxiang Zhao, Chaozhan Lin, Yuan Zhou, Fangle Liu, Chenchen Zhu, Aizhi Wu.
      Betulinic acid (BA), a naturally occurring lupane-type triterpenoid, possesses a wide range of potential activities against different types of cancer. However, the molecular mechanisms involved in anti-cervical cancer about BA were rarely investigated. Herein, the role of BA in cervical cancer suppression by ROS-mediated endoplasmic reticulum stress (ERS) and autophagy was deeply discussed. The findings revealed that BA activated Keap1/Nrf2 pathway and triggered mitochondria-dependent apoptosis due to ROS production. Furthermore, BA increased the intracellular Ca2+ levels, inhibited the expression of Beclin1 and promoted the expression of GRP78, LC3-II, and p62 associated with ERS and autophagy. Besides, BA initiated the formation of autophagosomes and inhibited autophagic flux by the co-administration of BA with 3-methyladenine (3-MA) and chloroquine (CQ), respectively. The in vivo experiment manifested that hydroxychloroquine (HCQ) enhanced the apoptosis induced by BA. For the first time, we demonstrated that BA could initiate early autophagy, inhibit autophagy flux, and induce protective autophagy in HeLa cells. Thus, BA could be a potential chemotherapy drug for cervical cancer, and inhibition of autophagy could enhance the anti-tumor effect of BA. However, the interactions of signaling factors between ERS-mediated and autophagy-mediated apoptosis deserve further attention.
    Keywords:  Apoptosis; Autophagy; Betulinic acid; Endoplasmic reticulum stress; ROS; Treatment of cervical cancer; Triterpenoid
    DOI:  https://doi.org/10.1007/s11418-024-01782-6
  32. Environ Int. 2024 Feb 24. pii: S0160-4120(24)00118-1. [Epub ahead of print]185 108532
    The size-dependence and reversibility of polystyrene nanoplastics-induced lipid accumulation in mice: Possible roles of lysosomes.
    Yan-Yang Lu, Lu Lu, Hong-Yun Ren, Weizhen Hua, Nengxing Zheng, Fu-Yi Huang, Jiani Wang, Meiping Tian, Qingyu Huang.
      Nanoplastics (NPs) continue to accumulate in global aquatic and terrestrial systems, posing a potential threat to human health through the food chain and/or other pathways. Both in vivo and in vitro studies have confirmed that the liver is one of the main organs targeted for the accumulation of NPs in living organisms. However, whether exposure to NPs induces size-dependent disorders of liver lipid metabolism remains controversial, and the reversibility of NPs-induced hepatotoxicity is largely unknown. In this study, the effects of long-term exposure to environmentally relevant doses of polystyrene nanoplastics (PS-NPs) on lipid accumulation were investigated in terms of autophagy and lysosomal mechanisms. The findings indicated that hepatic lipid accumulation was more pronounced in mice exposed to 100 nm PS-NPs compared to 500 nm PS-NPs. This effect was effectively alleviated after 50 days of self-recovery for 100 nm and 500 nm PS-NPs exposure. Mechanistically, although PS-NPs exposure activated autophagosome formation through ERK (mitogen-activated protein kinase 1)/mTOR (mechanistic target of rapamycin kinase) signaling pathway, the inhibition of Rab7 (RAB7, member RAS oncogene family), CTSB (cathepsin B), and CTSD (cathepsin D) expression impaired lysosomal function, thereby blocking autophagic flux and contributing to hepatic lipid accumulation. After termination of PS-NPs exposure, lysosomal exocytosis was responsible for the clearance of PS-NPs accumulated in lysosomes. Furthermore, impaired lysosomal function and autophagic flux inhibition were effectively alleviated. This might be the main reason for the alleviation of PS-NPs-induced lipid accumulation after recovery. Collectively, we demonstrate for the first time that lysosomes play a dual role in the persistence and reversibility of hepatotoxicity induced by environmental relevant doses of NPs, which provide novel evidence for the prevention and intervention of liver injury associated with nanoplastics exposure.
    Keywords:  Autophagy; Hepatic lipid accumulation; Lysosome; Nanoplastics; Reversibility
    DOI:  https://doi.org/10.1016/j.envint.2024.108532
  33. Cell Commun Signal. 2024 Feb 26. 22(1): 151
    The in vitro and in vivo depigmentation activity of coenzyme Q0, a major quinone derivative from Antrodia camphorata, through autophagy induction in human melanocytes and keratinocytes.
    You-Cheng Hseu, Jou-Tsen Yeh, Chithravel Vadivalagan, Siang-Jyun Chen, Yugandhar Vudhya Gowrisankar, Sudhir Pandey, Yuan-Tai Hsu, Hung-Rong Yen, Hui-Chi Huang, Jhih-Hsuan Hseu, Hsin-Ling Yang.
      BACKGROUND: Coenzyme Q0 (CoQ0), a novel quinone derivative of Antrodia camphorata, has been utilized as a therapeutic agent (including antioxidant, anti-inflammatory, antiangiogenic, antiatherosclerotic, and anticancer agents); however, its depigmenting efficiency has yet to be studied.METHODS: We resolved the depigmenting efficiency of CoQ0 through autophagy induction in melanoma (B16F10) and melanin-feeding keratinocyte (HaCaT) cells and in vivo Zebrafish model. Then, MPLC/HPLC analysis, MTT assay, Western blotting, immunofluorescence staining, LC3 transfection, melanin formation, GFP-LC3 puncta, AVO formation, tyrosinase activity, and TEM were used.
    RESULTS: CoQ0-induced autophagy in B16F10 cells was shown by enhanced LC3-II accumulation, ATG7 expression, autophagosome GFP-LC3 puncta, and AVOs formation, and ATG4B downregulation, and Beclin-1/Bcl-2 dysregulation. In α-MSH-stimulated B16F10 cells, CoQ0 induced antimelanogenesis by suppressing CREB-MITF pathway, tyrosinase expression/activity, and melanin formation via autophagy. TEM data disclosed that CoQ0 increased melanosome-engulfing autophagosomes and autolysosomes in α-MSH-stimulated B16F10 cells. CoQ0-inhibited melanogenesis in α-MSH-stimulated B16F10 cells was reversed by pretreatment with the autophagy inhibitor 3-MA or silencing of LC3. Additionally, CoQ0-induced autophagy in HaCaT cells was revealed by enhanced LC3-II accumulation, autophagosome GFP-LC3 puncta and AVO formation, ATG4B downregulation, ATG5/ATG7 expression, and Beclin-1/Bcl-2 dysregulation. In melanin-feeding HaCaT cells, CoQ0 induced melanin degradation by suppressing melanosome gp100 and melanin formation via autophagy. TEM confirmed that CoQ0 increased melanosome-engulfing autophagosomes and autolysosomes in melanin-feeding HaCaT cells. Treatment with 3-MA reversed CoQ0-mediated melanin degradation in melanin-feeding HaCaT cells. In vivo study showed that CoQ0 suppressed endogenous body pigmentation by antimelanogenesis and melanin degradation through autophagy induction in a zebrafish model.
    CONCLUSIONS: Our results showed that CoQ0 exerted antimelanogenesis and melanin degradation by inducing autophagy. CoQ0 could be used in skin-whitening formulations as a topical cosmetic application.
    Keywords:  Autophagy; CoQ0; Melanin degradation; Melanogenesis; α-MSH
    DOI:  https://doi.org/10.1186/s12964-024-01537-6
  34. JCI Insight. 2024 Feb 27. pii: e175501. [Epub ahead of print]
    Allelic heterogeneity of TTNtv cardiomyopathy can be modeled in adult zebrafish.
    Ping Zhu, Jiarong Li, Feixiang Yan, Shahidul Islam, Xueying Lin, Xiaolei Xu.
