bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–04–13
fifty-six papers selected by
Viktor Korolchuk, Newcastle University



  1. J Cell Biol. 2025 May 05. pii: e202502030. [Epub ahead of print]224(5):
      Selective autophagy targets specific cellular cargo for degradation. In this issue, Zhao et al. (https://doi.org/10.1083/jcb.202410150) uncovered that Rab GTPases serve as pivotal "autophagy cues" for recruitment of cargo receptors to facilitate mitophagy, lipophagy, and xenophagy, contributing to the precise spatiotemporal regulation of selective autophagy.
    DOI:  https://doi.org/10.1083/jcb.202502030
  2. Autophagy. 2025 Apr 09.
      Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly, with dysfunction of the retinal pigment epithelium (RPE) central to disease pathogenesis. Using our uniquely developed MLST8 (MTOR associated protein, LST8 homolog) knock-in animal model with RPE-specific overexpression, which drives MTOR (mechanistic target of rapamycin kinase) upregulation, we demonstrate that increased MTOR complexes 1 and 2 in the RPE disrupts macroautophagy/autophagy by suppressing autophagosome formation genes and impairing MAP1LC3/LC3 processing. This leads to autophagosome accumulation and defective autolysosome formation, driving RPE dysfunction and AMD-like pathology, including subretinal debris build up and photoreceptor degeneration. Notably, MTOR inhibition with torin1 treatment or CRYBA1 overexpression rescues these defects, restoring autophagy and RPE integrity. Our findings reveal that autophagy disruption mediated by both MTORC1 and MTORC2 drives AMD-like pathology in our mouse model, establishing autophagy regulation as a promising avenue for therapeutic intervention in this vision-threatening disease.
    Keywords:  Age-related macular degeneration; MLST8; MTORC1; MTORC2; autophagy; retinal pigment epithelium
    DOI:  https://doi.org/10.1080/15548627.2025.2491097
  3. Autophagy. 2025 Apr 11. 1-2
      Chaperone-mediated autophagy (CMA) is a selective autophagic pathway that targets specific proteins for lysosomal degradation, playing a crucial role in maintaining cellular homeostasis. Recent research has highlighted the involvement of CMA in aging and age-related diseases, yet its regulation remains complex. The study by Khawaja et al. provides novel insights into the sex-specific and cell-type-specific regulation of CMA during aging. This commentary discusses the key findings of this study, their implications for autophagy and aging research, and potential future directions. Understanding these regulatory mechanisms is essential for developing targeted therapies to combat age-related diseases and promote healthy aging.
    Keywords:  Aging; cell-type-specific; chaperone-mediated autophagy (CMA); lysosome; proteostasis; sex-specific
    DOI:  https://doi.org/10.1080/15548627.2025.2489530
  4. J Cell Biol. 2025 Jun 02. pii: e202411092. [Epub ahead of print]224(6):
      The transmembrane autophagy protein ATG9 has multiple functions essential for autophagosome formation. Here, we uncovered a novel function of ATG-9 in regulating lysosome biogenesis and integrity in Caenorhabditis elegans. Through a genetic screen, we identified that mutations attenuating the lipid scrambling activity of ATG-9 suppress the autophagy defect in epg-5 mutants, in which non-degradative autolysosomes accumulate. The scramblase-attenuated ATG-9 mutants promote lysosome biogenesis and delivery of lysosome-localized hydrolases and also facilitate the maintenance of lysosome integrity. Through manipulation of phospholipid levels, we found that a reduction in phosphatidylethanolamine (PE) also suppresses the autophagy defects and lysosome damage associated with impaired lysosomal degradation. Our results reveal that modulation of phospholipid composition and distribution, e.g., by attenuating the scramblase activity of ATG-9 or reducing the PE level, regulates lysosome function and integrity.
    DOI:  https://doi.org/10.1083/jcb.202411092
  5. J Cell Biol. 2025 May 05. pii: e202410150. [Epub ahead of print]224(5):
      Selective autophagy plays a crucial role in maintaining cellular homeostasis by specifically targeting unwanted cargo labeled with "autophagy cues" signals for autophagic degradation. In this study, we identify Rab GTPases as a class of such autophagy cues signals involved in selective autophagy. Through biochemical and imaging screens, we reveal that human Rab GTPases are common autophagy substrates. Importantly, we confirm the conservation of Rab GTPase autophagic degradation in different model organisms. Rab GTPases translocate to damaged mitochondria, lipid droplets, and invading Salmonella-containing vacuoles (SCVs) to serve as degradation signals. Furthermore, they facilitate mitophagy, lipophagy, and xenophagy, respectively, by recruiting receptors. This interplay between Rab GTPases and receptors may ensure the de novo synthesis of isolation membranes around Rab-GTPase-labeled cargo, thereby mediating selective autophagy. These processes are further influenced by upstream regulators such as LRRK2, GDIs, and RabGGTase. In conclusion, this study unveils a conserved mechanism involving Rab GTPases as autophagy cues signals and proposes a model for the spatiotemporal control of selective autophagy.
    DOI:  https://doi.org/10.1083/jcb.202410150
  6. Mol Cell. 2025 Mar 27. pii: S1097-2765(25)00201-1. [Epub ahead of print]
      Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with diseases like lysosomal storage disorders (LSDs). How lysosomal defects are detected and lysosomal function restored remain incompletely understood. Here, we show that STING mediates a neuroinflammatory gene signature in three distinct LSD mouse models, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi mouse brain tissue revealed that STING also mediates the expression of lysosomal genes that are regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-sequencing (snRNA-seq) analysis show that STING regulates lysosomal gene expression in microglia. Mechanistically, we show that STING activation leads to TFEB dephosphorylation, nuclear translocation, and expression of lysosomal genes. This process requires STING's proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Furthermore, we show that the STING-TFEB axis facilitates lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control mechanism that responds to lysosomal dysfunction.
    Keywords:  Krabbe disease; Niemann-Pick disease; STING; TFEB; innate immunity; lysosomal storage disorder; lysosome repair; neuroinflammation; non-canonical autophagy
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.008
  7. Front Cell Dev Biol. 2025 ;13 1559125
      Lysosomes are dynamic organelles critical for cellular degradation and signaling, safeguarded by a limiting membrane that prevents leakage of harmful contents into the cytoplasm. Upon lysosomal damage, cells deploy defensive mechanisms, including a key process called CASM (conjugation of ATG8 to single membranes), which lipidates ATG8 proteins onto the limiting membrane to support protective pathways. CASM operates through two pathways: VAIL, induced by lysosomal pH changes via V-ATPase and ATG16L1, and STIL, triggered by sphingomyelin exposure and mediated by TECPR1. This review examines CASM's role in lysosomal damage responses, exploring the mechanisms of damaging agents, distinctions between VAIL and STIL, and the downstream effects of decorating lysosomes with ATG8, including effector recruitment for membrane repair or removal.
    Keywords:  Atg8; CASM; STIL; VAIL; atg8ylation; autophagy; lysosome damage
    DOI:  https://doi.org/10.3389/fcell.2025.1559125
  8. Cell Mol Biol Lett. 2025 Apr 07. 30(1): 42
      Ischemia-reperfusion (I/R) injury describes the pathological process wherein tissue damage, initially caused by insufficient blood supply (ischemia), is exacerbated upon the restoration of blood flow (reperfusion). This phenomenon can lead to irreversible tissue damage and is commonly observed in contexts such as cardiac surgery and stroke, where blood supply is temporarily obstructed. During ischemic conditions, the anaerobic metabolism of tissues and organs results in compromised enzyme activity. Subsequent reperfusion exacerbates mitochondrial dysfunction, leading to increased oxidative stress and the accumulation of reactive oxygen species (ROS). This cascade ultimately triggers cell death through mechanisms such as autophagy and mitophagy. Autophagy constitutes a crucial catabolic mechanism within eukaryotic cells, facilitating the degradation and recycling of damaged, aged, or superfluous organelles and proteins via the lysosomal pathway. This process is essential for maintaining cellular homeostasis and adapting to diverse stress conditions. As a cellular self-degradation and clearance mechanism, autophagy exhibits a dualistic function: it can confer protection during the initial phases of cellular injury, yet potentially exacerbate damage in the later stages. This paper aims to elucidate the fundamental mechanisms of autophagy in I/R injury, highlighting its dual role in regulation and its effects on both organ-specific and systemic responses. By comprehending the dual mechanisms of autophagy and their implications for organ function, this study seeks to explore the potential for therapeutic interventions through the modulation of autophagy within clinical settings.
    Keywords:  Apoptosis; Autophagy; I/R injury; Mitophagy; Necroptosis
    DOI:  https://doi.org/10.1186/s11658-025-00713-x
  9. Autophagy Rep. 2025 ;pii: 2464376. [Epub ahead of print]4(1):
      Brain and nervous system functions depend upon maintaining the integrity of synaptic structures over the lifetime. Autophagy, a key homeostatic quality control system, plays a central role not only in neuronal development and survival/cell death, but also in regulating synaptic activity and plasticity. Glutamate is the major excitatory neurotransmitter that activates downstream targets, with a key role in learning and memory. However, an excess of glutamatergic stimulation is pathological in stroke, epilepsy and neurodegeneration, triggering excitotoxic cell death or a sublethal process of excitatory mitochondrial calcium toxicity (EMT) that triggers dendritic retraction. Markers of autophagy and mitophagy are often elevated following excitatory neuronal injuries, with the potential to influence cell death or neurodegenerative outcomes of these injuries. Interestingly, leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two kinases linked to autophagy, mitophagy and Parkinson disease, play important roles in regulating mitochondrial calcium handling, synaptic density and function, and maturation of dendritic spines. Mutations in LRRK2, PINK1, or proteins linked to Alzheimer's disease perturb mitochondrial calcium handling to sensitize neurons to excitatory injury. While autophagy and mitophagy can play both protective and harmful roles, studies in various excitotoxicity and stroke models often implicate autophagy in a pathogenic role. Understanding the role of autophagic degradation in regulating synaptic loss and cell death following excitatory neuronal injuries has important therapeutic implications for both acute and chronic neurological disorders.
