bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–03–15
34 papers selected by
Viktor Korolchuk, Newcastle University
  1. The Roles of SQSTM1/p62 in Selective Autophagy and Oncogenic Signaling.
  2. Kenny is the adaptor protein for ubiquitin-dependent mitophagy in Drosophila melanogaster.
  3. Autophagy in ocular diseases: from mechanisms to therapeutic potential.
  4. PDCoV NSP5 cleaves the selective autophagy receptor CCDC50 to disrupt autophagic degradation of the viral envelope protein.
  5. Neutralization of DBI/ACBP for the prevention of ciliopathy-associated obesity.
  6. TANK-binding kinase 1 protects against MASH progression via mitochondrial quality control.
  7. Reversible one-way lipid transfer at ER-autophagosome membrane contact sites via Atg2.
  8. TBK1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: Mechanistic Insights into Impaired Autophagy and Proteostatic Failure.
  9. FUNDC1-dependent mitophagy determines axon regeneration capacity.
  10. Time-resolved functional genomics using deep learning reveals global hierarchical control of autophagy.
  11. Impaired α-Synuclein aggregate clearance in neuronal cells drive their spread to microglia through tunneling nanotubes.
  12. Hsv2, a yeast PROPPIN, drives bulk and selective microautophagy.
  13. The interplay between mitophagy and ferroptosis in Alzheimer's disease: Mechanisms and therapeutic implications.
  14. Tuberous sclerosis complex.
  15. Interplay Between Autophagy, Cellular Senescence, and Brain Aging: Neuroprotective Implications of Intermittent Fasting.
  16. TG2 (transglutaminase 2) promotes PINK1/Parkin-dependent mitophagy in pulmonary hypertension by regulating the TRPC6.
  17. Crosstalk Between Autophagy and Paraptosis: A New Frontier in Cancer Therapy.
  18. Mechanoresilience of lysosomes conferred by TMEM63A.
  19. Impaired mitophagy contributes to osteogenesis and mineralization disorders in fibrous dysplasia.
  20. USP14 inhibitor IU1 alleviates amyloid-β mediated toxicity in Alzheimer's disease cell and worm models.
  21. Distinct TRAPP complexes activate Ypt/Rab GTPases in secretion and autophagy.
  22. Loss of DDI2 rewires proteostasis through CCN1-driven compensatory autophagy.
  23. ORMDL Proteins Turnover via Proteasome and Autophagy Is Cell-Type Dependent and Tied to Ceramide Homeostasis.
  24. Mitochondrial quality in aging and neurodegeneration: The emerging role of mitochondria-derived vesicles.
  25. Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy.
  26. A lysosomal requiem for glioblastoma cells.
  27. Lipophagy fuels phosphatidylcholine synthesis for Newcastle disease virus replication.
  28. Mechanistic Modulation of Autophagy by Bioactive Natural Products: Implications for Human Aging and Longevity.
  29. Autophagolysosomal exocytosis inverts Src kinase onto the cell surface in cancer.
  30. Glycative Stress Disrupts the Mitochondrial-Lysosome Axis and Promotes Geroconversion in Aging Cardiomyocytes.
  31. Sirtuin 2 inhibits global protein synthesis via Rheb-GTPase degradation.
  32. Quantifying Lysosomal Degradation of Extracellular Proteins With a Fluorescent Protein-Based Internalization Assay.
  33. ATG9B Regulates Mitochondrial Integrity and Apoptotic Tumor Cell Death.
  34. Restriction of Individual Branched-Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice.
  1. Int J Mol Sci. 2026 Mar 02. pii: 2342. [Epub ahead of print]27(5):
    The Roles of SQSTM1/p62 in Selective Autophagy and Oncogenic Signaling.
    Young-Jun Kim, Hwa-Hyeong Lee, Tae Young Jung, Young-Hoon Jeong, Key-Hwan Lim, Ji Min Han.