      Allelic heterogeneity (AH) has been noted in truncational TTN (TTNtv)-associated dilated cardiomyopathy (DCM), i.e., mutations affecting A-band-encoding exons are pathogenic, but those affecting Z-disc-encoding exons are likely benign. The lack of an in vivo animal model that recapitulates AH hinders the deciphering of the underlying mechanism. Here, we explored zebrafish as a candidate vertebrate model by phenotyping a collection of zebrafish ttntv alleles. We noted that cardiac function and sarcomere structure are more severely disrupted in ttntv-A than in ttntv-Z homozygous embryos. Consistently, cardiomyopathy-like phenotypes were presented in ttntv-A but not ttntv-Z adult heterozygous mutants. The phenotypes observed in ttntv-A alleles were recapitulated in null mutants with the entire titin-encoding sequences removed. Defective autophagic flux, largely due to impaired autophagosome-lysosome fusion, was also only noted in ttntv-A but not ttntv-Z models. Moreover, we found that genetic manipulation of ulk1a restored autophagy flux and rescued cardiac dysfunction in ttntv-A animals. Together, our findings presented adult zebrafish as an in vivo animal model for studying AH in TTNtv DCM, demonstrated TTN loss-of-function sufficient to trigger ttntv DCM in zebrafish, and uncovered ulk1a as a potential therapeutic target gene for TTNtv DCM.
    Keywords:  Autophagy; Cardiology; Cardiovascular disease; Genetic diseases; Genetics
    DOI:  https://doi.org/10.1172/jci.insight.175501
  35. Nat Microbiol. 2024 Feb 27.
    Autophagy promotes efficient T cell responses to restrict high-dose Mycobacterium tuberculosis infection in mice.
    Siwei Feng, Michael E McNehlan, Rachel L Kinsella, Chanchal Sur Chowdhury, Sthefany M Chavez, Sumanta K Naik, Samuel R McKee, Jacob A Van Winkle, Neha Dubey, Amanda Samuels, Amanda Swain, Xiaoyan Cui, Skyler V Hendrix, Reilly Woodson, Darren Kreamalmeyer, Asya Smirnov, Maxim N Artyomov, Herbert W Virgin, Ya-Ting Wang, Christina L Stallings.
      Although autophagy sequesters Mycobacterium tuberculosis (Mtb) in in vitro cultured macrophages, loss of autophagy in macrophages in vivo does not result in susceptibility to a standard low-dose Mtb infection until late during infection, leaving open questions regarding the protective role of autophagy during Mtb infection. Here we report that loss of autophagy in lung macrophages and dendritic cells results in acute susceptibility of mice to high-dose Mtb infection, a model mimicking active tuberculosis. Rather than observing a role for autophagy in controlling Mtb replication in macrophages, we find that autophagy suppresses macrophage responses to Mtb that otherwise result in accumulation of myeloid-derived suppressor cells and subsequent defects in T cell responses. Our finding that the pathogen-plus-susceptibility gene interaction is dependent on dose has important implications both for understanding how Mtb infections in humans lead to a spectrum of outcomes and for the potential use of autophagy modulators in clinical medicine.
    DOI:  https://doi.org/10.1038/s41564-024-01608-x
  36. J Cell Sci. 2024 Feb 15. pii: jcs261625. [Epub ahead of print]137(4):
    Structure-based engineering of Tor complexes reveals that two types of yeast TORC1 produce distinct phenotypes.
    Yoshiaki Kamada, Chiharu Umeda, Yukio Mukai, Hokuto Ohtsuka, Yoko Otsubo, Akira Yamashita, Takahiro Kosugi.
      Certain proteins assemble into diverse complex states, each having a distinct and unique function in the cell. Target of rapamycin (Tor) complex 1 (TORC1) plays a central role in signalling pathways that allow cells to respond to the environment, including nutritional status signalling. TORC1 is widely recognised for its association with various diseases. The budding yeast Saccharomyces cerevisiae has two types of TORC1, Tor1-containing TORC1 and Tor2-containing TORC1, which comprise different constituent proteins but are considered to have the same function. Here, we computationally modelled the relevant complex structures and then, based on the structures, rationally engineered a Tor2 mutant that could form Tor complex 2 (TORC2) but not TORC1, resulting in a redesign of the complex states. Functional analysis of the Tor2 mutant revealed that the two types of TORC1 induce different phenotypes, with changes observed in rapamycin, caffeine and pH dependencies of cell growth, as well as in replicative and chronological lifespan. These findings uncovered by a general approach with huge potential - model structure-based engineering - are expected to provide further insights into various fields such as molecular evolution and lifespan.
    Keywords:  Lifespan; Protein complex; Protein engineering; Target of rapamycin; Yeast
    DOI:  https://doi.org/10.1242/jcs.261625
  37. J Alzheimers Dis Rep. 2024 ;8(1): 329-344
    Dimethyl Fumarate Exerts a Neuroprotective Effect by Enhancing Mitophagy via the NRF2/BNIP3/PINK1 Axis in the MPP+ Iodide-Induced Parkinson's Disease Mice Model.
    Poojitha Pinjala, Kamatham Pushpa Tryphena, Amrita Kulkarni, Prince Giri Goswami, Dharmendra Kumar Khatri.
      Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder linked to the loss of dopaminergic neurons in the substantia nigra. Mitophagy, mitochondrial selective autophagy, is critical in maintaining mitochondrial and subsequently neuronal homeostasis. Its impairment is strongly implicated in PD and is associated with accelerated neurodegeneration.Objective: To study the positive effect of dimethyl fumarate (DMF) on mitophagy via the NRF2/BNIP3/PINK1 axis activation in PD disease models.
    Methods: The neuroprotective effect of DMF was explored in in vitro and in vivo PD models. MTT assay was performed to determine the DMF dose followed by JC-1 assay to study its mitoprotective effect in MPP+ exposed SHSY5Y cells. For the in vivo study, C57BL/6 mice were divided into six groups: Normal Control (NC), Disease Control (DC), Sham (Saline i.c.v.), Low Dose (MPP+ iodide+DMF 15 mg/kg), Mid Dose (MPP+ iodide+DMF 30 mg/kg), and High Dose (MPP+ iodide+DMF 60 mg/kg). The neuroprotective effect of DMF was assessed by performing rotarod, open field test, and pole test, and biochemical parameter analysis using immunofluorescence, western blot, and RT-PCR.
    Results: DMF treatment significantly alleviated the loss of TH positive dopaminergic neurons and enhanced mitophagy by increasing PINK1, Parkin, BNIP3, and LC3 levels in the MPP+ iodide-induced PD mice model. DMF treatment groups showed good locomotor activity and rearing time when compared to the DC group.
    Conclusions: DMF confers neuroprotection by activating the BNIP3/PINK1/Parkin pathway, enhancing the autophagosome formation via LC3, and improving mitophagy in PD models, and could be a potential therapeutic option in PD.
    Keywords:  1-methyl-4-phenyl pyridinium iodide; Alzheimer’s disease; Parkinson’s disease; autophagy; dimethyl fumarate; nuclear factor E2-related factor 2
    DOI:  https://doi.org/10.3233/ADR-230128
  38. Eur J Neurosci. 2024 Feb 28.
    Diabetes mellitus and Alzheimer's disease: Vacuolar adenosine triphosphatase as a potential link.
    Bin Guo, Qi-Ye Li, Xue-Jia Liu, Guo-Hui Luo, Ya-Juan Wu, Jing Nie.
      Globally, the incidence of diabetes mellitus (DM) and Alzheimer's disease (AD) is increasing year by year, causing a huge economic and social burden, and their pathogenesis and aetiology have been proven to have a certain correlation. In recent years, more and more studies have shown that vacuolar adenosine triphosphatases (v-ATPases) in eukaryotes, which are biomolecules regulating lysosomal acidification and glycolipid metabolism, play a key role in DM and AD. This article describes the role of v-ATPase in DM and AD, including its role in glycolysis, insulin secretion and insulin resistance (IR), as well as its relationship with lysosomal acidification, autophagy and β-amyloid (Aβ). In DM, v-ATPase is involved in the regulation of glucose metabolism and IR. v-ATPase is closely related to glycolysis. On the one hand, v-ATPase affects the rate of glycolysis by affecting the secretion of insulin and changing the activities of key glycolytic enzymes hexokinase (HK) and phosphofructokinase 1 (PFK-1). On the other hand, glucose is the main regulator of this enzyme, and the assembly and activity of v-ATPase depend on glucose, and glucose depletion will lead to its decomposition and inactivation. In addition, v-ATPase can also regulate free fatty acids, thereby improving IR. In AD, v-ATPase can not only improve the abnormal brain energy metabolism by affecting lysosomal acidification and autophagy but also change the deposition of Aβ by affecting the production and degradation of Aβ. Therefore, v-ATPase may be the bridge between DM and AD.