    Keywords:  Alzheimer disease; Epilepsy; Glutamate toxicity; Leucine-rich repeat kinase 2; Mitochondrial Na+/Ca2+ exchanger; Mitochondrial calcium uniporter; PTEN-induced kinase 1; Parkinson disease; hypoxia-ischemia; post-synaptic calcium
    DOI:  https://doi.org/10.1080/27694127.2025.2464376
  10. J Mol Biol. 2025 Apr 08. pii: S0022-2836(25)00200-1. [Epub ahead of print] 169134
      Autophagy is a conserved cellular process essential for homeostasis and development that plays a central role in the degradation and recycling of cellular components. Recent studies reveal bidirectional interactions between autophagy and steroid-hormone signaling. Steroids are signaling molecules synthesized from cholesterol that regulate key physiological and developmental processes - including autophagic activity. Conversely, other work demonstrates that autophagy regulates steroid production by controlling the availability of precursor sterol substrate. Insights from Drosophila and mammalian models provide compelling evidence for the conservation of these mechanisms across species. In this review we explore how steroid hormones modulate autophagy in diverse tissues and contexts, such as metabolism and disease, and discuss advances in our understanding of autophagy's regulatory role in steroid hormone production. We examine the implications of these interactions for health and disease and offer perspectives on the potential for harnessing this functionality for addressing cholesterol-related disorders.
    DOI:  https://doi.org/10.1016/j.jmb.2025.169134
  11. bioRxiv. 2025 Mar 25. pii: 2025.03.24.645038. [Epub ahead of print]
      Autophagosomes form from seed membranes that expand through bulk-lipid transport via the bridge-like lipid transporter ATG2. The origins of the seed membranes and their relationship to the lipid transport machinery are poorly understood. Using proximity labeling and a variety of fluorescence microscopy techniques, we show that ATG2A localizes to extra-Golgi ARFGAP1 puncta during autophagosome biogenesis. ARFGAP1 itself is dispensable during macroautophagy, but among other proteins associating to these membranes, we find that Rab1 is essential. ATG2A co-immunoprecipitates strongly with Rab1a, and siRNA-mediated depletion of Rab1 blocks autophagy downstream of LC3B lipidation, similar to ATG2A depletion. Further, when either autophagosome formation or the early secretory pathway is perturbed, ARFGAP1 and Rab1a accumulate at ectopic locations with autophagic machinery. Our results suggest that ATG2A engages a Rab1a complex on select early secretory membranes at an early stage in autophagosome biogenesis.
    Significance Statement: This study elucidates the role of early secretory membranes in autophagosome biogenesis. The authors demonstrate that Rab1/ARFGAP1 positive membranes are essential to autophagy and are recruited to the phagophore assembly site at an early step of autophagosome biogenesis. These membranes interact with the bridge-like lipid transport protein ATG2A and are positive for LC3B and WIPI2, suggesting that Rab1 membranes are a direct source for autophagosome growth.
    DOI:  https://doi.org/10.1101/2025.03.24.645038
  12. Autophagy Rep. 2025 Dec 31. pii: 27694127.2025.2464986. [Epub ahead of print]4(1):
      Viruses adapt and modulate cellular pathways to allow their replication in host cells. The catabolic pathway of macroautophagy, for simplicity referred to as autophagy, is no exception. In this review, we discuss anti-viral functions of both autophagy and select components of the autophagy machinery, and how viruses have evaded them. Some viruses use the membrane remodeling ability of the autophagy machinery to build their replication compartments in the cytosol or efficiently egress from cells in a non-lytic fashion. Some of the autophagy machinery components and their remodeled membranes can even be found in viral particles as envelopes or single membranes around virus packages that protect them during spreading and transmission. Therefore, studies on autophagy regulation by viral infections can reveal functions of the autophagy machinery beyond lysosomal degradation of cytosolic constituents. Furthermore, they can also pinpoint molecular interactions with which the autophagy machinery can most efficiently be manipulated, and this may be relevant to develop effective disease treatments based on autophagy modulation.
    Keywords:  Endosomal damage; interferon; replication organelle; secretory autophagy; virophagy
    DOI:  https://doi.org/10.1080/27694127.2025.2464986
  13. Cell Regen. 2025 Apr 10. 14(1): 14
      Autophagy is a crucial cellular process that facilitates the degradation of damaged organelles and protein aggregates, and the recycling of cellular components for the energy production and macromolecule synthesis. It plays an indispensable role in maintaining cellular homeostasis. Over recent decades, research has increasingly focused on the role of autophagy in regulating adult stem cells (SCs). Studies suggest that autophagy modulates various cellular processes and states of adult SCs, including quiescence, proliferation, self-renewal, and differentiation. The primary role of autophagy in these contexts is to sustain homeostasis, withstand stressors, and supply energy. Notably, the dysfunction of adult SCs during aging is correlated with a decline in autophagic activity, suggesting that autophagy is also involved in SC- and aging-associated disorders. Given the diverse cellular processes mediated by autophagy and the intricate mechanisms governing adult SCs, further research is essential to elucidate both universal and cell type-specific regulatory pathways of autophagy. This review discusses the role of autophagy in regulating adult SCs during quiescence, proliferation, self-renewal, and differentiation. Additionally, it summarizes the relationship between SC aging and autophagy, providing therapeutical insights into treating and ameliorating aging-associated diseases and cancers, and ultimately promoting longevity.
    Keywords:  Adult stem cell; Aging; Autophagy; Cancer; Homeostasis
    DOI:  https://doi.org/10.1186/s13619-025-00224-2
  14. Mol Genet Metab. 2025 Apr 02. pii: S1096-7192(25)00094-0. [Epub ahead of print]145(1): 109103
      Niemann-Pick disease type C (NPC) is an ultra-rare, fatal neurodegenerative disease. It is characterized by lysosomal dysfunction with cytotoxic accumulation of unesterified cholesterol and glycosphingolipids in lysosomes, which causes neurodegeneration and peripheral organ dysfunction. Arimoclomol, an orally available small molecule, is the first FDA-approved treatment for NPC when used in combination with miglustat. Here, we present the results of a series of in vitro studies performed to explore the pathways by which arimoclomol targets the fundamentals of NPC etiology. While the precise cellular interactions of arimoclomol remain unclear, the increased translocation of the transcription factors EB and E3 (TFEB and TFE3) from the cytosol to the nucleus is a key initial step for triggering a cascade of downstream events that can rescue cellular functions. Activation of TFEB and TFE3 raises the expression rates of coordinated lysosomal expression and regulation (CLEAR) genes including NPC1 that are essential for the regulation of lysosomal function. The subsequent upregulation of CLEAR network proteins combined with increased unfolded protein response activation was shown to enlarge the pool of matured NPC1 capable of reaching the lysosome to reduce cholesterol accumulation. By also amplifying expression of CLEAR genes associated with autophagy, arimoclomol has the potential to act on different pathways and improve cell viability independent of NPC1 protein levels and functionality. In summary, the findings presented illustrate how arimoclomol improves lysosomal function and potentially autophagy flux to decrease lipid burden in NPC patient fibroblasts.
    Keywords:  Arimoclomol; CLEAR genes; Lysosomal storage diseases; Niemann-pick disease type C; Transcription factor E3; Transcription factor EB
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109103
  15. Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2411429122
      The Atg8-family proteins, including LC3B (microtubule-associated protein 1 light chain 3 beta), are pivotal for key steps in the autophagy process. Proper regulation of LC3B homeostasis is essential for its function. Although LC3B is modulated by various posttranslational modifications (PTMs), the impact of these modifications on LC3B protein homeostasis remains unclear. Neddylation, a recently identified ubiquitin-like modification, plays diverse biological roles. Here, we identify LC3B as a specific target for neddylation. This modification weakens LC3B's interaction with the ubiquitin E3 ligases VHL and BIRC6, thereby reducing LC3B ubiquitination. Depletion of ubiquitin-conjugating enzyme E2M (UBE2M), the primary E2 enzyme in the neddylation pathway, destabilizes LC3B and suppresses autophagy activity. Heterozygous Ube2m knockout (Ube2m+/-) mice exhibit pronounced aging-like phenotypes, with reduced LC3B expression and impaired autophagy in skin tissues. Our findings demonstrate that LC3B neddylation is vital for maintaining its stability and regulating autophagy flux, offering a potential therapeutic avenue to mitigate aging-related processes.
    Keywords:  LC3B; UBE2M; autophagy; neddylation; skin aging
    DOI:  https://doi.org/10.1073/pnas.2411429122
  16. Pharmacol Rev. 2025 Mar 14. pii: S0031-6997(25)07461-7. [Epub ahead of print]77(3): 100053
      Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.