      Autophagy is a critical cellular mechanism that regulates the degradation of misfolded and aggregated proteins and non-functional intracellular organelles. Based on the fundamental qualities of the substrates targeted for degradation and the distinct molecular mechanisms involved, autophagy can be classified into three major types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Sequestosome 1 (SQSTM1)/p62, which functions as a signaling hub integrating nuclear factor kappa B (NF-κB), the mechanistic target of rapamycin complex 1 (mTORC1), and Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (NRF2) pathways, serves as a selective macroautophagy/autophagy receptor that binds ubiquitinated cargo proteins and recruits them to the autophagosome for subsequent degradation in the autolysosome. Furthermore, the phase separation of p62 is an important regulatory process in the autophagy mechanism, but recent studies have demonstrated that impaired or excessive autophagy mediated by p62 is associated with cancer development. This review summarizes the role of autophagy-including its types, mechanisms, and the pathway related to the ubiquitin-dependent selective autophagy receptor p62-in cancer progression.
    Keywords:  autophagy; cancer; oncogene; p62; ubiquitin
    DOI:  https://doi.org/10.3390/ijms27052342
  2. Autophagy Rep. 2026 ;5(1): 2638025
    Kenny is the adaptor protein for ubiquitin-dependent mitophagy in Drosophila melanogaster.
    Hubert Osei Acheampong, Ryan Insolera.
      Mitophagy is the selective degradation program for damaged and unnecessary mitochondria to maintain cellular mitostasis and survival. Specific mutations in the mediators for the canonical ubiquitin (ub)-dependent mitophagy pathway have been identified with unique neurological diseases like Parkinson disease and ALS (amyotrophic lateral sclerosis), metabolic diseases, and cancer. Mammalian OPTN (optineurin) has been shown as a SAR (selective autophagy receptor) for ub-dependent mitophagy in vitro with direct connections of its mutations with glaucoma and ALS. Despite the in vitro demonstration of OPTN's role in mitophagy, the in vivo physiological characterization of OPTN's mitophagy function is largely unexplored. In our recent study, we provide in vivo evidence that the Drosophila melanogaster (Dm) protein, Kenny, directly mediates the sequestration of target mitochondria for the progression and completion of ub-dependent mitophagy. This result establishes Kenny as the Dm homolog of OPTN. Previously, Kenny had only been characterized for its role in innate immune activation and modulation. The conclusion from this study provides avenues for further understanding the in vivo signaling regulating Kenny's role in mitophagy and investigating homologous disease-relevant mutations of OPTN in Dm.
    Keywords:  ALS; Kenny; VPS13D; autophagosome; autophagy; mitochondria; mitophagy adaptor; optineurin; phagophore; ubiquitin
    DOI:  https://doi.org/10.1080/27694127.2026.2638025
  3. Front Cell Dev Biol. 2026 ;14 1727005
    Autophagy in ocular diseases: from mechanisms to therapeutic potential.
    Qi Zhao, Yumeng Lin, Zhongyu Han, Yiwei Tian, Yaqi Yang, Qiaoyin Gou, Yuan Ju, Duoduo Xu, Lijuan Wei.
      Autophagy represents a fundamental and evolutionarily preserved mechanism of degradation and metabolism in eukaryotic cells. This process is triggered by a variety of stressors, including nutrient deprivation, energy deficits, protein misfolding, low oxygen levels, and pathogen infections by pathogens. Autophagy plays a vital role in maintaining cellular equilibrium. The process of vision is notably complex, making the eye one of the most metabolically active tissues in the human body. The proper function of the eye relies on the preservation of metabolic homeostasis and the structural integrity of organelles within various types of cells, including those found in the cornea, lens, retina, and optic nerve. As a result, any disruption in autophagy is closely linked to numerous ocular conditions. This review meticulously examines and elucidates the role of autophagy in ophthalmic diseases and explores its involvement in disease progression and treatment strategies, with the aim of presenting potential therapeutic approaches and a foundational framework for future research into the management of ophthalmic disorders.