    Keywords:  Alzheimer's disease; diabetes mellitus; insulin resistance; vacuolar adenosine triphosphatases; β-amyloid
    DOI:  https://doi.org/10.1111/ejn.16286
  39. Cell Death Discov. 2024 Feb 24. 10(1): 98
    The interplay of mitophagy, autophagy, and apoptosis in cisplatin-induced kidney injury: involvement of ERK signaling pathway.
    Iva Suman, Lidija Šimić, Gordana Čanadi Jurešić, Sunčica Buljević, Damir Klepac, Robert Domitrović.
      AKI induced by CP chemotherapy remains an obstacle during patient treatments. Extracellular signal-regulated protein kinases 1/2 (ERK), key participants in CP-induced nephrotoxicity, are suggested to be involved in the regulation of mitophagy, autophagy, and apoptosis. Human renal proximal tubular cells (HK-2) and BALB/cN mice were used to determine the role of ERK in CP-induced AKI. We found that active ERK is involved in cell viability reduction during apoptotic events but exerts a protective role in the early stages of treatment. Activation of ERK acts as a maintainer of the mitochondrial population and is implicated in mitophagy initiation but has no significant role in its conduction. In the late stages of CP treatment when ATP is deprived, general autophagy that requires ERK activation is initiated as a response, in addition to apoptosis activation. Furthermore, activation of ERK is responsible for the decrease in reserve respiratory capacity and controls glycolysis regulation during CP treatment. Additionally, we found that ERK activation is also required for the induction of NOXA gene and protein expression as well as FoxO3a nuclear translocation, but not for the regular ERK-induced phosphorylation of FoxO3a on Ser294. In summary, this study gives detailed insight into the involvement of ERK activation and its impact on key cellular processes at different time points during CP-induced kidney injury. Inhibitors of ERK activation, including Mirdametinib, are important in the development of new therapeutic strategies for the treatment of AKI in patients receiving CP chemotherapy.
    DOI:  https://doi.org/10.1038/s41420-024-01872-0
  40. Eur J Med Chem. 2024 Feb 23. pii: S0223-5234(24)00131-4. [Epub ahead of print]268 116251
    Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice.
    Shiyi Yin, Mengmeng Shen, Yongjiang Zhang, Jiannan Wu, Run Song, Xiaoyi Lai, Zhenzhen Tian, Tingting Wang, Weina Jin, Junqiang Yan.
      Parkinson's disease (PD) is characterized by the progressive death of dopamine (DA) neurons and the pathological accumulation of α-synuclein (α-syn) fibrils. In our previous study, simulated PHB2 phosphorylation was utilized to clarify the regulatory role of c-Abl in PHB2-mediated mitophagy in PD models. In this investigation, we employed an independently patented PHB2Y121 phosphorylated antibody in the PD model to further verify that the c-Abl inhibitor STI571 can impede PHB2Y121 phosphorylation, decrease the formation of α-Syn polymers, and improve autophagic levels. The specific involvement of Nur77 in PD pathology has remained elusive. We also investigate the contribution of Nur77, a nuclear transcription factor, to α-syn and mitophagy in PD. Our findings demonstrate that under α-syn, Nur77 translocates from the cytoplasm to the mitochondria, improving PHB-mediated mitophagy by regulating c-Abl phosphorylation. Moreover, Nur77 overexpression alleviates the expression level of pS129-α-syn and the loss of DA neurons in α-syn PFF mice, potentially associated with the p-c-Abl/p-PHB2 Y121 axis. This study provides initial in vivo and in vitro evidence that Nur77 protects PD DA neurons by modulating the p-c-Abl/p-PHB2 Y121 axis, and STI571 holds promise as a treatment for PD.
    Keywords:  Mitophagy; Nur77; PHB2; Parkinson's disease; STI571; c-Abl; α-synuclein
    DOI:  https://doi.org/10.1016/j.ejmech.2024.116251
  41. Methods Mol Biol. 2024 Feb 28.
    Visualizing Lipophagy as a New Mechanism of the Synthesis of Sex Steroids in Human Ovary and Testis Using Immunofluorescence Staining Method.
    Yashar Esmaeilian, Sevgi Yusufoglu, Ece Iltumur, Gamze Bildik, Ozgur Oktem.
      Immunofluorescence, a transformative tool in cellular biology, is employed to dissect the intricate mechanisms of cholesterol trafficking in human reproductive tissues. Autophagy, a key player in cellular homeostasis, particularly lipophagy, emerges as a free cholesterol source for steroidogenesis. In this chapter, we describe a comprehensive immunofluorescence staining protocol, with details provided for the precise visualization of subcellular dynamics of mitochondria, lysosomes, and lipid droplets in ex vivo testicular tissue and primary luteal granulosa cell culture models, pivotal components in sex steroid biosynthesis. Here, we detail the culture, treatment, and immunofluorescence protocols, providing a comprehensive guide for researchers. The provided immunofluorescence toolkit serves as a valuable resource for researchers, paving way for advancements in human reproductive health to investigate the intricate interplay between autophagy, lipophagy, and cholesterol trafficking.
    Keywords:  Autophagy; Confocal microscopy; ImageJ; Immunofluorescence staining; Luteinized granulosa cells; Steroidogenesis; Testis
    DOI:  https://doi.org/10.1007/7651_2024_520
  42. Methods Mol Biol. 2024 ;2772 301-309
    In Vivo Analysis of ER-Associated Protein Degradation and Ubiquitination in Arabidopsis thaliana.
    Jiaqi Sun, Huanquan Zheng.
      The endoplasmic reticulum (ER) is the cellular site for the biosynthesis of proteins and lipids. The ER is highly dynamic, whose homeostasis is maintained by proper ER shaping, unfolded protein response (UPR), ER-associated degradation (ERAD), and selective autophagy of the ER (ER-phagy). In ERAD and ER-phagy, unfolded/misfolded proteins are degraded in the 26S proteasome and the vacuole, respectively. Both processes are vital for normal plant development and plant responses to environmental stresses. While it is known that ubiquitination of a protein initiates EARD, recent research indicated that ubiquitination of a protein also promotes the turnover of the protein through ER-phagy. In this chapter, we describe in detail two in vivo methods for investigating (1) the degradation efficiency and (2) ubiquitination level of an ER-associated protein in Arabidopsis thaliana.
    Keywords:  ER-associated protein degradation; ER-phagy; Endoplasmic reticulum; In vivo analysis; Ubiquitination
    DOI:  https://doi.org/10.1007/978-1-0716-3710-4_23
  43. Front Cell Dev Biol. 2024 ;12 1287447
    Mitochondrial DNA leakage triggers inflammation in age-related cardiovascular diseases.
    Wanyue Ding, Jingyu Chen, Lei Zhao, Shuang Wu, Xiaomei Chen, Hong Chen.
      Mitochondrial dysfunction is one of the hallmarks of cardiovascular aging. The leakage of mitochondrial DNA (mtDNA) is increased in senescent cells, which are resistant to programmed cell death such as apoptosis. Due to its similarity to prokaryotic DNA, mtDNA could be recognized by cellular DNA sensors and trigger innate immune responses, resulting in chronic inflammatory conditions during aging. The mechanisms include cGAS-STING signaling, TLR-9 and inflammasomes activation. Mitochondrial quality controls such as mitophagy could prevent mitochondria from triggering harmful inflammatory responses, but when this homeostasis is out of balance, mtDNA-induced inflammation could become pathogenic and contribute to age-related cardiovascular diseases. Here, we summarize recent studies on mechanisms by which mtDNA promotes inflammation and aging-related cardiovascular diseases, and discuss the potential value of mtDNA in early screening and as therapeutic targets.
    Keywords:  cardiovasuclar diseases; inflammation; innate immunity; mitochondrial DNA; senescence
    DOI:  https://doi.org/10.3389/fcell.2024.1287447
  44. Nat Metab. 2024 Feb;6(2): 359-377
    Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk.