    DOI:  https://doi.org/10.1016/j.pharmr.2025.100053
  17. Autophagy. 2025 Apr 09.
      Autophagy plays a critical role in colitis-associated colorectal cancer (CAC). However, non-autonomous regulation of macroautophagic/autophagic flux during inflammation remains largely unexplored. Here, we show that F2rl1/Par2 deficiency (F2rl1[ΔIEC]) aggravated azoxymethane-dextran sulfate sodium-induced CAC based on tumor number and burden, promoted autophagy dysfunction characterized by SQSTM1/p62 accumulation and autophagosome-lysosome fusion inhibition in IECs, and reduced lysosomal acidification by suppressing FOXA2-induced V-ATPase ATP6V0E1 transcription. FOXA2 or ATP6V0E1 overexpression rescued autophagy impairment, reactive oxygen species accumulation, and DNA damage induced by F2RL1 deficiency in vitro and in vivo. Neutrophil-derived serine proteases suppressed FOXA2 expression, causing autophagy dysfunction. F2RL1 knockout completely blocked the effects of neutrophil proteases on FOXA2 and ATP6V0E1. The correlation between neutrophil and FOXA2-ATP6V0E1 activities was validated in ulcerative colitis and colorectal carcinoma. Therefore, F2RL1 deficiency in intestinal epithelial cells suppressed FOXA2 expression, leading to V-ATPase-mediated autophagic dysfunction and exacerbating CAC. Neutrophils may contribute to impaired autophagy and promote CAC by inactivating canonical F2RL1/PAR2 signaling via its derived proteases. F2RL1/PAR2 signaling may participate in maintaining intestinal homeostasis via autophagy. These findings provide useful insights into F2RL1/PAR2 and its cleaving serine proteases in CAC and would help in developing new therapeutic strategies for this malignancy.
    Keywords:  Autophagy; F2RL1/PAR2; forkhead box protein A2; gut homeostasis; innate immunity; intestinal epithelium
    DOI:  https://doi.org/10.1080/15548627.2025.2489335
  18. Cell. 2025 Apr 04. pii: S0092-8674(25)00282-X. [Epub ahead of print]
      To maintain tissue homeostasis, many cells reside in a quiescent state until prompted to divide. The reactivation of quiescent cells is perturbed with aging and may underlie declining tissue homeostasis and resiliency. The unfolded protein response regulators IRE-1 and XBP-1 are required for the reactivation of quiescent cells in developmentally L1-arrested C. elegans. Utilizing a forward genetic screen in C. elegans, we discovered that macroautophagy targets protein aggregates to lysosomes in quiescent cells, leading to lysosome damage. Genetic inhibition of macroautophagy and stimulation of lysosomes via the overexpression of HLH-30 (TFEB/TFE3) synergistically reduces lysosome damage. Damaged lysosomes require IRE-1/XBP-1 for their repair following prolonged L1 arrest. Protein aggregates are also targeted to lysosomes by macroautophagy in quiescent cultured mammalian cells and are associated with lysosome damage. Thus, lysosome damage is a hallmark of quiescent cells, and limiting lysosome damage by restraining macroautophagy can stimulate their reactivation.
    Keywords:  aging; endoplasmic reticulum; lysosome; mTOR; macroautophagy; protein aggregates; quiescence
    DOI:  https://doi.org/10.1016/j.cell.2025.03.009
  19. Acta Biochim Biophys Sin (Shanghai). 2025 Apr 10.
      Heart failure may be linked to fluctuations in the rhythm of autophagy in cardiomyocytes throughout the day. Circadian rhythms depend on the regulation of core biological clock proteins, with PER2 playing a crucial role. Our previous research confirmed that the presence of β 1-adrenergic receptor autoantibodies (β 1-AAs) could inhibit myocardial autophagy, leading to cell death and heart failure. However, it remains unclear whether β 1-AA induces cardiac autophagy rhythm disorders by affecting PER2 expression. In this study, we find that β 1-AA disrupts the autophagy rhythm in cardiomyocytes, which is primarily indicated by decreased expression of the autophagy marker protein LC3. β 1-AA disrupts the rhythmic expression of the PER2 protein in myocardial cells, which is manifested mainly by a decrease in PER2 protein expression. Metoprolol is used to verify that the β 1-adrenergic receptor contributes to the reduction in the Per2 protein caused by β 1-AA. Knockdown of Per2 with lentivirus reduces the inhibition of LC3 expression caused by β 1-AA, whereas overexpression of Per2 in cardiomyocytes using lentivirus significantly restores the β 1-AA-induced decrease in LC3 expression. Moreover, mTORC1 activation is found to participate in β 1-AA-induced autophagy inhibition in cardiomyocytes after pretreatment with the mTORC1 inhibitor rapamycin. Furthermore, the decreased expression of the PER2 protein caused by β 1-AA disrupts the myocardial autophagy rhythm by promoting mTORC1 activation through lentiviruses that knock down or overexpress the Per2 gene. This study provides an experimental basis for the precise treatment of cardiovascular diseases from the perspective of biological rhythm.
    Keywords:  PER2; autophagy rhythm; biological clock; mTORC1; β-AA
    DOI:  https://doi.org/10.3724/abbs.2025023
  20. Mol Ther Oncol. 2025 Mar 20. 33(1): 200916
      Neuroblastoma (NB), a devastating pediatric cancer originating from neural crest cells crucial for nervous system development, poses a significant therapeutic challenge. Despite chemotherapy being the primary treatment, approximately 70% of high-risk NB cases develop resistance. Autophagy is vital for neuronal development, balance, and differentiation of neural stem cells into mature neurons. However, the intricate mechanisms governing autophagy and the pivotal genes orchestrating its regulation in NB remain largely elusive. In this study, we first identified Sin3A Associated Protein 30 (SAP30) as a novel regulator of autophagy in NB. Silencing SAP30 inhibits autophagy and disrupts starvation-induced physiological autophagy in NB cells. Conversely, ectopic expression of SAP30 induces autophagy in NB cells under normal or starvation conditions. Mechanistically, SAP30 transcriptionally regulates STX17, a crucial protein involved in autophagosome-lysosome fusion during autophagy. Reduction of SAP30 decreases STX17 expression, hindering its translocation to the autophagic membrane and inhibiting autophagosome-lysosome fusion. SAP30-mediated autophagy enhances cell growth and provides protection in NB cells treated with chemotherapy drugs. Notably, suppressing SAP30 in vivo increases LC3B accumulation, an autophagy marker, along with reduced proliferation markers, both in vivo and in PDX tumors. Therefore, SAP30 emerges as a potential target to enhance NB responsiveness to chemotherapy drugs.
    Keywords:  MT: Novel therapeutic targets and biomarker development special issue; SAP30; autophagosome; autophagy; chemotherapy response; neuroblastoma
    DOI:  https://doi.org/10.1016/j.omton.2024.200916
  21. Dev Cell. 2025 Apr 07. pii: S1534-5807(25)00153-4. [Epub ahead of print]60(7): 979-981
      The PI3K/AKT/mTOR pathway is considered a key therapeutic target in triple-negative breast cancer (TNBC). In this issue of Developmental Cell, Remy et al. challenge this idea by demonstrating that mTORC1 inhibition activates TFEB, promoting MT1-MMP exocytosis, ECM degradation, and increased cell invasion, especially when combined with chemotherapy.
    DOI:  https://doi.org/10.1016/j.devcel.2025.03.006
  22. Int J Biol Macromol. 2025 Apr 07. pii: S0141-8130(25)03485-3. [Epub ahead of print]309(Pt 2): 142933
      Atherosclerosis (AS) is a chronic vascular disorder that is characterized by the thickening and narrowing of arteries due to the development of atherosclerotic plaques. The traditional risk factors involved in AS are obesity, type 2 diabetes (T2D), dyslipidemia, hypertension, and smoking. Furthermore, non-traditional risk factors for AS, such as inflammation, sleep disturbances, physical inactivity, air pollution, and alterations of gut microbiota, gained attention in relation to the pathogenesis of AS. Interestingly, the pathogenesis of AS, is complex and related to different abnormalities of cellular and sub-cellular signaling pathways. It has been illustrated that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (MTOR) pathways are involved in AS pathogenesis. Mounting evidence indicated that AMPK plays a critical role in attenuating the development of AS by activating autophagy, which is impaired during atherogenesis. AMPK has a vasculoprotective effect by reducing lipid accumulation, inflammatory cell proliferation, and the release of pro-inflammatory cytokines, as well as decreasing inflammatory cell adhesion to the vascular endothelium. AMPK activation by metformin inhibits the migration of vascular smooth muscle cells (VSMCs) and AS development. However, the MTOR pathway contributes to AS by inhibiting autophagy, highlighting autophagy as a crucial link between the AMPK and MTOR pathways in AS pathogenesis. The MTOR is a key inducer of endothelial dysfunction and is involved in the development of AS. Therefore, both the AMPK and MTOR pathways play a crucial role in the pathogenesis of AS. However, the exact role of AMPK and MTOR pathways in the pathogenesis of AS is not fully clarified. Therefore, this review aims to discuss the potential role of the AMPK/MTOR signaling pathway in AS, and how AMPK activators and MTOR inhibitors influence the development and progression of AS. In conclusion, AMPK activators and MTOR inhibitors have vasculoprotective effects against the development and progression of AS.