    Keywords:  autophagy; corneal disease; glaucoma; mitophagy; retina
    DOI:  https://doi.org/10.3389/fcell.2026.1727005
  4. mBio. 2026 Mar 12. e0025926
    PDCoV NSP5 cleaves the selective autophagy receptor CCDC50 to disrupt autophagic degradation of the viral envelope protein.
    Ke Li, Hongyun Wei, Kangli Zhao, Dong Chen, Yu Sun, Peng Zhou, Hui Jin, Anan Jongkaewwattana, Sizhu Suolang, Dang Wang, Hongbo Zhou, Rui Luo.
      Selective autophagy is a critical host defense mechanism that eliminates viral components through lysosomal degradation during coronavirus infection. Coronaviruses (CoVs), however, deploy countermeasures that disrupt this process, and several underlying mechanisms remain unresolved. Here, we identify the autophagy receptor CCDC50 as a substrate of the coronavirus-encoded NSP5 protease. During porcine deltacoronavirus (PDCoV) infection, NSP5 cleaves CCDC50 at glutamine 171 (Q171), a conserved site also processed by NSP5 from PEDV, TGEV, and SARS-CoV-2. Functionally, CCDC50 restricts PDCoV replication by recognizing the envelope (E) protein when it is modified with K63-linked polyubiquitin at lysine 72 (K72) and routing it for autophagic degradation, independently of canonical receptors such as SQSTM1/p62 and NBR1. NSP5-mediated cleavage disrupts CCDC50 interaction with LC3 and ubiquitin, reduces its capacity to target E for degradation, and thereby compromises its antiviral activity. Taken together, our study identifies CCDC50 as a previously uncharacterized antiviral autophagy receptor in coronavirus infection and reveals that PDCoV circumvents this defense through NSP5-mediated cleavage to promote productive infection.IMPORTANCEIn our study, we investigated the interplay between host autophagy pathways and coronavirus infection. We identified the selective autophagy receptor CCDC50 as a potent antiviral factor that suppresses porcine deltacoronavirus (PDCoV) replication. We demonstrated that CCDC50 specifically recognizes the viral envelope (E) protein and targets it for autophagic degradation, thereby restricting the virus. However, we also uncovered a sophisticated viral escape mechanism. We found that PDCoV's main protease, NSP5, cleaves CCDC50 directly at a specific residue, glutamine 171. This proteolytic event impairs the ability of CCDC50 to interact with ubiquitin and the core autophagy machinery, effectively neutralizing its antiviral function and promoting viral replication. Significantly, we determined this to be a highly conserved strategy among coronaviruses. Our findings show that the NSP5 proteases of other divergent coronaviruses, including PEDV, TGEV, and even SARS-CoV-2, all target the same conserved site in CCDC50. These results reveal a common mechanism that coronaviruses use to subvert selective host autophagy.
    Keywords:  CCDC50; NSP5; PDCoV; cleavage; selective autophagy
    DOI:  https://doi.org/10.1128/mbio.00259-26
  5. Autophagy. 2026 Mar 11. 1-3
    Neutralization of DBI/ACBP for the prevention of ciliopathy-associated obesity.
    Yaiza Corral Nieto, Guido Kroemer, José Manuel Bravo-San Pedro.
      Obesity is a feature of only a subset of ciliopathies, including Alström syndrome, a rare genetic disorder caused by ALMS1 deficiency. In our recent work, we applied integrative multi-omics network analysis to one of these ciliopathies that develop with obesity, the Alms1-deficient mouse model and identified DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) as a central driver of ciliopathy-associated obesity. We found that ALMS1 deficiency induces early hepatic dyslipidemia accompanied by impaired macroautophagy/autophagy and pathological accumulation of DBI/ACBP, preceding overt obesity. Importantly, prophylactic DBI/ACBP neutralization with monoclonal antibodies prevents weight gain and metabolic alterations without restoring autophagic markers, indicating that DBI/ACBP acts as an obesogenic effector downstream of, or parallel to, defective autophagy. These findings position DBI/ACBP as a metabolically relevant autophagy-associated regulator in ciliopathy and suggest that therapeutic benefit can be achieved by targeting autophagy-linked effectors without directly correcting autophagic flux. This punctum discusses our results in the context of hepatic autophagy and lipid metabolism, highlighting DBI/ACBP as a mechanistic link between ciliary dysfunction, altered autophagy, and metabolic disease.
