bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–02–08
28 papers selected by
Viktor Korolchuk, Newcastle University
  1. TGFB-inducible VASN (vasorin) promotes lysosomal acidification.
  2. The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
  3. NCOA4 initiates ferritinophagy by avidly binding GATE16 using two short linear interaction motifs.
  4. Quantitative and temporal analysis of autophagy: Differential Response to amino acid and glucose starvation.
  5. Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia.
  6. MONNA alleviates MPTP-induced Parkinson's disease in zebrafish by activating TFEB dependently on ER Calcium.
  7. PRKN activation for mitophagy requires an NME3-regulated phosphatidic acid signal that separates mitochondria from endoplasmic reticulum tethering.
  8. Mechanistic advances in exercise‑mediated regulation of autophagy dysfunction in Alzheimer's disease (Review).
  9. Cullin-3 adaptor SHKBP1 inhibits SQSTM1/p62 oligomerization and Keap1 sequestration.
  10. Legionella Lem26 functions as an ATG8-activated effector that inhibits host autophagy.
  11. Autophagy activation by taurine alleviates prion-induced mitochondrial dysfunction and neurotoxicity.
  12. Reduced late endosome/lysosome function promotes SLE through chronic PI3k activity and SHP-1/SHIP-1 defects.
  13. Cis or trans: a puzzle of Parkin activation mechanism.
  14. Cyclic stretch induces autophagy-mediated focal adhesion remodeling and activates mitochondria.
  15. Visualizing PINK1 Activity Dynamics in Single Cells with a Phase Separation-Based Kinase Activity Reporter.
  16. Covalent modification of a glutamic acid inspired by HaloTag technology.
  17. A novel SO2 probe inhibits lysophagy induced by Senecavirus A infection by promoting LAMP1 Cys375 sulfenylation.
  18. Cathepsin-dependent amyloid formation drives mechanical rupture of lysosomal membranes.
  19. Mitochondrial transplantation ameliorates rheumatoid arthritis by targeting abnormal CGAS-STING1 signaling activation, autophagosome accumulation, and necroptosis.
  20. TBK1 activity regulates the directionality of axonal transport of signalling endosomes.
  21. HRD1 negatively regulates autolysosome formation by inhibiting liquid-liquid phase separation of SNAP29.
  22. Loss of Galectin-3 in the epidermis exacerbates psoriasis pathogenesis via inhibiting autophagy.
  23. Growth arrest-specific 6 rejuvenates senescent HUCMSCs through upregulating Nrf2 for diabetic wound therapy.
  24. Mitophagy in pancreatic cancer: mechanistic insights and implications for novel therapeutic strategies.
  25. Proteostasis of organelles in aging and disease.
  26. (Pro)renin receptor (PRR) exacerbates diabetic cardiomyopathy by suppressing LRRK2-Mediated mitophagy and promoting senescence.
  27. Spatiotemporal in vivo protein degradation.
  28. PLETHORA-autophagy axis activates organ regeneration through ROS modulation.
  1. Autophagy. 2026 Feb 02.
    TGFB-inducible VASN (vasorin) promotes lysosomal acidification.
    Jiong Yan, Yan Zhang, Swati Choksi, Melissa R Mikolaj, Adam Harned, Kedar Narayan, Zheng-Gang Liu.
      The lysosome is not only a degradative organelle but also an essential platform for signal transduction, such as with MTOR signaling. The reciprocal regulation between the lysosome and MTOR is central to macroautophagy/autophagy and metabolism. MTOR-mediated suppression of lysosomal acidification is important for lysosomal activity, autophagic flux, and cell survival. VASN is a transmembrane glycoprotein whose function is not fully understood. In the present study, we report that VASN is a TGFB-inducible protein and plays a crucial role in positively regulating lysosomal acidification. As a potential mechanism, we demonstrated that VASN localizes to the lysosome, interacts with lysosomal MTOR and STK11IP, and disrupts the binding of STK11IP to MTOR and the V-ATPase, which was recently reported to suppress lysosomal acidification. We found that VASN's function in modulating lysosomal activity is essential for optimal mitophagy induced by TGFB and terminal erythroid differentiation and is critical for the progression of mutant KRAS-driven lung cancer. Overall, our study identified VASN as a novel TGFB-inducible regulator of lysosomal function.
    Keywords:  Lysosome; MTOR; STK11IP; TGFB; V-ATPase; VASN; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2626397
  2. Curr Biol. 2026 Feb 03. pii: S0960-9822(26)00006-0. [Epub ahead of print]
    The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
    Ryan R Cupo, Eunice Domínguez-Martín, Richard Youle.
      Mitochondria contain a genome (mtDNA) encoding a handful of proteins essential for cellular respiration. mtDNA can leak into the cytosol and drive fitness defects. The first genes associated with mtDNA escape were discovered in yeast and aptly named "yeast mitochondrial escape" (YME) genes. We identify the mechanism by which an intermembrane space nuclease, endonuclease G (human ENDOG; yeast Nuc1), prevents mtDNA escape to the cytosol in yeast. Nuc1 nuclease activity and mitochondrial localization are essential for preventing mtDNA escape and suggest a direct role of Nuc1 in degrading mtDNA bound for escape. We find that blocking autophagy via atg1 and atg8 mutants prevents mtDNA escape in the absence of Nuc1. We further demonstrate that blocking mitophagy via atg11 and atg32 mutants prevents mtDNA escape, whereas inducing mitophagy increases mtDNA escape in the absence of Nuc1. Finally, we demonstrate that Nuc1 degrades mtDNA bound for escape via the vacuole, as an atg15 mutant that prevents disassembly of autophagic bodies in the vacuole also prevents mtDNA escape. Overall, our results implicate vacuolar entry of mitochondria during mitophagy as an important mtDNA escape pathway in yeast, which is normally mitigated via the degradation of mtDNA by Nuc1.
    Keywords:  Atg1; Atg32; Drp1; NUMT; STING; autophagy; fission; lysosome; nucleoid; vacuole
    DOI:  https://doi.org/10.1016/j.cub.2026.01.006
  3. Life Sci Alliance. 2026 Apr;pii: e202503611. [Epub ahead of print]9(4):
    NCOA4 initiates ferritinophagy by avidly binding GATE16 using two short linear interaction motifs.
    April Lee, Joseph H Davis.