    Keywords:  AMP-activated protein kinase; Atherosclerosis and atherogenesis; Mammalian target of rapamycin; Obesity; Pathogenesis; Type-2 diabetes
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142933
  23. Bone Joint Res. 2025 Apr 07. 14(4): 328-337
       Aims: To evaluate the role of autophagy in primary knee fibroblasts undergoing myofibroblast differentiation as an in vitro model of arthrofibrosis, a complication after total knee arthroplasty characterized by aberrant intra-articular scar tissue formation and limited range of motion.
    Methods: We conducted a therapeutic screen of autophagic-modulating therapies in primary human knee fibroblasts undergoing transforming growth factor-beta 1 (TGF-β1)-mediated myofibroblast differentiation. Autophagy was induced pharmacologically with rapamycin or by amino acid deprivation. Picrosirius red staining was performed to quantify collagen deposition. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were conducted to evaluate fibrotic gene expression levels.
    Results: Rapamycin, an mTOR complex 1 (mTORC1) inhibitor and autophagy inducer, reduced TGF-β1-mediated collagen deposition. Interestingly, we simultaneously report that myofibrogenic genes, including ACTA2, were highly upregulated following rapamycin-TGF-β1 treatment. When autophagy was induced through amino acid deprivation, we demonstrated suppressed extracellular matrix levels, fibrotic gene expression (e.g. ACTA2), and SMAD2 phosphorylation levels in TGF-β1-stimulated fibroblasts.
    Conclusion: Our findings demonstrate that the induction of cellular autophagy suppresses TGF-β1-induced collagen deposition in primary human knee fibroblasts. Taken together, these data suggest that cellular autophagy may be prophylactic against the pathogenesis of arthrofibrosis.
    DOI:  https://doi.org/10.1302/2046-3758.144.BJR-2024-0312.R1
  24. J Cell Biol. 2025 Jun 02. pii: e202406120. [Epub ahead of print]224(6):
      Protein aggregates are degraded by both the autophagy-lysosomal and the ubiquitin-proteasome pathways. Macroautophagy and microautophagy, two forms of the autophagy-lysosomal pathway, are widely conserved across eukaryotes. While macroautophagy has been extensively studied in the context of degradation of protein aggregates, microautophagy remains less explored. Here, we identify the UBAP1-containing ESCRT-I complex and PTPN23 as new regulators for degradation of aggregated proteins through an unbiased genome-wide CRISPR knockout screen, using a cell line expressing tau repeat domain (tauRD) aggregates. ESCRT-I recognizes ubiquitylated tauRD via the UEV domain of TSG101. The accessory protein PTPN23, instead of ESCRT-II, bridges ESCRT-I and ESCRT-III to complete the endosomal microautophagy of ubiquitylated tauRD aggregates. Our results uncover the molecular mechanism underlying the degradation of tau aggregates by endosomal microautophagy.
    DOI:  https://doi.org/10.1083/jcb.202406120
  25. Cell Death Dis. 2025 Apr 08. 16(1): 263
      Cholesterol plays a crucial role in tumor metabolism. Studies have shown that the serum cholesterol level of multiple myeloma (MM) patients significantly decreases, probably owing to the augmented uptake by MM cells. Despite its significance for MM, research on its metabolism within MM is limited. Our analysis of clinical data from 703 newly diagnosed MM patients revealed that low serum cholesterol is associated with poor prognosis, and it stems from the elevated cholesterol consumption by MM cells. By exploring the transcriptome and single-cell RNA-seq data of patients with different cholesterol levels in our center, we identified LRP8 as a key regulator of cholesterol metabolism in MM, which is closely related to prognosis and disease stages. We verified the oncogenic role of LRP8 in vitro and in vivo. Knockdown of LRP8 can facilitate apoptosis and cell cycle arrest in MM cells. Meanwhile, we employed mouse xenograft tumor model to replicate the phenomenon that MM cells with high LRP8 expression consume cholesterol, causing low serum cholesterol. Mechanistically, high LRP8 expression enhances cholesterol utilization and uptake by MM cells; LRP8 inhibition reduces cholesterol absorption, further weakening the activity of the cholesterol-dependent mTORC1 pathway in MM cells and inducing apoptosis. Concurrently, it triggers an upregulation of protective autophagy. Further suppression of autophagy can lead to extensive apoptosis of MM cells. Our study reveals that LRP8 regulates cholesterol metabolism in MM cells and influences the processes of cell apoptosis and autophagy through metabolic-related pathways. LRP8 holds potential as a therapeutic target for MM.
    DOI:  https://doi.org/10.1038/s41419-025-07625-w
  26. Autophagy. 2025 Apr 07.
      STING1 is an essential component of the innate immune defense against a wide variety of pathogens. Whereas induction of type I interferon (IFN) responses is one of the best-defined functions of STING1, our transcriptomic analysis revealed IFN-independent activities of STING1 in macrophages, including transcriptional upregulation of numerous lysosomal and autophagic genes. This upregulation was mediated by the STING1-induced activation of the transcription factors TFEB and TFE3, and led to increased autophagy, lysosomal biogenesis, and lysosomal acidification. TFEB and TFE3 also modulated IFN-dependent STING1 signaling by controlling IRF3 activation. IFN production and cell death were increased in TFEB- and TFE3-depleted iBMDMs. Conversely, TFEB overexpression led to reduced IRF3 activation and an almost complete inhibition of IFN synthesis and secretion, resulting in decreased CASP3 activation and increased cell survival. Our study reveals a key role of TFEB and TFE3 as regulators of STING1-mediated innate antiviral immunity.
    Keywords:  Autophagy; STING1; TFE3; TFEB; immune response; lysosomes
    DOI:  https://doi.org/10.1080/15548627.2025.2487036
  27. J Pathol. 2025 Apr 11.
      Cardiac hypertrophy is an adaptive response of the heart to pathological stimuli that may lead to cardiac dysfunction and heart failure. Histone deacetylase 6 (HDAC6) participates in the progression of multiple cardiovascular diseases, including chronic hypertension, ischemic stroke, and acute cardiac injury. A delicate balance of autophagy regulates heart homeostasis, whereas dysregulated autophagy is involved in myocardial hypertrophy. However, whether HDAC6 participates in pathological cardiac hypertrophy by regulating autophagy remains unclear. In this paper, we report for the first time that HDAC6 is involved in isoproterenol (ISO)-induced pathological cardiac hypertrophy by interacting with and ubiquitinating MAP1LC3B. First, the expression level of HDAC6 was found to be increased in cardiac hypertrophy models induced by ISO. HDAC6 overexpression promoted the expression of hypertrophic genes and enhanced cell surface area. Conversely, HDAC6 inhibition attenuated ISO-induced hypertrophic responses. Mechanistically, HDAC6 promoted hypertrophic responses by negatively regulating autophagy. Furthermore, HDAC6 interacted with MAP1LC3B and mediated its monoubiquitination, thereby contributing to reduced MAP1LC3B levels and impaired autophagy. Inhibition of HDAC6 activity in mice abrogated the hypertrophic effects of ISO by restoring MAP1LC3B expression. In summary, our data demonstrate that HDAC6 participates in ISO-induced cardiac hypertrophy by limiting the availability of MAP1LC3B and suppressing autophagy. © 2025 The Pathological Society of Great Britain and Ireland.
    Keywords:  HDAC6; ISO; MAP1LC3B; autophagy; cardiac hypertrophy; ubiquitination
    DOI:  https://doi.org/10.1002/path.6419
  28. Cell Mol Life Sci. 2025 Apr 09. 82(1): 153
      The haploid, olegenious yeast Rhodosporidium toruloides accumulates intracellular lipids and carotenoids upon metabolic stress. Target of Rapamycin (TOR) signaling, essential for cell proliferation, is known to affect cellular lipid accumulation. In contrast to the conventional surrugate cell model S. cerevisiae, which harbours two TOR kinases within its TOR complex, R. toruloides only harbours one TOR kinase, mimicking mammalian systems. We used a proteomics centered approach to probe the cellular response, of the two R. toruloides haplotypes, IFO0559 and IFO0880 upon treatment with the TOR inhibitor rapamycin, with an original focus on difference in carotenoid and lipid accumulation. Unexpectedly, IFO0880 displayed severe growth arrest in response to rapamycin, while IFO0559 did not. Proteomic anaysis revealed differential expression of several proteins involved in cell cycle control, lipogensis, amino acid metabolism and autophagy between the two haplotypes. Among those we identified several proteins previously described in both mammalian oncogenic and aging contexts. This differential haplotype response to rapamycin treatment positions R. toruloides as a promising cell surrugate model to study cellular mechanisms underlying rapamycin response especially for systems with high lipid contents, an emerging hallmark of different forms of mammalian cancer and age related disease.