    Keywords:  ALMS1; DBI/ACBP; autophagy; cilia; obesity
    DOI:  https://doi.org/10.1080/15548627.2026.2643410
  6. Exp Mol Med. 2026 Mar 13.
    TANK-binding kinase 1 protects against MASH progression via mitochondrial quality control.
    Sung-Min An, Jun Hee Jang, Jin Hyun Sung, Ji Won Myung, Yong Geun Jeon, Won Taek Lee, Jin Won Jeon, Kyung Min Yim, Jae-Ho Lee, Bichen Zhang, Jong Bae Seo, Seung Soon Im, Jae Bum Kim, Alan R Saltiel, Jin Young Huh.
      Mitochondrial dysfunction is a critical driver of metabolic dysfunction-associated steatotic liver disease progression to steatohepatitis (MASH), yet the mechanisms governing mitochondrial quality control in hepatocytes remain poorly defined. Here we identify TANK-binding kinase 1 (TBK1) as an essential regulator of hepatic mitophagy and lysosomal activity. Using TBK1-deficient hepatocytes and liver-specific TBK1-knockout mice, we show that TBK1 loss leads to the accumulation of depolarized, reactive oxygen species-producing mitochondria due to impaired mitophagy flux, including defective lysosomal degradation. Mechanistically, TBK1 is required for p62 phosphorylation at Ser403 and partially modulates mTOR signaling to preserve lysosomal activity. Notably, both human samples and murine steatohepatitis models exhibited a substantial decline in TBK1 kinase activity. Therapeutic restoration of TBK1 expression via AAV8 delivery in MASH mouse model enhanced mitophagy, reduced mitochondrial burden and ameliorated liver fibrosis. Collectively, these findings establish TBK1 as a critical guardian of mitochondrial and lysosomal homeostasis in MASH.
    DOI:  https://doi.org/10.1038/s12276-026-01672-9
  7. J Cell Biol. 2026 May 04. pii: e202506039. [Epub ahead of print]225(5):
    Reversible one-way lipid transfer at ER-autophagosome membrane contact sites via Atg2.
    Li Hao, Tomoki Midorikawa, Yuta Ogasawara, Takuma Tsuji, Takuma Kishimoto, Yutaro Hama, Huichao Lang, Nobuo N Noda, Kuninori Suzuki.
      Bridge-like lipid transfer proteins (LTPs) contain a repeating β-groove domain and long hydrophobic grooves that act as bridges at membrane contact sites (MCSs) to efficiently transfer lipids. Atg2 is one such bridge-like LTP essential for autophagosome formation, during which a newly synthesized isolation membrane (IM) emerges and expands through lipid supply. However, studies on Atg2-mediated lipid transfer are limited to in vitro studies due to the lack of a suitable probe for monitoring phospholipid dynamics in vivo. Here, we characterized the lipophilic dye octadecyl rhodamine B (R18), which internalizes and labels the endoplasmic reticulum (ER) in a manner that requires flippases and oxysterol-binding protein-related proteins. Using R18, we demonstrated phospholipid transfer from the ER to the IM during autophagy in vivo. Upon autophagy termination, our data suggested the reversible phospholipid flow from the IM to the ER in response to environmental changes. Our findings highlight the critical role of bridge-like LTPs in MCS-mediated phospholipid homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202506039
  8. Cells. 2026 Mar 06. pii: 477. [Epub ahead of print]15(5):
    TBK1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: Mechanistic Insights into Impaired Autophagy and Proteostatic Failure.
    Francesca Manganelli, Camilla Perfetto, Olga Carletta, Valeria Gerbino.