    Xiangyu Zhang, Divya Kapoor, Se-Jin Jeong, Alan Fappi, Jeremiah Stitham, Vasavi Shabrish, Ismail Sergin, Eman Yousif, Astrid Rodriguez-Velez, Yu-Sheng Yeh, Arick Park, Arif Yurdagul, Oren Rom, Slava Epelman, Joel D Schilling, Marco Sardiello, Abhinav Diwan, Jaehyung Cho, Nathan O Stitziel, Ali Javaheri, Irfan J Lodhi, Bettina Mittendorfer, Babak Razani.
      High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants ( NCT03946774 and NCT03994367 ) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.
    DOI:  https://doi.org/10.1038/s42255-024-00984-2
  45. Reprod Sci. 2024 Feb 29.
    Dysregulation of CREB5 Impairs Decidualization and Maternal-Fetal Interactions by Inhibiting Autophagy in Recurrent Spontaneous Abortion.
    Zhidian Li, Fangfang Dai, Ronghui Zhu, Yuwei Zhang, Jing Chen, Liping Chen, Hua Liu, Yanxiang Cheng.
      BACKGROUND: Clinically, recurrent spontaneous abortion (RSA) is a pregnancy illness that is difficult to treat. Impaired decidualization is a documented cause of RSA, but the etiology and mechanism are still unknown. cAMP-responsive element binding protein 5 (CREB5) is a member of the ATF/CREB family. CREB5 has been reported to be related to pathological pregnancy, but there are few related studies on this topic in patients with RSA, and the underlying mechanism is unclear.METHODS: We collected decidual tissues from RSA patients and healthy pregnant women to measure the expression level of CREB5, PRL, IGFBP1, ATG5, LC3B, and SQSTM/p62. Then, the changes in CREB5 expression and autophagy levels were measured in human endometrial stromal cells (hESCs) during decidualization. The expression levels of PRL and IGFBP1 were tested in sh-CREB5/ov-CREB5 hESCs after decidualization induction, and the autophagy level in sh-CREB5/ov-CREB5 hESCs was measured without decidualization induction. The decidualization ability of sh-CREB5 and ov-CREB5 hESCs treated with an autophagy inducer or inhibitor was measured. To investigate the effect of CREB5 in hESCs on the invasion and migration of HTR8/SVneo cells, we performed a coculture experiment. Finally, we examined the expression of CREB5 and autophagy key proteins in mouse decidual tissues by constructing an abortion mouse model.
    RESULTS: In our study, we found that the expression of CREB5 was unusually elevated in the uterine decidua of RSA patients, but the expression of PRL, IGFBP1, and autophagy were decreased. During the decidualization of hESCs, the expression of CREB5 gradually decreases in a time-dependent manner with increasing autophagy. Moreover, by knocking down or overexpressing CREB5 in hESCs, it was found that CREB5 can impair decidualization and reduce autophagy in hESCs. Furthermore, the damage caused by CREB5 in terms of decidualization can be reversed by the addition of an autophagy inducer (rapamycin). In addition, CREB5 can increase the secretion of proteins (IL-1β and TGF-β1) in hESCs to inhibit trophoblast invasion and migration.
    CONCLUSIONS: Our data support the supposition that CREB5 disturbs the decidualization of endometrial stromal cells and interactions at the maternal-fetal interface by inhibiting autophagy and that its abnormal upregulation and dysfunction may lead to RSA. It may function as a diagnostic and therapeutic target for RSA. Similarly, we found that in the spontaneous abortion mouse model, the expression of CREB5 in the decidual tissue of the abortion group was significantly increased, and autophagy was decreased.
    Keywords:  Autophagy; CREB5; Decidualization; RSA; hESCs
    DOI:  https://doi.org/10.1007/s43032-024-01474-2
  46. Biomed Pharmacother. 2024 Feb 28. pii: S0753-3322(24)00221-X. [Epub ahead of print]173 116337
    The Janus face of mitophagy in myocardial ischemia/reperfusion injury and recovery.
    Jiaxin Deng, Qian Liu, Linxi Ye, Shuo Wang, Zhenyan Song, Mingyan Zhu, Fangfang Qiang, Yulin Zhou, Zhen Guo, Wei Zhang, Ting Chen.
      In myocardial ischemia/reperfusion injury (MIRI), moderate mitophagy is a protective or adaptive mechanism because of clearing defective mitochondria accumulates during MIRI. However, excessive mitophagy lead to an increase in defective mitochondria and ultimately exacerbate MIRI by causing overproduction or uncontrolled production of mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase 1 (Pink1), Parkin, FUN14 domain containing 1 (FUNDC1) and B-cell leukemia/lymphoma 2 (BCL-2)/adenovirus E1B19KD interaction protein 3 (BNIP3) are the main mechanistic regulators of mitophagy in MIRI. Pink1 and Parkin are mitochondrial surface proteins involved in the ubiquitin-dependent pathway, while BNIP3 and FUNDC1 are mitochondrial receptor proteins involved in the non-ubiquitin-dependent pathway, which play a crucial role in maintaining mitochondrial homeostasis and mitochondrial quality. These proteins can induce moderate mitophagy or inhibit excessive mitophagy to protect against MIRI but may also trigger excessive mitophagy or insufficient mitophagy, thereby worsening the condition. Understanding the actions of these mitophagy mechanistic proteins may provide valuable insights into the pathological mechanisms underlying MIRI development. Based on the above background, this article reviews the mechanism of mitophagy involved in MIRI through Pink1/Parkin pathway and the receptor mediated pathway led by FUNDC1 and BNIP3, as well as the related drug treatment, aim to provide effective strategies for the prevention and treatment of MIRI.
    Keywords:  BNIP3; FUNDC1; Myocardial ischemia/reperfusion injury; Pink1/Parkin; The Janus face of mitophagy
    DOI:  https://doi.org/10.1016/j.biopha.2024.116337
  47. Exp Mol Med. 2024 Mar 01.
    Advanced glycation end products promote meniscal calcification by activating the mTOR-ATF4 positive feedback loop.
    Sheng Yang, JiaJun Xie, ZhiJie Pan, HongMei Guan, YueSheng Tu, YuanJian Ye, ShouBin Huang, ShiQiang Fu, KangXian Li, ZhiWei Huang, XiaoQi Li, ZhanJun Shi, Le Li, Yang Zhang.
      The meniscus is vital for maintaining knee homeostasis and function. Meniscal calcification is one of the earliest radiological indicators of knee osteoarthritis (KOA), and meniscal calcification is associated with alterations in biomechanical properties. Meniscal calcification originates from a biochemical process similar to vascular calcification. Advanced glycation end products (AGEs) and their receptors (RAGEs) reportedly play critical roles in vascular calcification. Herein, we investigated whether targeting AGE-RAGE is a potential treatment for meniscal calcification. In our study, we demonstrated that AGE-RAGE promotes the osteogenesis of meniscal cells and exacerbates meniscal calcification. Mechanistically, AGE-RAGE activates mTOR and simultaneously promotes ATF4 accumulation, thereby facilitating the ATF4-mTOR positive feedback loop that enhances the osteogenic capacity of meniscal cells. In this regard, mTOR inhibits ATF4 degradation by reducing its ubiquitination, while ATF4 activates mTOR by increasing arginine uptake. Our findings substantiate the unique role of AGE-RAGE in the meniscus and reveal the role of the ATF4-mTOR positive feedback loop during the osteogenesis of meniscal cells; these results provide potential therapeutic targets for KOA.
    DOI:  https://doi.org/10.1038/s12276-024-01190-6
  48. Int J Biol Macromol. 2024 Feb 24. pii: S0141-8130(24)01182-6. [Epub ahead of print]263(Pt 2): 130379
    Role of BcSfb3, the subunit of COPII vesicles, in fungal development and pathogenicity, ER-phagy and autophagy in the gray mold fungus Botrytis cinerea.
    Guanbo Wang, Haonan Zhao, Jian Zou, Wenxing Liang, Zhijian Zhao, Delong Li.