    Keywords:  Haplotypes; Rapamycin; Rhodosporidium; Target of rapamycin; Time-resolved proteomics
    DOI:  https://doi.org/10.1007/s00018-025-05662-4
  29. Sci Rep. 2025 Apr 11. 15(1): 12516
      Diabetic retinopathy (DR) is a common complication of diabetes mellitus, characterized by progressive neurodegeneration and vision impairment. The Ca2+/calmodulin-dependent protein kinase II alpha (CaMK2A) and cAMP response element-binding protein (CREB) signaling pathway has been implicated in various neurological disorders. However, its role in DR pathogenesis remains elusive. We established a DR mouse model by streptozotocin administration and performed histological, biochemical, and molecular analyses to investigate the involvement of CaMK2A/CREB signaling and its interplay with mitophagy. Additionally, we employed in vitro high-glucose (HG) treatment in primary mouse retinal ganglion cells to dissect the underlying mechanisms. Pharmacological and genetic modulations were utilized to target CaMK2A/CREB pathway and mitophagy. In the DR model, we observed retinal degeneration, increased apoptosis, and reduced neurotransmitter production, accompanied by enhanced mitophagy and activation of the CaMK2A/CREB pathway. HG induction in retinal ganglion cells recapitulated these findings, and autophagy inhibition partially rescued cell death but failed to suppress CaMK2A/CREB activation, suggesting mitophagy as a downstream consequence. CaMK2A knockdown or CREB phosphorylation inhibition attenuated HG-induced mitophagy, apoptosis, and neurotransmitter depletion, while CREB activation exacerbated these effects. CaMK2A silencing mitigated DR progression, oxidative stress, inflammation, and neuronal loss, akin to dopamine/carbidopa administration in DR mouse model. Our findings reveal the involvement of CaMK2A/CREB signaling activation and enhanced mitophagy in DR, suggesting these pathways may be therapeutically relevant targets for DR management.
    Keywords:  CREB; CaMK2A; Diabetic retinopathy; Mitophagy; Neurodegeneration
    DOI:  https://doi.org/10.1038/s41598-025-97371-y
  30. Nat Commun. 2025 Apr 10. 16(1): 3409
      Mobilisation of Damage-Associated Molecular Patterns (DAMPs) determines the immunogenic properties of apoptosis, but the mechanisms that control DAMP exposure are still unclear. Here we describe an unconventional autophagic pathway that inhibits the release of ATP, a critical DAMP in immunogenic apoptosis, from dying cells. Mitochondrial BAK activated by BH3-only molecules interacts with prohibitins and stomatin-1 through its latch domain, indicating the existence of an interactome specifically assembled by unfolded BAK. This complex engages the WD40 domain of the autophagic effector ATG16L1 to induce unconventional autophagy, and the resulting LC3-positive vesicles contain ATP. Functional interference with the pathway increases ATP release during cell death, reduces ATP levels remaining in the apoptotic bodies, and improves phagocyte activation. These results reveal that an unconventional component of the autophagic burst that often accompanies apoptosis sequesters intracellular ATP to prevent its release, thus favouring the immunosilent nature of apoptotic cell death.
    DOI:  https://doi.org/10.1038/s41467-025-58619-3
  31. Nat Commun. 2025 Apr 09. 16(1): 3312
      Lipid dyshomeostasis and tau pathology are present in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). However, the relationship between lipid dyshomeostasis and tau pathology remains unclear. We report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased in excitatory neurons of human neural organoids (HNOs) with the MAPT R406W mutation. Human FTLD, AD cases, and PS19 tau mice also have increased GRAMD1B expression. We show that overexpression of GRAMD1B increases levels of free cholesterol, lipid droplets, and impairs autophagy flux. Modulating GRAMD1B in iPSC-derived neurons also alters key autophagy-related components such as PI3K, phospho-AKT, and p62, as well as phosphorylated tau, and CDK5R1. Blocking GRAMD1B function decreases free cholesterol and lipid droplets. Knocking down GRAMD1B additionally reduces phosphorylated tau, and CDK5R1 expression. Our findings elucidate the role of GRAMD1B in the nervous system and highlight its relevance to FTLD and AD.
    DOI:  https://doi.org/10.1038/s41467-025-58585-w
  32. Nature. 2025 Apr 09.
      Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders1. As a key modulator of brain homeostasis2, it remains elusive whether and how brain autophagy is engaged in stress dynamics. Here we discover that acute stress activates, whereas chronic stress suppresses, autophagy mainly in the lateral habenula (LHb). Systemic administration of distinct antidepressant drugs similarly restores autophagy function in the LHb, suggesting LHb autophagy as a common antidepressant target. Genetic ablation of LHb neuronal autophagy promotes stress susceptibility, whereas enhancing LHb autophagy exerts rapid antidepressant-like effects. LHb autophagy controls neuronal excitability, synaptic transmission and plasticity by means of on-demand degradation of glutamate receptors. Collectively, this study shows a causal role of LHb autophagy in maintaining emotional homeostasis against stress. Disrupted LHb autophagy is implicated in the maladaptation to chronic stress, and its reversal by autophagy enhancers provides a new antidepressant strategy.
    DOI:  https://doi.org/10.1038/s41586-025-08807-4
  33. EMBO J. 2025 Apr 07.
      Biomolecular condensates are cellular compartments without enveloping membranes, enabling them to dynamically adjust their composition in response to environmental changes through post-translational modifications. Recent work has revealed that interferon-induced ADP-ribosylation (ADPr), which can be reversed by a SARS-CoV-2-encoded hydrolase, is enriched within a condensate. However, the identity of the condensate and the responsible host ADP-ribosyltransferase remain elusive. Here, we demonstrate that interferon induces ADPr through transcriptional activation of PARP14, requiring both the physical presence and catalytic activity of PARP14 for condensate formation. Interferon-induced ADPr colocalizes with PARP14 and its associated E3 ligase, DTX3L. These PARP14/ADPr condensates contain key components of p62 bodies-including the selective autophagy receptor p62, its binding partner NBR1 and the associated protein TAX1BP1, along with K48-linked and K63-linked polyubiquitin chains-but lack the autophagosome marker LC3B. Knockdown of p62 disrupts the formation of these ADPr condensates. Importantly, these structures are unaffected by autophagy inhibition, but depend on ubiquitination and proteasome activity. Taken together, these findings demonstrate that interferon triggers PARP14-mediated ADP-ribosylation in p62 bodies, which requires an active ubiquitin-proteasome system.
    Keywords:  ADP-Ribosylation; Condensates; Interferon; Ubiquitin-Proteasome System; p62
    DOI:  https://doi.org/10.1038/s44318-025-00421-4
  34. Anal Chem. 2025 Apr 08.
      Tracking autophagy in cancer cells is crucial for enhancing cancer therapies. Existing methods are often inefficient and cannot distinguish cancer from normal cells during autophagy. Herein, a sequentially activated peptide probe, NBD-1p-Dabcyl, was developed for achieving cancer cell-specific imaging of autophagy. The probe self-assembled and fluoresced brightly upon sequential processing by alkaline phosphatase (ALP) and autophagy-related protease (ATG4B), where NBD-1p-Dabcyl was dephosphorylated by ALP to give NBD-1-Dabcyl, which was then processed by ATG4B into nanofibers emitting strong fluorescence. Notably, the bright fluorescence of NBD was observed in cancer cells MDA-MB-231 and HeLa, while normal cells NIH3T3 exhibited weaker fluorescence, allowing differentiation between cancer and normal cells using a rapamycin (Rap)-induced autophagy cell model. The enhanced fluorescence in cancer cells was attributed to the higher activities of intracellular ALP and ATG4B. Next, NBD-1p-Dabcyl was used to assess the inhibition efficiency of an autophagy inhibitor NSC 185058 in MDA-MB-231 cells, where a strong correlation between fluorescence intensity and inhibitor concentration suggested that NBD-1p-Dabcyl could predict the activity of autophagy inhibitors. Finally, animal experiments revealed that NBD-1p-Dabcyl effectively facilitated in situ fluorescence imaging of autophagy in tumor tissues. The design of this sequentially activated peptide probe offers a practical approach for monitoring autophagy in cancer cells, enabling high-throughput screening of autophagy inhibitors for cancer therapy.
    DOI:  https://doi.org/10.1021/acs.analchem.4c06950
  35. J Inflamm Res. 2025 ;18 4665-4680
      The Vacuolar Protein Sorting 35 (VPS35)-Retromer complex plays a pivotal role in intracellular protein trafficking and recycling. As an integral component of the Retromer complex, VPS35 selectively recognizes and retrogradely transports membrane protein receptors to the trans-Golgi network, thereby preventing the degradation of transmembrane proteins by lysosomes after they have fulfilled their physiological functions, and facilitating their continued activity. VPS35 regulates autophagy, mitophagy, mitochondrial homeostasis, and various other biological processes, including epidermal regeneration, neuronal iron homeostasis, and synaptic function. Studies have shown that mutations or dysfunctions in VPS35 disrupt the normal operation of Retromer, impair neuronal health and survival, and contribute to the onset of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Additionally, VPS35 modulates tumor growth and metastasis in cancers such as liver and breast cancer through the regulation of multiple signaling pathways. Targeting VPS35 might be a potential therapy in clinic treatment of neurodegenerative diseases and cancers.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; anemia; autophagy; cancer; endosome-lysosome pathway; mitochondrial homeostasis; retinal ganglion cell degeneration; retromer; vacuolar protein sorting 35
    DOI:  https://doi.org/10.2147/JIR.S510768
  36. Autophagy. 2025 Apr 09. 1-12
      LAMP2 is a ubiquitously expressed protein critical for autophagy. Alternative splicing gives rise to three isoforms. However, the roles of major LAMP2 isoforms in the heart are not known. To address this knowledge gap, we generated lamp2a and lamp2b knockout (KO) mice to investigate the role of these isoforms in heart function and autophagy. Deletion of either Lamp2a or Lamp2b did not alter cardiac structure or function. Lack of all LAMP2 isoforms led to increased cardiac fibrosis and reduced survival during pressure overload, which were not observed in lamp2a or lamp2b KO mice. Also, LAMP2B loss did not affect levels of the autophagy markers LC3-II and SQSTM1/p62. Conversely, LAMP2A was upregulated in hearts lacking LAMP2B, potentially preserving autophagy and cardiac function. Reintroducing LAMP2A in lamp2 KO mice effectively reduced autophagosome accumulation and improved cardiac function. Overall, these data support LAMP2 isoform functional redundancy in the myocardium under pathological conditions.Abbreviations: AAV: adeno-associated virus; ACTA2: actin alpha 2, smooth muscle, aorta; CMA: chaperone-mediated autophagy; KO: knockout; LAMP2: lysosomal-associated membrane protein 2; LV: Left ventricle; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NPPA: natriuretic peptide type A; NPPB: natriuretic peptide type B; SQSTM1/p62: sequestosome 1; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; TAC: transverse aortic constriction; WT: wild type.