      Mutations in the TANK-binding kinase 1 (TBK1) gene represent a significant genetic link across the Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) spectrum. As a multifunctional serine/threonine kinase, TBK1 serves as a central orchestrator of the autophagy-lysosome pathway, regulating critical stages from initial cargo recognition and autophagosome biogenesis to vesicle maturation and lysosomal fusion. This review examines the mechanisms by which TBK1 coordinates these diverse autophagic functions. We then focus on how ALS/FTD-associated mutations-ranging from truncating variants causing haploinsufficiency to domain-specific missense mutations-disrupt these essential processes.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); TANK-binding kinase 1 (TBK1); autophagy; frontotemporal dementia (FTD)
    DOI:  https://doi.org/10.3390/cells15050477
  9. Autophagy. 2026 Mar 08. 1-17
    FUNDC1-dependent mitophagy determines axon regeneration capacity.
    Wenlei Li, Yujiao Liu, Ruixuan Liu, Yuyuan Fan, Jinming Liu, Yingjie Guo, Zeping Hu, Lei Liu, Quan Chen, Bing Zhou.
      Neuronal axon regeneration is a complex and coordinated reorganization process that requires the involvement of mitochondria. Here, we demonstrated that FUNDC1 (FUN14 domain containing 1)-mediated mitophagy played a crucial role in determining the intrinsic capacity for axonal regrowth and peripheral nerve recovery. We found that acute nerve injury resulted in the accumulation of impaired mitochondria at the axonal injury site, accompanied by an increase in the expression of the mitophagy receptor FUNDC1. Strikingly, overexpression of FUNDC1 enhanced axonal regeneration both in vitro and in vivo, likely by maintaining a healthy mitochondrial population through mitophagy. Similarly, treatment with urolithin A (UA), a natural mitophagy inducer, promoted axon regrowth after injury. Conversely, fundc1 deletion impaired regeneration, an effect reversed by reintroducing wild type (WT) FUNDC1 in neurons but not an MAP1LC3B/LC3 (microtubule associated protein 1 light chain 3 beta)-interacting region (LIR) mutant. Metabolic profiling further demonstrated that FUNDC1-mediated mitophagy drives dorsal root ganglion (DRG) neurons regeneration through enhanced carnosine biosynthesis. Mechanistically, sciatic nerve injury (SNI) in Fundc1 transgenic (TG) mice upregulated NRF1 (nuclear respiratory factor 1) and PPARGC1A/PGC-1α (PPARG coactivator 1 alpha), which stimulated mitochondrial biogenesis and activated Carns1 (carnosine synthase 1) transcription. This increased carnosine biosynthesis, aiding peripheral nerve recovery through its antioxidant effects. Our findings highlighted FUNDC1-mediated mitophagy as a key mechanism in nerve regeneration, linking mitochondrial quality control, metabolic adaptation, and nerve regeneration.Abbreviations: Δψm: mitochondrial membrane potential; DIV: days in vitro; DRG: dorsal root ganglion; KO: knockout; LIR: LC3-interacting region; P60: postnatal day 60; PNS: peripheral nervous system; PSI: post sciatic nerve injury; ROS: reactive oxygen species; SD: standard deviation; SNI: sciatic nerve injury; TEM: transmission electron microscopy; TG: transgenic; TMRE: tetramethylrhodamine ethylester; UA: urolithin A; WT: wild type.
    Keywords:  Axon regeneration; FUNDC1; NRF1; carnosine; mitochondrial quality; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2629721
  10. Nat Cell Biol. 2026 Mar 13.
    Time-resolved functional genomics using deep learning reveals global hierarchical control of autophagy.
    Nathalia Chica, Aram N Andersen, Sara Orellana-Muñoz, Ignacio Garcia, Aurélie Nguéa P, Sigve Nakken, Pilar Ayuda-Durán, Linda Håkensbakken, Sebastian W Schultz, Eline Rødningen, Christopher D Putnam, Manuela Zucknick, Tor Erik Rusten, Jorrit M Enserink.