      Cells carefully regulate cytosolic iron, which is a vital enzymatic cofactor, yet is toxic in excess. In mammalian cells, surplus iron is sequestered in ferritin cages that, in iron-limiting conditions, can be degraded through the selective autophagy pathway ferritinophagy to liberate free iron. Prior work identified the ferritinophagy receptor protein NCOA4, which links ferritin and LC3/GABARAP-family member GATE16, effectively tethering ferritin to the autophagic machinery. Here, we elucidate the molecular mechanism underlying this interaction, discovering two short linear motifs in NCOA4 that each bind GATE16 with weak affinity. These binding motifs are highly avid and, in concert, support high-affinity NCOA4•GATE16 complex formation. We further find the minimal NCOA4383-522 fragment bearing these motifs is sufficient for ferritinophagy and that both motifs are necessary for this activity. This work suggests a general mechanism wherein selective autophagy receptors can distinguish between the inactive pools of monomeric LC3/GABARAPs and the active oligomerized forms that drive autophagy. Finally, we find that iron decreases affinity of the NCOA4383-522 fragment for GATE16, providing a plausible mechanism for iron-dependent regulation of ferritinophagy.
    DOI:  https://doi.org/10.26508/lsa.202503611
  4. PLoS One. 2026 ;21(2): e0340957
    Quantitative and temporal analysis of autophagy: Differential Response to amino acid and glucose starvation.
    Katie R Martin, Stephanie L Celano, Jessica D Guillaume, Ryan D Sheldon, Russell G Jones, Jeffrey P MacKeigan.
      Autophagy is a highly conserved, intracellular recycling process by which cytoplasmic contents are degraded in the lysosome. This process occurs at a low level constitutively; however, it is induced robustly in response to stressors, in particular, starvation of critical nutrients such as amino acids and glucose. That said, the relative contribution of these inputs is ambiguous, and many starvation medias are poorly defined or devoid of multiple nutrients. Here, we set out to create a quantitative dataset of autophagy across multiple stages in single, living cells, measured under normal growth conditions and during nutrient starvation of amino acids or glucose. We found that autophagy is induced by starvation of amino acids, but not glucose, in U2OS cells, and that MTORC1-mediated ULK1 regulation and autophagy are tightly linked to amino acid levels. While autophagy is engaged immediately during amino acid starvation, a heightened response occurs during a period marked by transcriptional upregulation of autophagy genes during sustained starvation. Finally, we demonstrated that cells immediately return to their initial, low-autophagy state when nutrients are restored, highlighting the dynamic relationship between autophagy and environmental conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0340957
  5. Mitochondrion. 2026 Feb 04. pii: S1567-7249(26)00010-3. [Epub ahead of print]88 102120
    Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia.
    Eunbin Jee, Maisha Medha, Hwayoung Baek, Jonghan Kim, Yuho Kim.
      Friedreich's ataxia (FRDA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein essential for iron-sulfur cluster assembly and iron homeostasis. In addition to neurological symptoms, cardiac dysfunction is common and represents a major cause of premature death in FRDA. Although iron overload has been suggested as a major player for FRDA-related cardiomyopathy, its underlying mechanisms remain unclear. Using heart-specific frataxin deficient mice, we observed that FRDA-related cardiac hypertrophy is accompanied by mitochondrial iron overload. Transmission electron microscopy (TEM) revealed iron aggregates within cardiac mitochondria, whose ultrastructure was severely altered. Along with the iron deposits and structural abnormalities, mitochondrial respiration was markedly impaired in FRDA hearts, despite the absence of increased oxidative stress. Notably, although dysfunctional mitochondria accumulate in parallel with enhanced mitochondrial biogenesis, the clearance of damaged or dysfunctional mitochondria (i.e., mitophagy) is disrupted, as evidenced by excessive accumulation of p62 and Parkin proteins. The lysosomal system, which plays a central role for mitochondrial turnover, appears to be dysregulated via the mTOR-TFEB axis. Hyperactivation mTOR inhibits lysosomal biogenesis and function, although lysosomal content remains unchanged. Collectively, our study provides mechanistic insight into the role of mitochondrial iron aggregates in the pathogenesis of FRDA-related cardiomyopathy and suggests a potential contribution of lysosomal dysfunction to impaired mitochondrial quality control in the context of cardiac frataxin deficiency.
    Keywords:  Cardiomyopathy; Frataxin; Iron overload; Lysosome; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2026.102120
  6. Cell Calcium. 2026 Jan 30. pii: S0143-4160(26)00018-7. [Epub ahead of print]134 103125
    MONNA alleviates MPTP-induced Parkinson's disease in zebrafish by activating TFEB dependently on ER Calcium.
    Meiqin Tang, Ting Luo, Chunlan Kang, Feng Wang, Dongqing Yang, Ruili Cui, Chanjing Li, Yihan Zhang, Yiyao Liu, Min Li, Mei Hu, Ping Li.
      A-synuclein aggregation is a biomarker of Parkinson's disease (PD) whose feature is the progressive loss of dopaminergic neuron in the middle brain. The removal of a-synuclein aggregation through autophagy-lysosome pathway is a promising strategy for PD treatment. Transcription factor EB (TFEB) is a master regulator of autophagic and lysosomal biogenesis and function. Here, we report a library screen of intracellular Ca2+ inducers to identify small-molecule agonists of TFEB and discover MONNA can promote autophagic and lysosomal activity. Notably, MONNA facilitates the reduction of pathological a-synuclein in the Parkinson's disease model both in vitro and in vivo, and ameliorates PD-like behaviors in zebrafish. Mode of action studies reveal MONNA induces TFEB nuclear translocation through a Ca2+-dependent mechanism involving Calcineurin (CaN). Endoplasmic reticulum (ER) but not lysosome Ca2+ is critical to MONNA-induced TFEB activation and autophagy induction. Furthermore, Sarcoendoplasmic reticulum calcium ATPase (SERCA) pump of ER modulates TFEB nuclear translocation induced by MONNA. Our findings demonstrate that MONNA is the first ER Ca2+-dependent small synthetic TFEB agonist promoting the degradation of a-synuclein aggregates and alleviating Parkinson's disease. This ER Ca2+-Calcineurin-TFEB signaling pathway would broaden the way to develop drugs for PD.