      Cytoplasmic coat protein complex II (COPII) plays a multifunctional role in the transport of newly synthesized proteins, autophagosome formation, and endoplasmic reticulum (ER)-ER-phagy. However, the molecular mechanisms of the COPII subunit in ER-phagy in plant pathogens remain unknown. Here, we identified the subunit of COPII vesicles (BcSfb3) and explored the importance of BcSfb3 in Botrytis cinerea. BcSfb3 deletion affected vegetative growth, conidiation, conidial morphology, and plasma membrane integrity. We confirmed that the increase in infectious hyphal growth was delayed in the ΔBcSfb3 mutant, reducing its pathogenicity in the host plant. Furthermore, the ΔBcSfb3 mutant was sensitive to ER stress, which caused massive ER expansion and induced the formation of ER whorls that were taken up into the vacuole. Further examination demonstrated that BcSfb3 deletion caused ER stress initiated by unfolded protein response, and which led to the promotion of ER-phagy and autophagy that participate in sclerotia formation. In conclusion, these results demonstrate that BcSfb3 plays an important role in fungal development, pathogenesis, ER-phagy and autophagy in B. cinerea.
    Keywords:  Autophagy; Botrytis cinerea; Cytoplasmic coat protein complex II (COPII); ER-phagy; Sclerotia formation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.130379
  49. Autophagy. 2024 Feb 26.
    Sodium butyrate ameliorates high glucose-suppressed neuronal mitophagy by restoring PRKN expression via inhibiting the RELA-HDAC8 complex.
    Ji Hyeon Cho, Chang Woo Chae, Jae Ryong Lim, Young Hyun Jung, Su Jong Han, Jee Hyeon Yoon, Ji Yong Park, Ho Jae Han.
      Damaged mitochondria accumulation in diabetes is one of the main features that contribute to increased incidence of cognitive impairment by inducing apoptosis. Butyrate is a major metabolite produced by microbiota that has neuroprotective effects by regulating mitochondrial function. However, detailed mechanisms underlying how butyrate can regulate neuronal mitophagy remain unclear. Here, we examined the regulatory effects of sodium butyrate (NaB) on high glucose-induced mitophagy dysregulation, neuronal apoptosis, and cognitive impairment and its underlying mechanisms in human-induced pluripotent stem cell-derived neurons, SH-SY5Ys, and streptozotocin (STZ)-induced diabetic mice. In our results, diabetic mice showed gut-microbiota dysbiosis, especially a decreased number of butyrate-producing bacteria and reduced NaB plasma concentration. NaB ameliorated high glucose-induced neuronal mitochondrial dysfunction by recovering PRKN/Parkin-mediated mitophagy. High glucose-induced reactive oxygen species (ROS) and -inhibited PRKAA/AMPKα stimulated the RELA/p65-HDAC8 complex, which downregulated PRKN protein expression by binding to the PRKN promoter region. NaB restored PRKN expression by blocking RELA nuclear translocation and directly inhibiting HDAC8 in the nucleus. In addition, HDAC8 overexpression inhibited the positive effect of NaB on high glucose-induced mitophagy dysfunction and neuronal apoptosis. Oral administration of NaB improved cognitive impairment in diabetic mice by restoring mitophagy in the hippocampus. Taken together, NaB ameliorates neuronal mitophagy through PRKN restoration by inhibiting RELA-HDAC8 complexes, suggesting that NaB is an important substance for protecting neuronal apoptosis in diabetes-associated cognitive impairment.
    Keywords:  Autophagy; Scfas; diabetes; gut-brain axis; mitochondria; neuronal apoptosis
    DOI:  https://doi.org/10.1080/15548627.2024.2323785
  50. J Alzheimers Dis. 2024 Feb 24.
    Impact of Suramin on Key Pathological Features of Sporadic Alzheimer's Disease-Derived Forebrain Neurons.
    Robert A Culibrk, Katherine A Ebbert, Daniel J Yeisley, Rui Chen, Fatir A Qureshi, Juergen Hahn, Mariah S Hahn.
      Background: Alzheimer's disease (AD) is characterized by disrupted proteostasis and macroautophagy (hereafter "autophagy"). The pharmacological agent suramin has known autophagy modulation properties with potential efficacy in mitigating AD neuronal pathology.Objective: In the present work, we investigate the impact of forebrain neuron exposure to suramin on the Akt/mTOR signaling pathway, a major regulator of autophagy, in comparison with rapamycin and chloroquine. We further investigate the effect of suramin on several AD-related biomarkers in sporadic AD (sAD)-derived forebrain neurons.
    Methods: Neurons differentiated from ReNcell neural progenitors were used to assess the impact of suramin on the Akt/mTOR signaling pathway relative to the autophagy inducer rapamycin and autophagy inhibitor chloroquine. Mature forebrain neurons were differentiated from induced pluripotent stem cells (iPSCs) sourced from a late-onset sAD patient and treated with 100μM suramin for 72 h, followed by assessments for amyloid-β, phosphorylated tau, oxidative/nitrosative stress, and synaptic puncta density.
    Results: Suramin treatment of sAD-derived neurons partially ameliorated the increased p-Tau(S199)/Tau ratio, and fully remediated the increased glutathione to oxidized nitric oxide ratio, observed in untreated sAD-derived neurons relative to healthy controls. These positive results may be due in part to the distinct increases in Akt/mTOR pathway mediator p-p70S6K noted with suramin treatment of both ReNcell-derived and iPSC-derived neurons. Longer term neuronal markers, such as synaptic puncta density, were unaffected by suramin treatment.
    Conclusions: These findings provide initial evidence supporting the potential of suramin to reduce the degree of dysregulation in sAD-derived forebrain neurons in part via the modulation of autophagy.
    Keywords:  Alzheimer’s disease; autophagy; induced pluripotent stem cells; neurons; suramin
    DOI:  https://doi.org/10.3233/JAD-230600
  51. Nat Commun. 2024 Feb 28. 15(1): 1799
    A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.
    Sun Woo Sophie Kang, Rory P Cunningham, Colin B Miller, Lauryn A Brown, Constance M Cultraro, Adam Harned, Kedar Narayan, Jonathan Hernandez, Lisa M Jenkins, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.
      In the liver, mitochondria are exposed to different concentrations of nutrients due to their spatial positioning across the periportal and pericentral axis. How the mitochondria sense and integrate these signals to respond and maintain homeostasis is not known. Here, we combine intravital microscopy, spatial proteomics, and functional assessment to investigate mitochondrial heterogeneity in the context of liver zonation. We find that periportal and pericentral mitochondria are morphologically and functionally distinct; beta-oxidation is elevated in periportal regions, while lipid synthesis is predominant in the pericentral mitochondria. In addition, comparative phosphoproteomics reveals spatially distinct patterns of mitochondrial composition and potential regulation via phosphorylation. Acute pharmacological modulation of nutrient sensing through AMPK and mTOR shifts mitochondrial phenotypes in the periportal and pericentral regions, linking nutrient gradients across the lobule and mitochondrial heterogeneity. This study highlights the role of protein phosphorylation in mitochondrial structure, function, and overall homeostasis in hepatic metabolic zonation. These findings have important implications for liver physiology and disease.
    DOI:  https://doi.org/10.1038/s41467-024-45751-9
  52. Dev Biol. 2024 Feb 23. pii: S0012-1606(24)00028-9. [Epub ahead of print]
    Circadian clock genes REV-ERBα regulates the secretion of IL-1β in deciduous tooth pulp stem cells by regulating autophagy in the process of physiological root resorption of deciduous teeth.
    Tiankai Di, Mingzhu Guo, Jinlong Xu, Chao Feng, Yang Du, Lulu Wang, Yujiang Chen.
      Physiological root resorption is a common occurrence during the development of deciduous teeth in children. Previous research has shown that the regulation of the inflammatory microenvironment through autophagy in DDPSCs is a significant factor in this process. However, it remains unclear why there are variations in the autophagic status of DDPSCs at different stages of physiological root resorption. To address this gap in knowledge, this study examines the relationship between the circadian clock of DDPSCs, the autophagic status, and the periodicity of masticatory behavior. Samples were collected from deciduous teeth at various stages of physiological root resorption, and DDPSCs were isolated and cultured for analysis. The results indicate that the circadian rhythm of important autophagy genes, such as Beclin-1 and LC3, and the clock gene REV-ERBα in DDPSCs, disappears under mechanical stress. Additionally, the study found that REV-ERBα can regulate Beclin-1 and LC3. Evidence suggests that mechanical stress is a trigger for the regulation of autophagy via REV-ERBα. Overall, this study highlights the importance of mechanical stress in regulating autophagy of DDPSCs via REV-ERBα, which affects the formation of the inflammatory microenvironment and plays a critical role in physiological root resorption in deciduous teeth.