    Keywords:  Autophagy; LAMP2A; LAMP2B; compensatory mechanism; heart function; mouse model
    DOI:  https://doi.org/10.1080/15548627.2025.2484620
  37. Science. 2025 Apr 11. 388(6743): 204-211
      Variants in GBA1 resulting in decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of GBA1 variants suggests that additional genes contribute to PD and DLB manifestation. By using a pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain-containing 3 (COMMD3) protein, a component of the COMMD/coiled-coil domain-containing protein 22 (CCDC22)/CCDC93 (CCC) and Commander complexes, as a modifier of GCase and lysosomal activity. Loss of COMMD3 increased the release of lysosomal proteins through extracellular vesicles, leading to their impaired delivery to endolysosomes and consequent lysosomal dysfunction. Rare variants in the Commander gene family were associated with increased PD risk. Thus, COMMD genes and related complexes regulate lysosomal homeostasis and may represent modifiers in PD and other neurodegenerative diseases associated with lysosomal dysfunction.
    DOI:  https://doi.org/10.1126/science.adq6650
  38. Autophagy. 2025 Apr 07.
      Adipose tissue macrophages (ATMs) are key cellular components that respond to nutritional excess, contributing to obesity-induced inflammation and insulin resistance. However, the mechanisms underlying macrophage polarization and recruitment in adipose tissue during obesity remain unclear. In this study, we investigated mitophagy-dependent metabolic reprogramming in ATMs and identified a crucial role of the mitophagy receptor BNIP3 in regulating macrophage polarization in response to obesity. Mitophagic flux in ATMs increased following 12 weeks of high-fat diet (HFD) feeding, with Bnip3 levels upregulated in a HIF1A dependent manner, without affecting other mitophagy receptors. Macrophage-specific bnip3 knockout reduced HFD-induced adipose tissue inflammation and improved glucose tolerance and insulin sensitivity. Mechanistically, hypoxic conditions in vitro induced HIF1A-BNIP3-mediated mitophagy and glycolytic shift in macrophages. Furthermore, HIF1A-BNIP3 signaling-enhanced lipopolysaccharide-induced pro-inflammatory activation in macrophages. These findings demonstrate that BNIP3-mediated mitophagy regulates the glycolytic shift and pro-inflammatory polarization in macrophages and suggest that BNIP3 could be a therapeutical target for obesity-related metabolic diseases.
    Keywords:  Adipose tissue macrophages; BNIP3; hypoxia; inflammation; metabolic diseases; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2487035
  39. Cell Death Differ. 2025 Apr 08.
      Hepatic very low-density lipoprotein (VLDL) is essential for maintaining lipid metabolism in the liver. Sphingosine kinases (SphKs) are essential rate-limiting enzymes that catalyze sphingosine phosphorylation to Sphingosine-1-phosphate (S1P). SphKs exist as two isoforms, SphK1 and SphK2, both highly expressed in the liver. SphK1 plays a critical role in regulating hepatic inflammation and drug metabolism. This study aimed to determine whether SphK2 regulates hepatic lipid metabolism, particularly VLDL secretion. Immunohistochemical staining revealed decreased SphK2 protein levels within regions proximal to hepatic lipid accumulation in individuals diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD). Sphk2-/- mice exhibited spontaneous hepatocyte lipid accumulation and reduced VLDL secretion. Proteomic analysis revealed that SphK2 deficiency impaired soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) complex interactions involved in vesicular transport and organelle membrane fusion. Furthermore, SphK2 deficiency results in accelerated degradation of the SEC22B, STX5A, and GS28 proteins via chaperone-mediated autophagy (CMA), impeding VLDL transport to the Golgi apparatus. MYH1485, a specific activator of mTOR, induces mTORC2 phosphorylation, thereby inhibiting the degradation of SNARE complexes by CMA and counteracting the lipid accumulation induced by SphK2 deficiency. Exogenous S1P supplementation markedly reversed the reduction in mTORC2 phosphorylation and suppressed CMA, thereby improving VLDL secretion. Our study elucidates an inventive regulatory mechanism by which SphK2 modulates CMA by activating mTORC2 phosphorylation, promoting VLDL secretion, and balancing lipid metabolism in the liver. These findings provide insights into SphK2 function and the underlying mechanisms involved in the regulation of VLDL secretion, which may facilitate MASLD treatment. Proposed model for the role of SphK2 in hepatic VLDL secretion. In hepatocytes, the inhibition of SphK2 activity decreased S1P production, which subsequently downregulates the mTORC2 pathway. This process accelerates the degradation of the SNARE complex components STX5A, GS28, and SEC22B via CMA, which regulates the mutual recognition between VTVs and the Golgi apparatus, ultimately reducing VLDL secretion in hepatocytes.
    DOI:  https://doi.org/10.1038/s41418-025-01507-6
  40. bioRxiv. 2025 Mar 28. pii: 2025.03.25.645097. [Epub ahead of print]
      Non-canonical conjugation of ATG8 proteins, including LC3, to single membranes implicates the autophagy machinery in cell functions unrelated to metabolic stress. One such pathway is LC3-associated phagocytosis (LAP), which aids in phagosome maturation and subsequent signaling upon cargo uptake mediated by certain innate immunity-associated receptors. Here, we show that a specific isoform of RAB5 GTPases, the molecular switches controlling early endosome traffic, is necessary for LAP. We demonstrate that RAB5c regulates phagosome recruitment and function of complexes required for phosphatidylinositol-3-phosphate [PI(3)P] and reactive oxygen species (ROS) generation by macrophages. RAB5c facilitates phagosome translocation of the V-ATPase transmembrane core, which is needed for ATG16L1 binding and consequent LC3 conjugation. RAB5c depletion impaired macrophage elimination of the fungal pathogen Aspergillus fumigatus and disruption of the V-ATPase-ATG16L1 axis increased susceptibility in vivo . Therefore, early endosome-to-phagosome traffic is differentially regulated to promote LAP and ROS contributes to resistance against A. fumigatus by effecting LAP.
    HIGHLIGHTS: RAB5c is required for LC3-associated phagocytosisRAB5c finetunes NAPDH oxidase assembly and ROS generation in the phagosomeRAB5c regulates V-ATPase assembly on the phagosome RAB5c and V-ATPase-ATG16L1 axis are required for the killing of A. fumigatus.
    DOI:  https://doi.org/10.1101/2025.03.25.645097
  41. Physiol Rev. 2025 Apr 03.
      In 2005, the Arabidopsis thaliana two-pore channel TPC1 channel was identified as a vacuolar Ca²⁺-release channel. In 2009 three independent groups published studies on mammalian TPCs as NAADP-activated endolysosomal Ca2+ release channels, results that were eventually challenged by two other groups, claiming mammalian TPCs to be PI(3,5)P2 activated Na+ channels. By now this dispute seems to have been largely reconciled. Lipophilic small molecule agonists of TPC2, mimicking either the NAADP or the PI(3,5)P2 mode of channel activation, revealed, together with structural evidence, that TPC2 can change its selectivity for Ca2+ versus Na+ in a ligand-dependent fashion (N- versus P-type activation). Furthermore, NAADP-binding proteins, JPT2 and Lsm12 were discovered, corroborating the hypothesis that NAADP activation of TPCs only works in the presence of these auxiliary NAADP-binding proteins. Pathophysiologically, loss or gain of function of TPCs has effects on autophagy, exocytosis, endocytosis, and intracellular trafficking, e.g., LDL cholesterol trafficking leading to fatty liver disease or viral and bacterial toxin trafficking, corroborating roles of TPCs in infectious diseases such as Ebola or Covid19. Defects in trafficking of EGFR and 1-integrin suggested roles in cancer. In neurodegenerative lysosomal storage disease models, P-type activation of TPC2 was found to have beneficial effects on both in vitro and in vivo hallmarks of Niemann- Pick disease type C1, Batten disease, and Mucolipidosis type IV. Here, we cover the latest on structure, function, physiology, and pathophysiology of these channels with a focus initially on plant followed by mammalian TPCs, and we discuss their potential as drug targets, including currently available pharmacology.