    Keywords:  ER Ca(2+); MONNA; Transcription factor EB (TFEB); a-synuclein; autophagy
    DOI:  https://doi.org/10.1016/j.ceca.2026.103125
  7. Autophagy. 2026 Feb 04. 1-19
    PRKN activation for mitophagy requires an NME3-regulated phosphatidic acid signal that separates mitochondria from endoplasmic reticulum tethering.
    Chih-Wei Chen, Ying-Jung Chen, Xiaojing Cuili, Yi-Han Chen, Zee-Fen Chang.
      PINK1-dependent activation of PRKN/parkin on depolarized mitochondria causes mitophagy. The deficiency of NME3, a nucleoside diphosphate kinase/NDPK on the outer mitochondria membrane (OMM), is associated with a fatal neurodegenerative disorder. Here, we report that NME3 deficiency impairs p-S65-ubiquitin (Ub)-dependent PRKN binding on depolarized mitochondria without involving the loss of Ub phosphorylation by PINK1. Our mechanistic investigation revealed that NME3 interacts with PLD6/MitoPLD to generate phosphatidic acid (PA) from cardiolipin on the OMM of damaged mitochondria after depolarization. This lipid signal is essential for positioning MFN2 nearby PINK1 for phosphorylation of Ub conjugates on MFN2, thus enabling the subsequent amplification of PRKN binding to mitochondria. We provide further evidence that mitochondria-endoplasmic reticulum (Mito-ER) tethering prohibits the proximity of MFN2 with PINK1 and PRKN amplification on mitochondria. Importantly, the loss of NME3-regulated PA signal causes Mito-ER tethering. Overall, our findings suggest that NME3 cooperates with PLD6 to generate PA as a critical step in Mito-ER untethering, allowing MFN2 access to PINK1 for p-S65-poly-Ub-dependent feedforward activation of PRKN.Abbreviation ACTB: actin beta; BDNF brain derived neurotrophic factor; CL: cardiolipin; CRISPR: clustered regularly interspaced short palindromic repeats; DAG: diacylglycerol; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone; FRET: Förster resonance energy transfer; IF: immunofluorescence; KO: knockout; KD: knockdown; LPIN1: lipin 1; MERCS: mitochondria-endoplasmic reticulum contact sites; MFN2: mitofusin 2; Mito: mitochondria; OMM: outer mitochondrial membrane; p-Ub: phosphorylated ubiquitin; PA: phosphatidic acid; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PLA: proximity ligation assay; PLD6/MitoPLD: phospholipase D family member 6; PRKN: parkin RBR E3 ubiquitin protein ligase; RA: retinoic acid; RT-qPCR: reverse transcription-quantitative polymerase chain reaction; TEM: transmission electron microscopy; TN-NME3: TOMM20-NΔ-NME3; TOMM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin beta class I; Ub: ubiquitin; VDAC: voltage dependent anion channel; WB: western blot.
    Keywords:  MFN2; NME3; PINK1; PRKN; mitophagy; phosphatidic acid
    DOI:  https://doi.org/10.1080/15548627.2026.2623981
  8. Int J Mol Med. 2026 Apr;pii: 84. [Epub ahead of print]57(4):
    Mechanistic advances in exercise‑mediated regulation of autophagy dysfunction in Alzheimer's disease (Review).
    Wei Li, Wen-Hong Wang, Yi Song, Xu-Jiong Li, Yan Li, Xia Wang, Ting-Ting Tian, Xiao Huang, Li Zhao.
      Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive cognitive decline and whose pathology is closely linked to cellular autophagy dysfunction. Autophagy is a key process involved in cell clearance. Impaired autophagy can drive neuronal damage and death related to AD pathology. Therefore, targeting autophagy dysfunction has emerged as a promising therapeutic strategy. Exercise, as a non‑pharmaceutical and low‑cost intervention method, can enhance autophagy activity and alleviate AD symptoms. However, the mechanism by which it regulates autophagy in AD remains unclear. The present review summarizes evidence that exercise acts as an effective early intervention. Exercise activates key cellular signaling pathways (mammalian target of rapamycin, sirtuin 1 and adiponectin receptor 1) and regulates microRNAs (small non‑coding RNAs) and irisin (a muscle hormone) to restore normal autophagy. The present review also explores the use of exercise combined with natural products for potential synergistic therapeutic effects. This review provides insights into developing new AD prevention and management strategies by detailing how exercise corrects AD‑related autophagy dysfunction.
    Keywords:  Alzheimer's disease; autophagy dysfunction; exercise; mechanism
    DOI:  https://doi.org/10.3892/ijmm.2026.5755
  9. J Cell Biol. 2026 Apr 06. pii: e202501207. [Epub ahead of print]225(4):
    Cullin-3 adaptor SHKBP1 inhibits SQSTM1/p62 oligomerization and Keap1 sequestration.
    Lin Luan, Xiaofu Cao, Zijun Xia, Shivanshi Vaid, Manuel D Leonetti, Jeremy M Baskin.
      SQSTM1/p62 is a master regulator of the autophagic and ubiquitination pathways of protein degradation and the antioxidant response. p62 functions in these pathways via reversible assembly and sequestration of additional factors into cytoplasmic phase-separated structures termed p62 bodies. The physiological roles of p62 in these various pathways depend on numerous mechanisms for regulating p62 body formation and dynamics that are incompletely understood. Here, we identify a new mechanism for regulation of p62 oligomerization and incorporation into p62 bodies by SHKBP1, a cullin-3 E3 ubiquitin ligase adaptor, that is independent of its potential functions in ubiquitination. We map an SHKBP1-p62 protein-protein interaction outside of p62 bodies that limits p62 assembly into p62 bodies and affects the antioxidant response involving sequestration of Keap1 and nuclear translocation of Nrf2. These studies provide a non-ubiquitination-based mechanism for an E3 ligase adaptor in regulating p62 body formation and cellular responses to oxidative stress.
    DOI:  https://doi.org/10.1083/jcb.202501207
  10. mBio. 2026 Feb 05. e0359525
    Legionella Lem26 functions as an ATG8-activated effector that inhibits host autophagy.
    Kevin R Parducho, Zi Yang, Emily Guinn, Daniel Choi, Shanta Nag, Thomas J Melia, Craig R Roy.