    Keywords:  Autophagy; Circadian clock; Deciduous dental pulp stem cells; IL-1β; Mechanical stress; Physiological root resorption; REV-ERBα
    DOI:  https://doi.org/10.1016/j.ydbio.2024.02.008
  53. Nat Metab. 2024 Feb;6(2): 203-204
    A leucine-macrophage mTORC1 connection drives increased risk of atherosclerosis with high-protein diets.
    Adam J Rose, Patricia M Rusu.
      
    DOI:  https://doi.org/10.1038/s42255-023-00952-2
  54. Nucleic Acids Res. 2024 Feb 27. pii: gkae156. [Epub ahead of print]
    LC3B drives transcription-associated homologous recombination via direct interaction with R-loops.
    Junghyun Yoon, Yiseul Hwang, Hansol Yun, Jee Min Chung, Soyeon Kim, Gyeongmin Kim, Yeji Lee, Byoung Dae Lee, Ho Chul Kang.
      Exploring the connection between ubiquitin-like modifiers (ULMs) and the DNA damage response (DDR), we employed several advanced DNA damage and repair assay techniques and identified a crucial role for LC3B. Notably, its RNA recognition motif (RRM) plays a pivotal role in the context of transcription-associated homologous recombination (HR) repair (TA-HRR), a particular subset of HRR pathways. Surprisingly, independent of autophagy flux, LC3B interacts directly with R-loops at DNA lesions within transcriptionally active sites via its RRM, promoting TA-HRR. Using native RNA immunoprecipitation (nRIP) coupled with high-throughput sequencing (nRIP-seq), we discovered that LC3B also directly interacts with the 3'UTR AU-rich elements (AREs) of BRCA1 via its RRM, influencing its stability. This suggests that LC3B regulates TA-HRR both proximal to and distal from DNA lesions. Data from our LC3B depletion experiments showed that LC3B knockdown disrupts end-resection for TA-HRR, redirecting it towards the non-homologous end joining (NHEJ) pathway and leading to chromosomal instability, as evidenced by alterations in sister chromatid exchange (SCE) and interchromosomal fusion (ICF). Thus, our findings unveil autophagy-independent functions of LC3B in DNA damage and repair pathways, highlighting its importance. This could reshape our understanding of TA-HRR and the interaction between autophagy and DDR.
    DOI:  https://doi.org/10.1093/nar/gkae156
  55. bioRxiv. 2024 Feb 15. pii: 2024.02.14.580336. [Epub ahead of print]
    A quantitative ultrastructural timeline of nuclear autophagy reveals a role for dynamin-like protein 1 at the nuclear envelope.
    Philip J Mannino, Andrew Perun, Ivan Surovstev, Nicholas R Ader, Lin Shao, Thomas J Melia, Megan C King, C Patrick Lusk.
      Autophagic mechanisms that maintain nuclear envelope homeostasis are bulwarks to aging and disease. By leveraging 4D lattice light sheet microscopy and correlative light and electron tomography, we define a quantitative and ultrastructural timeline of a nuclear macroautophagy (nucleophagy) pathway in yeast. Nucleophagy initiates with a rapid local accumulation of the nuclear cargo adaptor Atg39 at the nuclear envelope adjacent to the nucleus-vacuole junction and is delivered to the vacuole in ~300 seconds through an autophagosome intermediate. Mechanistically, nucleophagy incorporates two consecutive and genetically defined membrane fission steps: inner nuclear membrane (INM) fission generates a lumenal vesicle in the perinuclear space followed by outer nuclear membrane (ONM) fission to liberate a double membraned vesicle to the cytosol. ONM fission occurs independently of phagophore engagement and instead relies surprisingly on dynamin-like protein1 (Dnm1), which is recruited to sites of Atg39 accumulation at the nuclear envelope. Loss of Dnm1 compromises nucleophagic flux by stalling nucleophagy after INM fission. Our findings reveal how nuclear and INM cargo are removed from an intact nucleus without compromising its integrity, achieved in part by a non-canonical role for Dnm1 in nuclear envelope remodeling.
    DOI:  https://doi.org/10.1101/2024.02.14.580336
  56. Arch Pharm Res. 2024 Feb 28.
    New autophagy-modulating lanostane-type triterpenoids from a hallucinogenic poisonous mushroom Gymnopilus orientispectabilis.
    Seulah Lee, Mina Jang, Rhim Ryoo, Jongtae Roh, Sung-Kyun Ko, Ki Hyun Kim.
      Gymnopilus orientispectabilis, also known as "big laughter mushroom," is a hallucinogenic poisonous mushroom that causes excessive laughter upon ingestion. From the fruiting bodies of G. orientispectabilis, eight lanostane-type triterpenoids (1-8), including seven novel compounds: gymnojunols A-G (2-8), were isolated. The chemical structures of these new compounds (2-8) were determined by analyzing their 1D and 2D NMR spectra and HR-EISMS, and their absolute configurations were unambiguously assigned by quantum chemical ECD calculations and a computational method coupled with a statistical procedure (DP4+). Upon evaluating autophagic activity, compounds 2, 6, and 7 increased LC3B-II levels in HeLa cells to a similar extent as bafilomycin, an autophagy inhibitor. In contrast, compound 8 decreased the levels of both LC3B-I and LC3B-II, and a similar effect was observed following treatment with rapamycin, an autophagy inducer. Our findings provide experimental evidence for new potential autophagy modulators in the hallucinogenic poisonous mushroom G. orientispectabilis.
    Keywords:   Gymnopilus orientispectabilis ; Autophagic activity; ECD calculation; Lanostane-type triterpenoids; Structural elucidation
    DOI:  https://doi.org/10.1007/s12272-024-01486-1
  57. Sci Rep. 2024 02 26. 14(1): 4610
    Sodium butyrate exerts a neuroprotective effect in rats with acute carbon monoxide poisoning by activating autophagy through the mTOR signaling pathway.
    Jing Wen, Qiong Xu, Jing Li, Xuanyang Shen, Xiaolong Zhou, Jing Huang, Shiping Liu.
      Acute carbon monoxide (CO) poisoning is a prevalent type of poisoning that causes significant harm globally. Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is a severe complication that occurs after acute CO poisoning; however, the exact underlying pathological cause of DEACMP remains unclear. Accumulating evidence indicates that abnormal inflammation and immune-mediated brain damage, cellular apoptosis and autophagy, and direct neuronal toxicity are involved in the development of delayed neurologic sequelae. Sodium butyrate, a histone deacetylase inhibitor, has gained increasing attention for its numerous beneficial effects on various diseases, such as obesity, diabetes, inflammatory diseases, and cerebral damage. In this study, an acute carbon monoxide poisoning (ACOP) model is established in rats to investigate the mechanism of CO poisoning and the therapeutic potential of sodium butyrate. The results suggested that the ACOP rats had impaired spatial memory, and cell apoptosis was observed in the hippocampi with activated autophagy. Sodium butyrate treatment further increased the activation of autophagy in the hippocampi of CO-exposed rats, inhibited apoptosis, and consolidated spatial memory. These findings indicated that sodium butyrate may improve memory and cognitive function in ACMP rats by promoting autophagy and inhibiting apoptosis.
    DOI:  https://doi.org/10.1038/s41598-024-55198-z
  58. Bone. 2024 Feb 24. pii: S8756-3282(24)00041-3. [Epub ahead of print]182 117052
    Crosstalk between ALK3(BMPR1A) deficiency and autophagy signaling mitigates pathological bone loss in osteoporosis.
    Zhixing Niu, Yumeng Zhou, Muchun Liang, Fuqiang Su, Qiang Guo, Junjun Jing, Jing Xie, Demao Zhang, Xiaoheng Liu.