      Recycling of cellular components through autophagy maintains homeostasis in changing nutrient environments. Although its core mechanisms are extensively studied, understanding of its systems-wide dynamic regulation remains limited, particularly regarding how autophagy is inactivated once nutrients are restored. Here we mapped the genetic network that controls activation and inactivation of autophagy during nitrogen changes by combining time-resolved high-content imaging, deep learning and latent feature analysis. This dataset, termed AutoDRY, categorizes 5,919 mutants based on nutrient response kinetics and their contributions to autophagosome formation and clearance. Integrating these profiles with functional and genetic network data uncovered hierarchical and multilayered control of autophagy and revealed multiple new regulatory pathways. Notably, we identified the retrograde pathway as a pivotal time-varying modulator that tunes the expression of core autophagy genes and plays a central role in autophagy inactivation. Together, this study establishes a systems-level resource to guide future investigations of autophagy.
    DOI:  https://doi.org/10.1038/s41556-025-01837-0
  11. Nat Commun. 2026 Mar 12.
    Impaired α-Synuclein aggregate clearance in neuronal cells drive their spread to microglia through tunneling nanotubes.
    Ranabir Chakraborty, Francesca Palese, Philippa Samella, Veronica Testa, Jara Montero-Muñoz, Sylvie Syan, Takashi Nonaka, Masato Hasegawa, Antonella Consiglio, Chiara Zurzolo.
      Tunneling nanotubes (TNTs) play a crucial role in intercellular communication, enabling transfer of molecular cargoes over long distances between connected cells. Previous studies have demonstrated efficient, directional transfer of α-Synuclein (α-Syn) aggregates from neurons to microglia, with endosomal trafficking and lysosomal processing identified as the primary events following α-Syn internalization. Using human neuronal and microglial cell lines, we show that microglia exhibit higher lysosomal turnover, particularly through lysophagy, whereas neuronal lysosomes display compromised degradative capacity and impaired autophagic flux upon α-Syn exposure, resulting in compromised aggregate clearance. Such a response to α-Syn aggregates is also conserved in human iPSC-derived neurons and microglia. Moreover, perturbing aggregate clearance via autophagy inhibition enhances TNT-mediated transfer of α-Syn from neuronal cells to microglia. Microglia co-cultured with α-Syn-containing neurons upregulate autophagy flux, enabling efficient degradation of the transferred aggregates. These results highlight dysfunctional autophagy in neurons as a key driver outsourcing α-Syn aggregates to microglia.
    DOI:  https://doi.org/10.1038/s41467-026-69930-y
  12. Biochem Biophys Res Commun. 2026 Mar 06. pii: S0006-291X(26)00341-4. [Epub ahead of print]811 153577
    Hsv2, a yeast PROPPIN, drives bulk and selective microautophagy.
    Kohtaro Yasumori, Takashi Ushimaru.
      β-propellers that bind polyphosphoinositides (PROPPINs) are conserved autophagy effectors that recognize PI3P and PI(3,5)P2 to coordinate membrane remodeling. In budding yeast, Atg18 and Atg21 function at the phagophore/isolated membrane during macroautophagy, whereas the role of the less characterized PROPPIN Hsv2 has remained unclear. Here we demonstrate that Hsv2 is required for rapamycin-induced bulk microautophagy and for micronucleophagy. Loss of HSV2 attenuated processing of the vacuolar membrane reporter GFP-Pho8 and impaired the nucleolar protein reporter Nop1-GFP degradation under Atg1-deficient conditions. Upon TORC1 inactivation, Hsv2 accumulated as puncta on the vacuolar membrane where it colocalized with ESCRT components. An amphipathic-helix deletion mutant of Hsv2 failed to localize to the vacuolar membrane and exhibited diminished microautophagy, highlighting the importance of helix-dependent membrane association. Hsv2 also colocalized with the bridge-like lipid transfer protein Atg2, and deletion of ATG2, but not ATG1, reduced bulk microautophagy, suggesting a specific requirement for the Hsv2-Atg2 axis. These findings uncover a role for Hsv2 in microautophagy and suggest that the Hsv2-Atg2 complex promotes lipid supply to ESCRT-deforming sites on the vacuolar membrane, thereby sustaining membrane invagination and substrate engulfment.