      The intracellular pathogen Legionella pneumophila has evolved multiple effector proteins delivered into host cells by the Dot/Icm Type IVb secretion system that prevents recognition of the vacuole in which it resides by the host autophagy pathway. The number of effectors involved in this process remains unclear. Thus, we conducted a screen in Saccharomyces cerevisiae to identify Legionella effectors that were sufficient to block autophagy. This screen identified the Legionella protein Lem26 as an effector capable of autophagy inhibition. Lem26 production inhibited the recruitment of core autophagy proteins to autophagic targets and prevented the proteolytic processing of autophagy substrates in both yeast and mammalian systems. The Lem26 protein encodes an ADP-ribosyltransferase (ART) domain that was found to be essential for anti-autophagy activity. In vitro studies showed that purified Lem26 was inactive in solution, but the addition of pre-autophagosomal membranes obtained from fractionated mammalian cell lysates stimulated Lem26 ART activity. The addition of synthetic membranes containing lipid-conjugated ATG8 proteins was sufficient to stimulate Lem26 activity in vitro. An ATG8-interacting motif identified in Lem26 was critical for the activation of Lem26. These data establish that Lem26 is a Legionella effector that is recruited and activated upon interaction with autophagic membranes, and this promotes the posttranslational modification of proteins on the autophagic membrane to arrest the autophagy pathway.IMPORTANCEBacterial pathogens have evolved intricate mechanisms to specifically avoid detection by the host autophagy pathway, which is a cell-autonomous innate immune pathway conserved in all eukaryotic organisms. The intracellular pathogen Legionella pneumophila has co-evolved with evolutionarily diverse protozoan hosts for over 100 million years. Thus, these bacteria have devised multiple strategies for evading host autophagy. In this study, we analyzed roughly 300 different Legionella effector proteins for their ability to disrupt autophagy in yeast. The Legionella effector protein Lem26 was found to specifically block autophagy in both yeast and mammalian cells. Biochemical studies revealed that this protein is tightly regulated and is activated upon binding to autophagosomal membranes, which stimulates Lem26 ADP-ribosyltransferase activity and results in the modification of critical autophagy proteins colocalized to these membranes. Thus, Lem26 has evolved the capacity to disrupt host autophagy by proximity labeling of host determinants on autophagosomal membranes, which represents a unique strategy for autophagy inhibition.
    Keywords:  ADP ribosylation; autophagy; bacterial effectors; type IV secretion
    DOI:  https://doi.org/10.1128/mbio.03595-25
  11. Neurosci Lett. 2026 Jan 29. pii: S0304-3940(26)00024-8. [Epub ahead of print] 138526
    Autophagy activation by taurine alleviates prion-induced mitochondrial dysfunction and neurotoxicity.
    Seung-Ok Lee, You-Jin Lee.
      Taurine (2-aminoethanesulfonic acid) is a naturally abundant amino acid known to support mitochondrial stability and neuronal stress resistance; however, its role in prion peptide-induced neurotoxicity has not been established. Here, we investigated whether taurine protects neuronal cells from toxicity induced by the prion protein fragment PrP(106-126) and whether autophagic flux contributes to this effect. Using an in vitro neuroblastoma cell model, we found that taurine pretreatment restored autophagic flux, as reflected by increased LC3-II/LC3-I ratios and reduced p62 accumulation. Taurine also attenuated PrP(106-126)-induced loss of mitochondrial membrane potential and apoptotic cell death. Importantly, inhibition of autophagic degradation with chloroquine prevented these protective effects, supporting a causal role for autophagy. These findings suggest that taurine mitigates prion peptide-mediated mitochondrial dysfunction by restoring autophagic flux in neuronal cells. While limited to a single in vitro model, this study provides foundational evidence that taurine-mediated modulation of autophagy may represent a potential therapeutic avenue for protein misfolding-related neurodegenerative disorders.
    Keywords:  Autophagy; Mitochondria; Neurotoxicity; Prion; Taurine
    DOI:  https://doi.org/10.1016/j.neulet.2026.138526
  12. bioRxiv. 2026 Jan 23. pii: 2026.01.21.699761. [Epub ahead of print]
    Reduced late endosome/lysosome function promotes SLE through chronic PI3k activity and SHP-1/SHIP-1 defects.
    SunAh Kang, Andrew J Monteith, Liubov Arbeeva, Karissa Grier, Shruti Saxena-Beem, Anthony C Trujillo, Xinyun Bi, Kai Sun, Rebecca E Sadun, Mithu Maheswaranathan, Megan Eb Clowse, Saira Z Sheikh, Jennifer L Rogers, Barbara J Vilen.
      Degradation of cellular waste from phagocytosis, endocytosis and autophagy occurs through hydrolases that become activated during acidification of late endosomes and lysosomes (LELs). In a cross-sectional study we show diminished LEL acidification and the accumulation of surface-bound nucleosome on monocytes, dendritic cells, and B cells from SLE patients. Diminished acidification and exocytosis of undegraded IgG-ICs is evident in active, but not inactive disease. This is supported by our murine study where LEL acidification is diminished, promoting exocytosis and the accumulation of cell surface IgG-immune complexes. Mechanistically, LEL dysfunction is induced by chronic PI3k activation in lupus-prone MRL/ lpr mice. We also show that on a non-autoimmune C57BL/6 background, deficiency in SHP-1 and inhibition of SHIP-1 activity is sufficient to recapitulate LEL dysfunction found in MRL/ lpr mice. Non-acidic LELs are evident in 67% of patients, and associate with SLEDAI arthritis, rash, and nephritis. The high frequency of LEL dysfunction in SLE suggests it could serve as a biomarker identifying a specific disease endotype.
    DOI:  https://doi.org/10.64898/2026.01.21.699761
  13. Essays Biochem. 2026 Feb 02. pii: EBC20253048. [Epub ahead of print]69(5):
    Cis or trans: a puzzle of Parkin activation mechanism.
    Mohini Sherawat, Ankit Kumar, Dipti Ranjan Lenka, Atul Kumar.