      Postmenopausal osteoporosis is recognized to be one of the major skeleton diseases strongly associated with impaired bone formation. Previous reports have indicated that the importance of bone morphogenetic protein (BMP) signaling of osteoblast lineage in bone development via classical Smad signaling, however, its critical role in osteoporosis is still not well understood. In the current study, we aim to investigate the pathological role of BMPR1A, a key receptor of BMPs, in osteoporosis and its underlying mechanism. We first found that knockdown of BMPR1A by using Col1a1-creER in osteoblasts mitigated early bone loss of osteoporosis in mice, yet along with late bone maturation defects by reducing mineral adherence rate and bone formation rate in vivo. At the cellular level, we then observed that BMPR1A deficiency promoted the proliferation of pre-osteoblasts under osteoporotic conditions but hindered their late-stage mineralization. We finally elucidated that BMPR1A deficiency compensatorily triggered mTOR-autophagy perturbation by a higher level in early osteoporotic pre-osteoblasts thus resulting in the enhancement of transient cell proliferation but impairment of final mineralization. Taken together, this study indicated the significance of BMPR1A-mTOR/autophagy axis, as a double-edged sword, in osteoporotic bone formation and provided new cues for therapeutic strategies in osteoporosis.
    Keywords:  Autophagy; BMPR1A; Osteoblasts; Osteoporosis; Proliferation
    DOI:  https://doi.org/10.1016/j.bone.2024.117052
  59. Environ Pollut. 2024 Feb 23. pii: S0269-7491(24)00339-7. [Epub ahead of print]346 123625
    Cross-talk between Vimentin and autophagy regulates blood-testis barrier disruption induced by cadmium.
    Na Chen, Xiaoyan Wan, Mei Wang, Yamin Li, Xiaofei Wang, Ling Zeng, Jinzhao Zhou, Yanwei Zhang, Shun Cheng, Yi Shen.
      The blood-testis barrier (BTB) plays a vital role in mammalian spermatogenesis by separating the seminiferous epithelium into an adluminal and a basal compartment. Cadmium (Cd) is a toxic heavy metal that is widely present in the environment. We observed that Cd can induce BTB disruption, leading to apoptosis of testicular cells. However, the molecular mechanisms contributing to BTB injury induced by Cd have not yet been fully clarified. Vimentin (Vim) is an important desmosome-like junction protein that mediates robust adhesion in the BTB. In this study, we investigated how Vim responds to Cd. We found that Cd treatment led to a significant decrease in Vim expression, accompanied by a marked increase in LC3-II expression and a higer number of autophagosomes. Interestingly, we also observed that Cd-induced autophagy was associated with decreased Vim activity and enhanced apoptosis of testicular cells. To further investigate the role of autophagy in Vim regulation under Cd exposure, we treated cells with an autophagy inhibitor called 3-MA. We found that 3-MA treatment enhanced Vim expression and improved the disruption of the BTB under Cd exposure. Additionally, the inhibition of Vim confirmed the role of autophagy in modulating Vim expression. These results reveal a previously unknown regulatory mechanism of Cd involving the interplay between a heavy metal and a protein.
    Keywords:  Apoptosis; Autophagy; Blood-testis barrier; Cadmium; Desmosome-like junctions; Vimentin
    DOI:  https://doi.org/10.1016/j.envpol.2024.123625
  60. Bone. 2024 Feb 24. pii: S8756-3282(24)00047-4. [Epub ahead of print]182 117058
    DDIT3 deficiency accelerates bone remodeling during bone healing by enhancing osteoblast and osteoclast differentiation through ULK1-mediated autophagy.
    Meie Jia, Zhipeng Dong, Wei Dong, Beining Yang, Ying He, Yan Wang, Jiawei Wang.
      The coordination of osteoblasts and osteoclasts is essential for bone remodeling. DNA damage inducible script 3 (DDIT3) is an important regulator of bone and participates in cell differentiation, proliferation, autophagy, and apoptosis. However, its role in bone remodeling remains unexplored. Here, we found that Ddit3 knockout (Ddit3-KO) enhanced both bone formation and resorption. The increased new bone formation and woven bone resorption, i.e., enhanced bone remodeling capacity, was found to accelerate bone defect healing in Ddit3-KO mice. In vitro experiments showed that DDIT3 inhibited both osteoblast differentiation and Raw264.7 cell differentiation by regulating autophagy. Cell coculture assay showed that Ddit3-KO decreased the ratio of receptor activator of nuclear factor-κβ ligand (RANKL) to osteoprotegerin (OPG) in osteoblasts, and Ddit3-KO osteoblasts inhibited osteoclast differentiation. Meanwhile, DDIT3 knockdown (DDIT3-sh) increased receptor activator of nuclear factor-κβ (RANK) expression in Raw264.7 cells, and DDIT3-sh Raw264.7 cells promoted osteoblast differentiation, whereas, DDIT3 overexpression had the opposite effect. Mechanistically, DDIT3 promoted autophagy partly by increasing ULK1 phosphorylation at serine555 (pULK1-S555) and decreasing ULK1 phosphorylation at serine757 (pULK1-S757) in osteoblasts, thereby inhibiting osteoblast differentiation. DDIT3 inhibited autophagy partly by decreasing pULK1-S555 in Raw264.7 cells, thereby suppressing osteoclastic differentiation. Taken together, our data indicate that DDIT3 is one of the elements regulating bone remodeling and bone healing, which may become a potential target in bone defect treatment.
    Keywords:  Autophagy; Bone remodeling; DDIT3; Osteoblast; Osteoclast; ULK1
    DOI:  https://doi.org/10.1016/j.bone.2024.117058
  61. Antioxid Redox Signal. 2024 Feb 26.
    A novel synthesized cyclohexane-hydroxytyrosol derivative suppresses ovarian cancer cell growth through inducing ROS and blocking autophagic flux.
    Guanfei Zhang, Min Wang, Yilin Gao, Aikaterini-Christina Komianou, Eleftheria A Georgiou, Yan Wang, Yezi Zheng, Jiankang Liu, Ioannis K Kostakis, Lin Zhao.
      AIMS: Drug resistance in ovarian cancer (OC) cells often leads to recurrence, metastasis, and high mortality rates among OC patients. Hydroxytyrosol (HT) has been reported to inhibit the proliferation of ovarian and other types of cancer cells. Here we synthesized a novel cyclohexane-hydroxytyrosol derivative (Chx-HT) for enhanced anticaner efficacy. We examined the growth-suppressing effect of Chx-HT on OC cells in vitro and in xenograft mouse model and investigated the underlying mechanism.RESULTS: We demonstrated that Chx-HT inhibits proliferation, promotes apoptosis, remodels glucose and lipid metabolism by reducing fatty acid β-oxidation while increasing glycolysis, de novo fatty acid synthesis and lipid droplet accumulation, impairs mitochondrial respiration and induces oxidative stress both in vitro and in vivo. Additionally, Chx-HT blocks autophagic flux by obstructing the maturation of lysosomal cathepsins in the late-stage, but also activates autophagy through the p-AMPK/p-mTOR/p-ULK1 pathway in response to energy deficit.
    INNOVATION AND CONCLUSION: ROS plays a critical role in mediating the effects of Chx-HT on proliferation, apoptosis, autophagy, TCA cycle, FAO and mitochondrial respiration, and the autophagic activation underlies the effects of Chx-HT on glycolysis, de novo fatty acid synthesis, and lipid droplet accumulation in ovarian cancer cells. Cotreating OC cells with Chx-HT and autophagic inhibitor or glycolytic inhibitor results in an additive inhibition of proliferation. Our study indicates that Chx-HT stands for a promising OC therapeutic by ROS and autophagy blockade mediated metabolic remodeling.
    DOI:  https://doi.org/10.1089/ars.2023.0400
  62. Peptides. 2024 Feb 27. pii: S0196-9781(24)00036-6. [Epub ahead of print] 171183
    Cathelicidin LL-37 promotes wound healing in diabetic mice by regulating TFEB-dependent autophagy.
    Liuqing Xi, Juan Du, Wen Xue, Kan Shao, Xiaohong Jiang, Wenfang Peng, Wenyi Li, Shan Huang.