    Keywords:  TPC; TPCN1; TPCN2; lysosomal
    DOI:  https://doi.org/10.1152/physrev.00044.2024
  42. J Biol Chem. 2025 Apr 08. pii: S0021-9258(25)00342-4. [Epub ahead of print] 108493
      The endoplasmic reticulum (ER) is the membrane-bound organelle characterized by the reticular network of tubules. It is well established that the ER tubules are shaped by ER membrane proteins containing the conserved reticulon-homology domain (RHD). Membrane shaping by the RHD-containing proteins is also involved in regulation of ER-phagy, selective autophagy of the ER. However, it remains unclear whether there exists ER membrane-shaping proteins other than the RHD-containing proteins. In this study, we characterize Arl6IP5, an ER membrane protein containing the conserved PRA1 domain, as an ER membrane-shaping protein. Upon overexpression, Arl6IP5 induces the extensive network of the ER tubules, and constricts the ER membrane as judged by exclusion of a luminal ER enzyme from the ER tubules. The membrane constriction by Arl6IP5 allows the cells to maintain the tubular ER network in the absence of microtubules. siRNA-mediated knockdown of Arl6IP5 impairs the ER morphology, and the phenotype of the Arl6IP5 knockdown cells is rescued by exogenous expression of Arl6IP1, an RHD-containing protein. Furthermore, exogenous expression of Arl6IP5 rescues the phenotype of Arl6IP1 knockdown cells, and the PRA1 domain is sufficient to rescue it. Upon disruption of the possible short hairpin structures of the PRA1 domain, Arl6IP5 abolishes membrane constriction. The siRNA-mediated knockdown of Arl6IP5 impairs flux of the ER-phagy mediated by FAM134B. These results indicate that Arl6IP5 acts as an ER membrane-shaping protein involved in regulation of ER-phagy, implying that the PRA1 domain may serve as a general membrane-shaping unit other than the RHD.
    Keywords:  autophagy; endoplasmic reticulum (ER); membrane protein; membrane structure; protein domain
    DOI:  https://doi.org/10.1016/j.jbc.2025.108493
  43. Front Pharmacol. 2025 ;16 1564276
      Major depressive disorder, also known as MDD, affects more than 264 million people globally, making it a prevalent and critical health challenge. Traditional treatments show limited efficacy in many patients. Therefore, exploring new treatment methods is particularly crucial. Mitophagy, as a regulatory process, can help understand and treat MDD. This paper focuses on the molecular mechanisms of mitophagy, starting from proteins and related pathways, and its role in MDD. The study also explores the associations between mitophagy and neuroinflammation, oxidative stress, neurotransmitter synthesis, and neuroplasticity in MDD and discusses the progress of clinical research on the role of mitophagy in MDD. In addition, the article describes the current pharmaceutical and non-pharmaceutical interventions that can regulate mitophagy in MDD and unravels the potential and challenges of these therapeutic strategies in clinical settings. This article offers a deeper insight into the pathogenesis of MDD and offers a scientific basis for the development of new treatment strategies.
    Keywords:  major depressive disorder; mitophagy; mitophagy-related pathways; mitophagy-related proteins; therapeutic potential
    DOI:  https://doi.org/10.3389/fphar.2025.1564276
  44. Ann Neurol. 2025 Apr 07.
       OBJECTIVE: Despite substantial advancements in uncovering the genetic basis of Parkinson's disease (PD), a significant portion of cases characterized by familial PD remain genetically elusive. Here, we reported that biallelic variants in EPG5, a key autophagy gene responsible for Vici syndrome, are associated with PD.
    METHODS: Whole-exome sequencing (WES) was performed in the first cohort including 171 pedigrees with autosomal recessive PD (ARPD), 1,746 cases of sporadic early-onset PD (sEOPD, age at onset ≤ 50 years) and 1,652 healthy controls. Whole-genome sequencing (WGS) was performed in the second cohort consisting of 1,947 sporadic late-onset PD (sLOPD, age at onset >50 years) and 2,478 healthy controls.
    RESULTS: We identified 7 participants harboring compound heterozygous variants within the EPG5 gene across 1 family with ARPD (ARPD-F1), 4 sporadic EOPD cases, and 1 sporadic LOPD individual. A total of 10 novel variants in EPG5 were discovered in the 7 individuals, comprising 3 nonsense variants and 7 missense variants. The compound heterozygous variants in the EPG5 gene led to decreased expression of EPG5 protein, and impaired autophagy-lysosome function in cells derived from EPG5-PD individuals. We also revealed several key pathological features, including abnormal accumulation of autophagic vacuoles, aggregation of α-synuclein in skin tissue from EPG5-PD individuals. In mice, EPG5 deficiency led to progressive dopaminergic neurodegeneration in the substantia nigra of the midbrain.
    INTERPRETATION: Our results unveil a novel association between biallelic variants in EPG5 gene and PD, providing compelling initial evidence for the involvement of EPG5 and autophagy dysregulation in the development of PD. ANN NEUROL 2025.
    DOI:  https://doi.org/10.1002/ana.27242
  45. G3 (Bethesda). 2025 Apr 10. pii: jkaf074. [Epub ahead of print]
      It is understood that nutrient availability significantly impacts cellular growth and metabolism. The genetic basis for survival in nutrient-limited conditions, however, is not as thoroughly explored. The identification and description of the genes vital for growth in these conditions would therefore enhance the understanding of the signaling and biochemical pathways and processes crucial for cellular survival and growth under these constraints. A growth screen of a gene-deletion library representing 4934 genes of Saccharomyces cerevisiae was completed to discover genes required for normal growth under sulfur- and nitrogen-limited conditions. Genes were identified as required under these restrictive environments based on a comparison to their growth in a synthetic, defined control medium. After normalization and statistical analysis, 732 genes were noted as essential in sulfur-limited medium, and 761 genes were found for nitrogen-limited medium, with an overlap of 313 genes found to be needed in both, significantly more than expected by chance. KEGG and gene ontologies were analyzed to investigate those processes involved. Proteins identified act in central metabolism and in metabolism of amino acids, glycerolipids, glycerophospholipids, and vitamins as well as in the pathways of MAPK and phosphatidylinositol signaling and the processes of vesicle trafficking, autophagy, mitophagy, and endocytosis. Of these, the metabolism and signaling of phosphatidylinositols are not frequently identified in screens examining nutrient starvation in yeast, nor are vesicular fusion, endocytosis, or trafficking to the early endosome, as we have discovered here. This study invites further exploration into the roles of these processes in adaptation to nutrient stress.
    Keywords:   Saccharomyces cerevisiae ; autophagy; endosome; intracellular sorting; knockout screen; limited nutrients; nitrogen; pathway analysis; phosphatidylinositol; sulfur; vesicular transport
    DOI:  https://doi.org/10.1093/g3journal/jkaf074
  46. Nat Cell Biol. 2025 Apr 10.
      Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease. Here we show that VPS13C, a bridge-like lipid-transport protein and a Parkinson's disease gene, is a sensor of lysosome stress or damage. Following lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. Although another Parkinson's disease protein, LRRK2, is also recruited to stressed or damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage.
    DOI:  https://doi.org/10.1038/s41556-025-01653-6
  47. Nat Commun. 2025 Apr 12. 16(1): 3483
      Grafting is an agricultural technique that joins tissues from different plants to obtain useful rootstock traits. However, cellular processes involved in joint tissue repair remain poorly understood. We analyzed Nicotiana benthamiana (Nb) and Arabidopsis thaliana (At) interfamily heterografting as a high-stress model and At homografting as a low-stress model. Transmission electron micrographs reveal the formation of autophagic structures in cells near the graft boundary over a long period in Nb/At interfamily grafts and in a short period of a few days in At homografts. Using a GFP-ATG8 marker line, the autophagosomes were observed in the cells near the graft boundary, especially on the scion side, where nutrient depletion occurred. Grafting of At autophagy-defective mutants decreases grafting success rates and post-grafting growth. NbATG5 knockdown suppresses graft establishment in Nb/At interfamily heterografts. Moreover, At autophagy-defective mutants show reduced callus formation directed to wounds under the nutrient-deficient conditions. These results suggest that autophagy is induced during grafting, promoting callus formation and contributing to tissue connectivity.
    DOI:  https://doi.org/10.1038/s41467-025-58519-6
  48. Clin Transl Med. 2025 Apr;15(4): e70289
       BACKGROUND: The lung is the organ most commonly affected by sepsis. Additionally, acute lung injury (ALI) resulting from sepsis is a major cause of death in intensive care units. Macrophages are essential for maintaining normal lung physiological functions and are implicated in various pulmonary diseases. An essential autophagy protein, autophagy-related protein 16-like 1 (ATG16L1), is crucial for the inflammatory activation of macrophages.
    METHODS: ATG16L1 expression was measured in lung from mice with sepsis. ALI was induced in myeloid ATG16L1-, NLRP3- and STING-deficient mice by intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Using immunofluorescence and flow cytometry to assess the inflammatory status of LPS-treated bone marrow-derived macrophages (BMDMs). A co-culture system of BMDMs and MLE-12 cells was established in vitro.
    RESULTS: Myeloid ATG16L1-deficient mice exhibited exacerbated septic lung injury and a more intense inflammatory response following LPS treatment. Mechanistically, ATG16L1-deficient macrophages exhibited impaired LC3B lipidation, damaged mitochondria and reactive oxygen species (ROS) accumulation. These abnormalities led to the activation of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), subsequently enhancing proinflammatory response. Overactivated ATG16L1-deficient macrophages aggravated the damage to alveolar epithelial cells and enhanced the release of double-stranded DNA (dsDNA), thereby promoting STING activation and subsequent NLRP3 activation in macrophages, leading to positive feedback activation of macrophage NLRP3 signalling. Scavenging mitochondrial ROS or inhibiting STING activation effectively suppresses NLRP3 activation in macrophages and alleviates ALI. Furthermore, overexpression of myeloid ATG16L1 limits NLRP3 activation and reduces the severity of ALI.