      The PARK2 gene, which encodes the E3 ubiquitin ligase Parkin, and the PARK6 gene, encoding phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), are frequently mutated in patients with Parkinson's disease (PD). Parkin is normally maintained in an autoinhibited conformation, and its activation is triggered by PINK1-mediated phosphorylation of both ubiquitin or NEDD8 and Parkin's ubiquitin-like (Ubl) domain. This review provides a comprehensive overview of the models proposed over the past decade to explain Parkin's autoinhibition and activation. We summarize key structural and biophysical studies that have progressively uncovered the molecular basis of Parkin activation, tracing the evolution of these insights. This review concludes by discussing the intriguing and still unresolved question of whether Parkin activation occurs through a cis or trans mechanism and outlines future directions for research aimed at understanding these pathways.
    Keywords:  PINK1; Parkin; Parkinson’s; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1042/EBC20253048
  14. Life Sci Alliance. 2026 Apr;pii: e202503347. [Epub ahead of print]9(4):
    Cyclic stretch induces autophagy-mediated focal adhesion remodeling and activates mitochondria.
    Lukas Lövenich, Bahareh Rahimi, Henrique Baeta, Maithreyan Kuppusamy, Moritz Walkenbach, Frederik Rastfeld, Georg Dreissen, Ronald Wein, Jörg Höhfeld, Rudolf Merkel, Pitter F Huesgen, Bernd Hoffmann.
      Mammalian cells are continuously exposed to internally generated or externally applied mechanical stimuli. Mechanosensitive proteins enable cells to sense mechanical stress and induce protective mechanisms like autophagy and cytoskeletal reorientation. However, how these contribute to cellular and tissue adaptations remains largely unknown. Here, we studied the response of rat smooth muscle cells (A7r5) to uniaxial cyclic stretch. Stretching induced autophagy and adaptive actin fiber reorientation. Inhibiting autophagy using chloroquine or expressing a Bag3 (T285D-S289D) phosphosite mutant that impairs chaperone-assisted selective autophagy (CASA) delayed reorientation. Proteomic analysis revealed a depletion of cytoskeletal and focal adhesion proteins after stretching, which was attenuated by autophagy inhibition. Stretching caused a reduction in focal adhesion (FA) size, and the remodeled FAs reoriented perpendicularly to the strain direction. Concurrently, prolonged stretching activated mitochondria, and inhibiting mitochondrial ATP synthesis slowed actin reorientation, suggesting that mitochondrial activity supports the mechanoresponse. Our findings highlight the role of autophagy and mitochondria in the structural remodeling of cells upon adaptation to mechanical stress.
    DOI:  https://doi.org/10.26508/lsa.202503347
  15. ACS Sens. 2026 Feb 03. XXX
    Visualizing PINK1 Activity Dynamics in Single Cells with a Phase Separation-Based Kinase Activity Reporter.
    Katie G Vineall, Alexia Andrikopoulos, Michael J Sun, Anna Yan, Ethan R Hartanto, Danielle L Schmitt.
      Phosphatase and tensin homologue-induced kinase 1 (PINK1) is a serine/threonine kinase that plays roles in mitophagy, cell death, and regulation of cellular bioenergetics. Current approaches for studying PINK1 function depend on bulk techniques that can only provide snapshots of activity and could miss the dynamics and cell-to-cell heterogeneity of PINK1 activity. Therefore, we sought to develop a novel PINK1 kinase activity reporter to characterize PINK1 activity. Taking advantage of the separation of phase-based activity reporter of kinase (SPARK) design, we developed a phase separation-based PINK1 biosensor (PINK1-SPARK). With PINK1-SPARK, we observe real-time PINK1 activity in single cells treated with mitochondria-depolarizing agents or pharmacological activators. We then developed a HaloTag-based PINK1-SPARK for multiplexed imaging of PINK1 activity with live-cell markers of mitochondrial damage. Thus, PINK1-SPARK is a new tool that enables temporal measurement of PINK1 activity in single live cells, allowing for further elucidation of the role of PINK1 in mitophagy and cell function.
    Keywords:  PINK1; biosensor; fluorescence; kinase activity reporter; mitophagy
    DOI:  https://doi.org/10.1021/acssensors.5c03859
  16. Nat Commun. 2026 Jan 30. 17(1): 1257
    Covalent modification of a glutamic acid inspired by HaloTag technology.
    Ruirui Zhang, Jie Liu, Raphael Gasper, Anke Unger, Farnusch Kaschani, Markus Kaiser, Petra Janning, Herbert Waldmann.
      For targeted covalent protein modification at low-reactivity aspartates and glutamates, new methods are in high demand. We report a technique inspired by the HaloTag technology, which employs nucleophilic substitution at chloroalkane-functionalised ligands by a specific aspartate residue. Embedding of alkyl bromide warheads into non-covalent inhibitors enables covalent modification of a glutamate in the lipoprotein binding chaperone - phosphodiesterase of retinal rod subunit delta (PDEδ), which shuttles prenylated lipoproteins between cellular membranes and thereby mediates their activity. Its hydrophobic ligand-binding pocket contains p.E88 as the only accessible nucleophile for covalent targeting. We show that a covalent inhibitor, termed DeltaTag, overcomes limitations of non-covalent inhibitors. DeltaTag labels PDEδ at its p.E88 under biologically relevant conditions, modulates mammalian target of rapamycin (mTOR) signalling by disrupting the PDEδ-Rheb (Ras homologue enriched in brain)-mTORC1 (mTOR complex 1) axis and inhibits cancer cell proliferation. This proof-of-concept study demonstrates that the design strategy holds promise for the covalent modification of proteins with lipophilic binding sites that lack accessible reactive amino acids but contain specific carboxylates.
    DOI:  https://doi.org/10.1038/s41467-026-68999-9
  17. PLoS Pathog. 2026 Feb;22(2): e1013932
    A novel SO2 probe inhibits lysophagy induced by Senecavirus A infection by promoting LAMP1 Cys375 sulfenylation.
    Shuo Wang, WenWen Han, BaoXiang Zhao, Ye Hong, Jun Li, JunYing Miao, ZhaoMin Lin.
      Lysophagy plays a key role in maintaining autophagy homeostasis, but the induction and regulation mechanisms of lysophagy are not clear. In this study, we found that Senecavirus A (SVA) dramatically decreased lysosomal-associated membrane protein 1(LAMP1), significantly increased lysosomal permeability, and induced lysophagy. We demonstrated that the SO2 probe (2-(4-(dimethylamino-) phenyl)1,1, 3-trimethyl-1h-benzo [e] indole-3-ium, DLC) could inhibited the degradation of LAMP1 and reduced lysophagy caused by SVA infection. DLC directly binds to LAMP1, and enhanced sulfenylation modification of LAMP1 at Cys375 to inhibit non-lysine ubiquitination. Finally, we verified the antiviral effects of DLC in cells and in BALB/c mice. Taken together, our study lays the foundation for the identification of SVA infection targets and the development of antiviral drugs in the future.