      Diabetic patients often experience impaired wound healing. Human cathelicidin LL-37 possesses various biological functions, such as anti-microbial, anti-inflammatory, and pro-wound healing activities. Autophagy has important effects on skin wound healing. However, little is known about whether LL-37 accelerates diabetic wound healing by regulating autophagy. In the study, we aimed to investigate the role of autophagy in LL-37-induced wound healing and uncover the underlying mechanisms involved. A full-thickness wound closure model was established in diabetic mice to evaluate the effects of LL-37 and an autophagy inhibitor (3-MA) on wound healing. The roles of LL-37 and 3-MA in regulating keratinocyte migration were assessed using transwell migration and wound healing assays. The activation of transcription factor EB (TFEB) was measured using western blotting and immunofluorescence (IF) assays of its nuclear translocation. The results showed that LL-37 treatment improved wound healing in diabetic mice, whereas these effects were reversed by 3-MA. In vitro, 3-MA decreased the effects of LL-37 on promoting HaCat keratinocyte migration in the presence of high glucose (HG). Mechanistically, LL-37 promoted TFEB activation and resulted in subsequent activation of autophagy, as evidenced by increased nuclear translocation of TFEB and increased expression of ATG5, ATG7, and beclin 1 (BECN1), whereas these changes were blocked by TFEB knockdown. As expected, TFEB knockdown damaged the effects of LL-37 on promoting keratinocyte migration. Collectively, these results suggest that LL-37 accelerates wound healing in diabetic mice by activating TFEB-dependent autophagy, providing new insights into the mechanism by which LL-37 promotes diabetic wound healing.
    Keywords:  LL-37; TFEB; autophagy; cathelicidin; diabetes wound healing
    DOI:  https://doi.org/10.1016/j.peptides.2024.171183
  63. Cell Mol Life Sci. 2024 Feb 27. 81(1): 101
    BOP1 contributes to the activation of autophagy in polycystic ovary syndrome via nucleolar stress response.
    Rui Ji, Zhimo Zhang, Zhe Yang, Xin Chen, Tailang Yin, Jing Yang.
      Abnormal autophagy is one of the vital features in polycystic ovary syndrome (PCOS). However, the underlying molecular mechanisms remain unelucidated. In this study, we aimed to investigate whether Block of Proliferation 1 (BOP1) is involved in the onset of autophagy activation of granulosa cells in PCOS. Firstly, we found that BOP1 expression was significantly down-regulated in the ovaries of PCOS mice, which was associated with the development of PCOS. Next, local injection of lentiviral vectors in the ovary for the overexpression of BOP1 significantly alleviated the phenotypes of elevated androgens, disturbed estrous cycle, and abnormal follicular development in PCOS mice. Subsequently, we found that knockdown of BOP1 activated autophagy of granulosa cells in the in vitro experiments, whereas overexpression of BOP1 inhibited autophagy in both in vivo and in vitro models. Mechanistically, BOP1 knockdown triggered the nucleolus stress response, which caused RPL11 to be released from the nucleolus into the nucleoplasm and inhibited the E3 ubiquitination ligase of MDM2, thereby enhancing the stability of p53. Subsequently, P53 inhibited mTOR, thereby activating autophagy in granulosa cells. In addition, the mRNA level of BOP1 was negatively correlated with antral follicle count (AFC), body-mass index (BMI), serum androgen levels, and anti-Mullerian hormone (AMH) in patients with PCOS. In summary, our study demonstrates that BOP1 downregulation inhibits mTOR phosphorylation through activation of the p53-dependent nucleolus stress response, which subsequently contributes to aberrant autophagy in granulosa cells, revealing that BOP1 may be a key target for probing the mechanisms of PCOS.
    Keywords:  Autophagy; Block of proliferation 1 (BOP1); Nucleolus stress; Polycystic ovary syndrome (PCOS)
    DOI:  https://doi.org/10.1007/s00018-023-05091-1
  64. Cell Death Differ. 2024 Feb 29.
    AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner.
    Weimin Xu, Zhebin Hua, Yaosheng Wang, Wenbo Tang, Weijun Ou, Fangyuan Liu, Yiqing Yang, Wenjun Ding, Zhongchuan Wang, Long Cui, Wensong Ge, Yubei Gu, Xiaolei Wang, YingWei Chen, Chen-Ying Liu, Peng Du.
      IκB kinase (IKK) complex is central regulators of the NF-κB pathway, and dysregulation of IKK phosphorylation leads to hyperactivation of proinflammatory response in various chronic inflammatory diseases, including inflammatory bowel disease (IBD). However, the dynamic modulation of IKK phosphorylation and dephosphorylation in intestinal inflammation remains uncharacterized. Here, we found that autophagy/beclin-1 regulator 1 (AMBRA1) was highly expressed in inflamed colons in a colitis mouse model and in clinical IBD samples. Importantly, AMBRA1 deletion significantly decreased proinflammatory cytokine expression and enhanced the therapeutic effect of infliximab on intestinal inflammation. Mechanistically, the N-term F1 domain of AMBRA1 was required for AMBRA1 to competitively interact with protein phosphatase 4 regulatory subunit 1 (PP4R1) and catalytic protein phosphatase 4 (PP4c) to suppress their interactions with IKK, promote the dissociation of the PP4R1/PP4c complex, and antagonize the dephosphorylation activity of this complex towards the IKK complex. In response to TNF-α stimulation, IKKα phosphorylates AMBRA1 at S1043 to stabilize AMBRA1 expression by impairing its binding to Cullin4A (CUL4A) to decrease its CUL4A-mediated K48-linked ubiquitination. Overall, our study identifies an autophagy-independent function of AMBRA1 as a positive modulator of IKK phosphorylation to promote intestinal inflammation, thus providing a new targeted therapeutic strategy for patients with refractory IBD.
    DOI:  https://doi.org/10.1038/s41418-024-01275-9
  65. Nat Cell Biol. 2024 Mar 01.
    ER remodelling by ER-phagy in neurogenesis.
    Maurizio Molinari.
      
    DOI:  https://doi.org/10.1038/s41556-024-01362-6
  66. Cell Death Dis. 2024 Feb 28. 15(2): 176
    mTOR pathway occupies a central role in the emergence of latent cancer cells.
    Kseniia V Aleksandrova, Mikhail L Vorobev, Irina I Suvorova.
      The current focus in oncology research is the translational control of cancer cells as a major mechanism of cellular plasticity. Recent evidence has prompted a reevaluation of the role of the mTOR pathway in cancer development leading to new conclusions. The mechanistic mTOR inhibition is well known to be a tool for generating quiescent stem cells and cancer cells. In response to mTOR suppression, quiescent cancer cells dynamically change their proteome, triggering alternative non-canonical translation mechanisms. The shift to selective translation may have clinical relevance, since quiescent tumor cells can acquire new phenotypical features. This review provides new insights into the patterns of mTOR functioning in quiescent cancer cells, enhancing our current understanding of the biology of latent metastasis.
    DOI:  https://doi.org/10.1038/s41419-024-06547-3
  67. Nat Aging. 2024 Mar 01.
    Lessons from inducible pluripotent stem cell models on neuronal senescence in aging and neurodegeneration.
    Isabelle R de Luzy, Michael K Lee, William C Mobley, Lorenz Studer.
      Age remains the central risk factor for many neurodegenerative diseases including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Although the mechanisms of aging are complex, the age-related accumulation of senescent cells in neurodegeneration is well documented and their clearance can alleviate disease-related features in preclinical models. Senescence-like characteristics are observed in both neuronal and glial lineages, but their relative contribution to aging and neurodegeneration remains unclear. Human pluripotent stem cell-derived neurons provide an experimental model system to induce neuronal senescence. However, the extensive heterogeneity in the profile of senescent neurons and the methods to assess senescence remain major challenges. Here, we review the evidence of cellular senescence in neuronal aging and disease, discuss human pluripotent stem cell-based model systems used to investigate neuronal senescence and propose a panel of cellular and molecular hallmarks to characterize senescent neurons. Understanding the role of neuronal senescence may yield novel therapeutic opportunities in neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s43587-024-00586-3
This page is being maintained by Thomas Krichel. It was last updated on 2024‒03‒03 at 0:19.