    CONCLUSIONS: Our findings reveal a new role for ATG16L1 in regulating macrophage NLRP3 feedback activation during sepsis, suggesting it as a potential therapeutic target for treating sepsis-induced ALI.
    KEY POINTS: Myeloid-specific ATG16L1 deficiency exacerbates sepsis-induced lung injury. ATG16L1-deficient macrophages exhibit impaired LC3B lipidation and ROS accumulation, leading to NLRP3 inflammasome activation. Uncontrolled inflammatory responses in ATG16L1-deficient macrophages aggravate alveolar epithelial cell damage. Alveolar epithelial cells release dsDNA, activating the cGAS-STING-NLRP3 signaling pathway, which subsequently triggers a positive feedback activation of NLRP3. Overexpression of ATG16L1 helps mitigate lung tissue inflammation, offering a novel therapeutic direction for sepsis-induced lung injury.
    Keywords:  ATG16L; NLRP3 inflammasome; STING; acute lung injury; macrophages
    DOI:  https://doi.org/10.1002/ctm2.70289
  49. J Cell Sci. 2025 Apr 11. pii: jcs.263651. [Epub ahead of print]
      Peroxisome proliferator-activated receptors (PPARs), such as PPARδ, are transcription factors that play a pivotal role in energy and fat metabolism. PPARδ activates genes involved in lipid and glucose metabolism and is expressed in various human tissues, including all brain regions and especially neurons, where it regulates lipid homeostasis and contributes to neuroprotection. However, the precise molecular mechanisms underlying these protective effects remain poorly understood. Here, we identify the Caenorhabditis elegans nuclear hormone receptor NHR-85 as a putative orthologue of human PPARδ. Furthermore, we show that NHR-85 functions as an essential regulator of fat and energy metabolism, with significant impact on mitochondrial homeostasis, at least in part through modulation of mitophagy. Finally, we find that NHR-85 prevents α-synuclein aggregation in a nematode model of Parkinson's disease, suggesting that it may play a protective role in neurodegenerative diseases. Our results indicate that NHR-85 is a functional orthologue of PPARδ and support the use of C. elegans as a powerful in vivo model for dissecting PPARδ-related metabolic and neurodegenerative processes.
    Keywords:  Fat metabolism; Mitochondrial homeostasis; Mitophagy; NHR-85; α-synuclein
    DOI:  https://doi.org/10.1242/jcs.263651
  50. iScience. 2025 Apr 18. 28(4): 112118
      Macroautophagy is thought to have a critical role in shaping and refining cellular proteostasis in eukaryotic cells recovering from DNA damage. Autophagy activation has been previously reported in DNA-damaged cells, often in association with increased cellular cytotoxicity. However, we now report a mechanism by which autophagy is suppressed in the absence of cytotoxicity within cells exposed to bacterial toxin-, chemical-, or radiation-mediated sources of genotoxicity. Specifically, our studies demonstrate the DNA damage response-dependent stabilization of the tumor suppressor p53, which is both required and sufficient for regulating the ubiquitination and proteasome-dependent reduction in cellular pools of microtubule-associated protein 1 light chain 3 (LC3A/B), a key precursor of autophagosome biogenesis and maturation, in both epithelial cells and an ex vivo organoid model. Our data indicate that the suppression of autophagy, through a p53-proteasome-LC3 regulatory axis, is a conserved cellular response to multiple sources of genotoxicity. Such a mechanism could provide a means for realigning proteostasis in cells undergoing DNA damage repair.
    Keywords:  biological sciences; cell biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112118
  51. Cell Death Differ. 2025 Apr 06.
      Mutations in the tumor suppressor gene Folliculin (FLCN) are responsible for Birt-Hogg-Dube' (BHD) syndrome, a rare inherited condition that predisposes affected individuals to skin tumors, pulmonary cysts, and kidney tumors. FLCN regulates key cellular pathways, including TFEB, TFE3, and mTORC1, which are critical for maintaining cell homeostasis. Loss of FLCN leads to both hyperactivation of mTORC1 and constitutive activation of TFEB and TFE3, contributing to tumorigenesis. While previous studies showed that Flcn liver-specific conditional knockout (FlcnLiKO) mice are protected from developing liver fibrosis and damage upon high-fat diet exposure, the potential role of FLCN loss in liver carcinogenesis remained unexplored. Here, we demonstrate that hepatic loss of FLCN in mice results in cancer associated with inflammation and fibrosis with features of cholangiocarcinoma (CCA). This phenotype emerges in mice over 90-week-old, with a male predominance. Moreover, FlcnLiKO mice are more prone to develop diethylnitrosamine (DEN)- or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- induced liver tumors with heterogenous histological features. Notably, depletion of TFE3, but not TFEB, in the liver of FlcnLiKO mice fully rescues the cancer phenotype and normalized mTORC1 signaling, highlighting TFE3 as the primary driver of liver cancer and mTORC1 hyperactivity in the absence of FLCN.
    DOI:  https://doi.org/10.1038/s41418-025-01486-8
  52. Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00188-1. [Epub ahead of print]85(7): 1258-1259
      Cancer cells subvert the immune system by reprogramming their metabolism. In a recent study in Nature, Ikeda et al.1 show how cancer cells can directly transfer mitophagy-resistant mitochondria to tumor-infiltrating lymphocytes, promoting their homoplasmic replacement and undermining cancer immunity.
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.026
  53. Metab Brain Dis. 2025 Apr 07. 40(4): 172
      Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease (PD). In a previous study, we reported that an extract of T. cordifolia (TCE) possessed antioxidant and anti-apoptotic properties that improved mitochondrial function against rotenone-induced neurotoxicity. However, the underlying molecular mechanism remains unclear. In this study, we found that rotenone (ROT)-induced PD mice exhibited mitochondrial abnormalities, including defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression, and mitochondrial fragmentation, accompanied by reduced expression of Pink1 and Parkin and increased apoptosis. These changes were partially reversed following oral administration of TCE. Moreover, TCE restored the activity and translocation of NF-E2-related factor 2 (Nrf2) and upregulated the expression of antioxidant enzymes (SOD1, SOD2, GSH, and GSSH). Interestingly, ROT also activates mitophagy. Our results suggest that ROT toxicity can cause neuronal cell death through mitophagy-mediated signaling in PD mice. However, TCE reversed this activity by inhibiting autophagic protein (LC3B-II/LC3B-I) activation and increasing specific mitochondrial proteins (TOM20, Pink1, and Parkin). Our findings indicated that TCE provides neuroprotection against rotenone-induced toxicity in PD mice by stimulating endogenous antioxidant enzymes and inhibiting ROT-induced oxidative stress by potentiating the Nrf-2/Pink1/Parkin-mediated survival mechanism.
    Keywords:   T. cordifolia ; Mitochondrial dysfunction.; Mitophagy; Nrf-2; Oxidative stress; PINK1/Parkin
    DOI:  https://doi.org/10.1007/s11011-025-01595-w
  54. bioRxiv. 2025 Mar 29. pii: 2025.03.26.645567. [Epub ahead of print]
      Shoc2 is a scaffold protein critical for regulating Raf-1 kinase activation and the amplitude of ERK1/2 signals. Hereditary Shoc2 mutations result in Noonan Syndrome with Loose anagen Hair (NSLH), a debilitating congenital disorder associated with lymphatic abnormalities. We demonstrate that zebrafish Shoc2 null larvae exhibit nearly a complete loss of lymphatic vasculature, suggesting that the Shoc2 gene plays a critical positive role during developmental lymphangiogenesis. The loss of lymphatics caused by Shoc2 deficiency can be rescued by endothelial autonomous expression of Shoc2, confirming its in vivo functional requirement in lymphatic endothelial cells. Shoc2 loss in primary human lymphatic endothelial cells promotes Raptor-mTOR binding and enhances mTORC1 signaling activity. Increased mTORC1 signaling leads to impaired mitochondrial respiration, IRF/IFN-induced signaling, and cell senescence. Notably, expression of the NSLH Shoc2 mutant S2G phenocopies Shoc2 loss, resulting in mTOR activation and increased IFN response. Together, these studies demonstrate the critical role of Shoc2 in lymphangiogenesis and establish a mechanistic link between Shoc2 signaling, mitochondrial function, and lymphangiogenesis, with potential implications for Ras-pathway-related congenital disorders.
    DOI:  https://doi.org/10.1101/2025.03.26.645567
  55. Drug Discov Today. 2025 Apr 04. pii: S1359-6446(25)00064-9. [Epub ahead of print] 104351
      The aberrant expression of the trans-active response DNA-binding protein of 43 kDa (TDP-43) has been closely associated with amyotrophic lateral sclerosis (ALS). Cytoplasmic inclusions containing TDP-43 can be found in the brain and spinal cord in up to 97% of ALS cases. Mutations in the TARDBP gene promote the nuclear export of TDP-43, increase cytoplasmic aggregation, and predispose TDP-43 to post-translational modifications. Cleavage of TDP-43 and the resulting C- and N-terminal fragments also contribute to the development of ALS. Cellularly, the resulting impairment of autophagy and mitochondria aggravates cellular damage and neurodegeneration. Given the contribution of pathogenic TDP-43 to the development of ALS, elucidating the mechanisms related to TDP-43 will facilitate finding therapeutic targets for the disease.
    Keywords:  TARDBP gene; TDP-43; amyotrophic lateral sclerosis; autophagy; neurodegeneration
    DOI:  https://doi.org/10.1016/j.drudis.2025.104351