    DOI:  https://doi.org/10.1371/journal.ppat.1013932
  18. bioRxiv. 2026 Jan 19. pii: 2026.01.17.700056. [Epub ahead of print]
    Cathepsin-dependent amyloid formation drives mechanical rupture of lysosomal membranes.
    Delong Li, Wenxin Zhang, Michaela Medina, Jan F M Stuke, Andre Schwarz, Jonas Brill, Johann Brenner, Felix Kraus, Simon Ohlerich, Javier Lizarrondo, Jeremy Pflaum, Julia H Grass, Lena-Marie Soltow, Dietmar Hammerschmid, Natalie Weber, Sonja Welsch, Julian D Langer, Maike Windbergs, J Wade Harper, Erin Schuman, Gerhard Hummer, Danielle A Grotjahn, Florian Wilfling.
      Lysosomal membrane integrity is essential for cellular homeostasis, and its failure drives lysosomal storage disorders (LSD) and neurodegeneration. The dipeptide L-leucyl-L-leucine methyl ester (LLOMe) is widely used to model lysosomal damage, yet its mechanism remains poorly understood. The prevailing view holds that LLOMe polymerizes into membrane-permeabilizing peptide chains within the lysosomal lumen. Using cryo-electron tomography in cultured cells and primary neurons, we visualized the structural basis of LLOMe-induced lysosomal damage. We reveal that LLOMe forms amyloid structures within lysosomes that directly interact with and rupture the limiting membrane through mechanical stress. In vitro reconstitution confirms this amyloid-mediated mechanism. These findings establish a structural paradigm for lysosomal membrane disruption and provide insights into how disease-relevant protein aggregates, implicated in neurodegeneration and LSD, may compromise lysosomal integrity.
    DOI:  https://doi.org/10.64898/2026.01.17.700056
  19. Autophagy. 2026 Feb 02.
    Mitochondrial transplantation ameliorates rheumatoid arthritis by targeting abnormal CGAS-STING1 signaling activation, autophagosome accumulation, and necroptosis.
    A Ram Lee, Jin Seok Woo, Seon-Yeong Lee, Yonghee Shin, Su Been Jeon, Yuseung Jo, Haeyoun Choi, Sung-Hwan Park, Taewook Kang, Mi-La Cho.
      Mitochondrial damage in fibroblast-like synoviocytes (FLSs) is a key factor involved in the development and progression of rheumatoid arthritis (RA). In this study, we investigated the role of mitochondrial dysfunction of FLSs in the pathogenesis of RA. We induced inflammation by stimulating FLSs with TNF and IL17. Then, we transplanted fresh mitochondria into stimulated FLSs and evaluated the mitochondrial and lysosomal functions, macroautophagic/autophagic activity, and the STING1-associated cell death pathway. Next, we transplanted mitochondria or gold nanoparticle-conjugated mitochondria (GNP-Mito) into collagen-induced arthritis (CIA) mice and evaluated their therapeutic effects in vivo. Mitochondrial and lysosomal activities were decreased and autophagosomes accumulated in the stimulated FLSs. Furthermore, the STING1 signaling pathway and STING1-associated cell death were increased in the inflammatory condition. Mitochondrial transplantation into stimulated FLSs enhanced the mitochondrial and lysosomal activities and activated the autophagic activity, as demonstrated by decreased numbers of autophagosomes and increased numbers of autolysosomes. Mitochondrial transplantation decreased and increased the Th17 and Treg populations, respectively. Mitochondrial function and autophagic activity were enhanced by mitochondrial transplantation. Taken together, our results demonstrate that mitochondrial dysfunction in FLSs plays a pivotal role in the pathophysiology of RA and mitochondrial transplantation has therapeutic potential for RA development and progression.
    Keywords:  Autophagy; CGAS-STING1; lysosome; mitochondria; rheumatoid arthritis (RA)
    DOI:  https://doi.org/10.1080/15548627.2026.2619283
  20. Life Sci Alliance. 2026 Apr;pii: e202503527. [Epub ahead of print]9(4):
    TBK1 activity regulates the directionality of axonal transport of signalling endosomes.
    David Villarroel-Campos, Jose Norberto S Vargas, Martin Wallace, Kai Sun, James N Sleigh, Pietro Fratta, Giampietro Schiavo.
      The polarised and complex morphology of neurons poses massive challenges for efficient cargo delivery between the axon and soma, a process termed axonal transport. We have previously shown that the retrograde axonal transport of pro-survival, neurotrophic signalling endosomes relies on Rab7 in motor neurons, and that their trafficking is impaired in the early stages of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we report the effect of Rab7 phosphorylation on the transport of these signalling endosomes. We show that the ALS-linked kinase TBK1 phosphorylates Rab7 at S72 in neurons, altering its binding to cytoplasmic dynein adaptors. Accordingly, both TBK1 knockdown and the expression of a loss-of-function Rab7 mutant (S72E) induce aberrant bidirectional movement of signalling endosomes without modifying neuronal polarity or endosomal sorting. This alteration is specific for signalling endosomes, as axonal transport of lysosomes and mitochondria remains unaffected. We have therefore discovered a new TBK1 function that ensures the unidirectional transport of signalling endosomes, suggesting that reduced TBK1 activity determines retrograde transport dysfunctions and long-range signalling impairments.
    DOI:  https://doi.org/10.26508/lsa.202503527
  21. Cell Rep. 2026 Jan 29. pii: S2211-1247(25)01686-9. [Epub ahead of print]45(2): 116914
    HRD1 negatively regulates autolysosome formation by inhibiting liquid-liquid phase separation of SNAP29.
    Wenyan Qu, Di Chen, Hongyu Zhao, Qiang Sheng, Juan Wang, Yujun Shen, Yuxian Shen.
      Autophagy is a highly conserved cellular process in which cytoplasmic contents are sequestrated by autophagosomes and delivered to lysosomes for degradation. Generation of degradative autolysosomes mediated by SNARE proteins is essential; however, the regulatory mechanisms governing this process remain underexplored. This study aimed to demonstrate that E3 ubiquitin ligase HRD1 regulates liquid-liquid phase separation (LLPS) of SNAP29, thereby modulating SNARE assembly. We found that HRD1 deficiency enhances autophagy activity and promotes autolysosome formation in a SNAP29-dependent manner. We also determined that SNAP29 forms highly dynamic condensates in in vivo and in vitro, which are crucial for the assembly of the SNARE complex. Mechanistically, HRD1 interacts with SNAP29 to suppress its condensation, whereas HRD1 depletion accelerates both SNAP29 condensate formation and SNARE complex assembly. Our findings reveal that HRD1 acts as a negative regulator in autolysosome formation by interacting with SNAP29, inhibiting its LLPS process, thereby modulating the binding affinity among SNARE components.
    Keywords:  CP: Cell biology; HRD1; SNAP29; SNARE assembly; autolysosome; liquid-liquid phase separation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116914
  22. Life Sci. 2026 Jan 28. pii: S0024-3205(26)00046-9. [Epub ahead of print]389 124238
    Loss of Galectin-3 in the epidermis exacerbates psoriasis pathogenesis via inhibiting autophagy.
    Shanshan Han, Meiqi Cheng, Shengtao Jiang, Pei Liu, Yue Hu, Qiong Wang, Yu Cai, Yinhong Song, Xuan Xia, Yuxin Wang, Yang Li, Jin Chao, Decheng Wang.
       AIMS: Galectin-3 (Gal3) is linked to psoriasis pathophysiology, however, the detailed mechanism of Gal3 involved in this course still needs further addressing. This study aimed to elucidate the role of Gal3 in psoriasis.
    MATERIALS AND METHODS: Imiquimod (IMQ)-induced psoriasis model in wild-type (WT) as well as Gal3 knockout (Gal3-/-) mice were established to investigate the impact of Gal3 expression on the development of psoriasis. Autophagy markers LC3 and P62 (SQSTM1) were detected. In vitro, HaCaT cells with Gal3 knockdown were established to detect the effect on the autophagic flux. Then the Sirt1 agonist SRT1720 was used to demonstrate whether Gal3 affects autophagy via Sirt1. The regulation of Sirt1 by Gal3 was demonstrated through half-life experiments.
    KEY FINDINGS: Gal3 was significantly reduced in the epidermis in IMQ-induced psoriasis model. The skin inflammation in Gal3-/- mice more severe than that in WT controls. A deficiency of Gal3 not only reduced the autophagy in psoriatic lesions of the mice model but also effectively inhibited autophagy in a cultured HaCaT cell model. Gal3 was demonstrated to be involved in the assembly of autophagosomes by regulating autophagic flux. In Gal3-depleted mouse skin and HaCaT cells, Sirt1 was downregulated, and SRT1720 could compensate for the impaired autophagy caused by Gal3 deficiency. Gal3 may be involved in the regulation of Sirt1 protein stability.
    SIGNIFICANCE: Gal3 loss exacerbates psoriasis by impairing the autophagic process. These findings position Gal3 as a key protective factor against psoriasis, providing new insights into its role in the pathogenesis of this disease.
    Keywords:  Autophagy; Galectin-3; Pathogenesis; Psoriasis; Sirt1
    DOI:  https://doi.org/10.1016/j.lfs.2026.124238
  23. Free Radic Biol Med. 2026 Jan 29. pii: S0891-5849(26)00077-8. [Epub ahead of print]
    Growth arrest-specific 6 rejuvenates senescent HUCMSCs through upregulating Nrf2 for diabetic wound therapy.
    Xiaofang Zhao, Chengyun Liu, Bei Song, Haohui Fan, Ting Liu, Xueke Guang, Guangyu Gao, Xinyue Zhang, Quan Zhou, Jingqiong Hu, Kun Wang, Weilin Lu.
      Diabetic foot ulcers, ranked as the most severe complications of diabetes, frequently demonstrate a limited response to conventional treatment modalities. Mesenchymal stem cells (MSCs) constitute a prospective regenerative strategy for diabetic wound healing. However, MSCs expanded ex vivo exhibit vulnerability to proliferative aging, thus limiting translational utility. Growth arrest-specific 6 (GAS6) is known to play multiple roles in various cell and tissue repair processes. This research delineates GAS6's impact on MSCs senescence and associated intracellular signaling pathways, while assessing its ability to augment aged MSCs regenerative capacity in diabetic wound healing. GAS6 significantly improved the aging phenotype of MSCs, while siGAS6 led to the aging of MSCs. GAS6 regulated the degradation of Keap1 through the p62-dependent autophagy pathway, thereby promoting the nuclear entry of Nrf2 to exert an anti-aging effect. Meanwhile, it was verified that GAS6 regulated Keap1 and Nrf2 by activating the PI3K/Akt pathway, thus delaying the aging of MSCs. The angiogenic capacity of aging MSCs-derived conditioned medium (MSCs-CM) was improved by GAS6 through the upregulation of Nrf2, which was verified at both cellular and animal levels. GAS6 promoted the accumulation of p62 by activating the PI3K/Akt signaling pathway. p62 bound to Keap1, promoted the degradation of Keap1, and competitively inhibited Keap1's binding to Nrf2, thereby reducing the ubiquitination and degradation of Nrf2. Ultimately, Nrf2 accumulated in the cell and translocated to the nucleus, where it bound to antioxidant genes and exerted an effect of delaying the senescence of MSCs. Additionally, GAS6 improved the angiogenic capacity of aging MSCs-CM by upregulating Nrf2.
    Keywords:  Diabetic wound healing; GAS6; Mesenchymal stem cells; Nrf2; Senescence
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.057
  24. Cell Death Discov. 2026 Feb 05.
    Mitophagy in pancreatic cancer: mechanistic insights and implications for novel therapeutic strategies.
    Zhefang Wang, Zicheng Lyu, Raphael Palmen, Qi Bao, Felix Popp, Qiongzhu Dong, Christiane J Bruns, Yue Zhao.
      Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges, primarily due to its propensity for developing resistance to therapeutic interventions. While the underlying mechanisms remain elusive, they are closely associated with mitochondrial adaptation in response to treatment. Mitophagy, a selective subtype of autophagy that eliminates damaged or surplus mitochondria, is crucial for tumorigenesis, progression, and treatment resistance in cancers. This review discusses the intricate regulatory pathways of mitophagy in PDAC, focusing on the PINK1/Parkin pathway and receptor-mediated pathways. Furthermore, it explores the therapeutic potential of targeting mitophagy to increase the effectiveness of existing treatments and improve patient survival. Current evidence indicates that combining mitophagy inhibition with conventional chemotherapy yields promising yet inconsistent results, which may be attributed to the context-dependent functions of mitophagy and a lack of specific inhibitors. This review highlights the therapeutic potential of targeting mitophagy in PDAC and underscores the necessity for biomarker-driven patient stratification and the development of pathway-specific modulators in future clinical efforts.
    DOI:  https://doi.org/10.1038/s41420-026-02948-9
  25. FEBS J. 2026 Feb 04.
    Proteostasis of organelles in aging and disease.
    Yara Nabawi, Cansu Doğan, Dunja Petrović, Gülce Perçin, Seda Koyuncu, David Vilchez.
      To maintain proteome integrity within distinct subcellular compartments, cells rely on tightly regulated proteostasis mechanisms, including protein synthesis, folding, trafficking, and degradation. Disruption of these processes leads to the accumulation of damaged proteins and structural changes that progressively compromise organelle function, contributing to aging and age-associated disorders, such as neurodegeneration, cancer, and metabolic dysfunction. Here, we discuss recent insights into how proteostasis influences the integrity and function of specific organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes, as well as membraneless organelles, such as stress granules, processing bodies, the nucleolus, and nuclear speckles. We further discuss how dysfunction in these systems contributes to different hallmarks of aging and disease progression, highlighting potential therapeutic strategies aimed at maintaining organelle homeostasis to promote healthy aging.
    Keywords:  aging; cellular stress responses; membraneless organelles; membrane‐bound organelles; neurodegenerative diseases; organelle dysfunction; protein aggregation; proteostasis; stress granules
    DOI:  https://doi.org/10.1111/febs.70439
  26. Free Radic Biol Med. 2026 Jan 29. pii: S0891-5849(26)00054-7. [Epub ahead of print]246 442-455
    (Pro)renin receptor (PRR) exacerbates diabetic cardiomyopathy by suppressing LRRK2-Mediated mitophagy and promoting senescence.
    Lihui Deng, Boyang Wang, Haipeng Jie, Meitong Liu, Luyao Yu, Shuzhen Wu, Lanlan Wang, Shengnan Li, Xiaohui Hu, Yalin Yu, Guohua Song, Bo Dong.
       BACKGROUND: Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus, leading to significant mortality. The (Pro)renin Receptor (PRR) is implicated in cardiovascular pathology, but its specific role in regulating mitochondrial quality control and cellular senescence in the context of DCM remains poorly understood. This study aimed to elucidate the mechanism by which PRR contributes to myocardial injury in DCM.
    METHODS: DCM was induced in mice using a high-fat diet combined with streptozotocin injection. The function of PRR was investigated in vivo and in high-glucose (HG)-stimulated neonatal rat cardiomyocytes (NRCMs) in vitro using adenoviral vectors for overexpression and knockdown. Cardiac function, myocardial remodeling (fibrosis, hypertrophy), mitophagy, and senescence were assessed using echocardiography, histological and immunofluorescence staining, Western blot, and RT-qPCR. RNA-sequencing was employed to identify downstream targets of PRR, and the protein-protein interaction was validated by co-immunoprecipitation and pull-down assays.
    RESULTS: PRR expression was significantly upregulated in the myocardium of DCM mice and in HG-treated NRCMs. Overexpression of PRR exacerbated cardiac dysfunction, myocardial fibrosis, and hypertrophy, which was associated with impaired mitophagy and increased cellular senescence. Conversely, genetic knockdown of PRR ameliorated these pathological changes. Mechanistically, PRR was found to physically interact with and suppress kinase activity of Leucine-rich repeat kinase 2 (LRRK2). Silencing LRRK2 abolished the protective effects of PRR knockdown, confirming that LRRK2 is a critical downstream mediator of PRR's detrimental effects.
    CONCLUSIONS: PRR exacerbates diabetic cardiomyopathy by suppressing LRRK2, leading to impaired mitophagy and accelerated cellular senescence. The PRR/LRRK2 axis may be a potentially promising and novel therapeutic paradigm for treating DCM, and targeting PRR may represent a possibly promising therapeutic strategy.
    Keywords:  Diabetic cardiomyopathy; LRRK2; Mitophagy; PRR; Senescence
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.036
  27. Nat Rev Drug Discov. 2026 Feb 03.
    Spatiotemporal in vivo protein degradation.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-026-00020-w
  28. Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2513954123
    PLETHORA-autophagy axis activates organ regeneration through ROS modulation.
    Akansha Ganguly, Aabha Humnabadkar, Komal Gautam, Viola Willemsen, Lin Xu, Yasin Dagdas, Kalika Prasad.
      Injury-induced disruption of cellular homeostasis leads to accumulation of stress at sites adjacent to a wound. How do these cells mitigate wound-induced stress and restore cellular homeostasis to promote regeneration? To address this question, we examined the role of autophagy-a conserved quality control pathway that recycles defective cellular components to sustain cellular homeostasis-in facilitating wound repair in plants. We demonstrate that transcriptional activation of autophagy-related gene 8 (ATG8) genes is essential for de novo root regeneration, but dispensable for wound induced callus formation from an excised leaf. Plant-specific transcription factors PLETHORA (PLT) activate the transcription of a subset of ATG8 genes and function nonredundantly in this process. Disrupting the PLT-ATG8 regulatory axis severely impairs organelle turnover, resulting in increased intracellular stress and ectopic accumulation of reactive oxygen species (ROS). PLT-ATG8 mediated positioning of optimal ROS levels promotes the expression of stem-cell regulators for successful de novo root regeneration. Altogether, our findings illustrate how plants utilize kingdom-specific developmental regulators, such as PLTs, to activate evolutionarily conserved pathways, effectively managing wound-induced cellular stress and facilitating organ regeneration.
    Keywords:  PLETHORA; ROS; autophagy; de novo root regeneration; stem cell
    DOI:  https://doi.org/10.1073/pnas.2513954123
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