    Keywords:  Atg2; Autophagy; Microautophagy; NVJ; PROPPIN; TORC1
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153577
  13. J Alzheimers Dis. 2026 Mar 13. 13872877261420211
    The interplay between mitophagy and ferroptosis in Alzheimer's disease: Mechanisms and therapeutic implications.
    Annan Liu, Liping Xing, Jianhui Li, Mingyuan Yao, Jing Song, Wang Guo, Peihan Duan, Honglin Li.
      Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. In recent years, two cellular processes have emerged as pivotal drivers of neurodegeneration in AD: mitophagy, the selective autophagic clearance of damaged mitochondria, and ferroptosis, an iron-dependent form of regulated cell death. This review outlines the molecular mechanisms of mitophagy and ferroptosis, with a focus on their interplay in AD. We propose that impaired mitophagy disrupts intracellular redox and iron homeostasis, thereby increasing neuronal susceptibility to ferroptosis. Conversely, ferroptosis-executing events, such as lethal lipid peroxidation, can further exacerbate mitochondrial dysfunction. This establishes a self-amplifying vicious cycle that accelerates disease progression. Furthermore, we summarize potential therapeutic strategies targeting this interactive network (e.g., Urolithin A, ferroptosis inhibitors) and highlight promising directions for future research. In contrast to previous reviews that have focused on each process in isolation, this work synthesizes evidence for a self-amplifying feedback loop between impaired mitophagy and exacerbated ferroptosis in AD. We posit that targeting this self-amplifying loop between mitophagy and ferroptosis may offer a novel and effective therapeutic paradigm for halting Alzheimer's disease progression.
    Keywords:  Alzheimer’s disease; ferroptosis; mechanism; mitochondria; mitophagy; therapeutic targets
    DOI:  https://doi.org/10.1177/13872877261420211
  14. Nat Rev Dis Primers. 2026 Mar 12. pii: 11. [Epub ahead of print]12(1):
    Tuberous sclerosis complex.
    Kellen Winden, E Martina Bebin, Shafali Jeste, Darcy A Krueger, Elahna Paul, Mustafa Sahin.
      Tuberous sclerosis complex (TSC) is a rare genetic disease caused by heterozygous loss-of-function variants in TSC1 or TSC2. Patients present with benign tumours known as hamartomas in the brain, eyes, lungs, kidneys, heart and skin. Many hamartomas contain mosaic second hit variants in TSC1 or TSC2. The most disabling features of TSC include epilepsy and TSC-associated neuropsychiatric disorders (TAND) such as intellectual disability and autism spectrum disorder. Remarkable progress has been made both in understanding the pathogenesis of TSC and in its clinical management, largely due to the discovery of the link between TSC1 and TSC2 and the mechanistic target of rapamycin (mTOR) signalling pathway. TSC1 and TSC2 form a protein complex that inhibits mTOR. Naturally occurring inhibitors of mTOR (rapamycin) and its analogues, collectively known as rapalogues, have been used to test various hypotheses in preclinical models and are approved for the treatment of several manifestations of TSC. Approved drug treatments (rapalogues) exist for subependymal giant cell astrocytomas, renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, facial angiofibromas and refractory seizures. However, there is still an unmet need for effective treatment of TAND and refractory epilepsy, despite the available medical and surgical options.
    DOI:  https://doi.org/10.1038/s41572-026-00688-9
  15. Cell Mol Neurobiol. 2026 Mar 11.
    Interplay Between Autophagy, Cellular Senescence, and Brain Aging: Neuroprotective Implications of Intermittent Fasting.
    Ishika Singh, Shreya Bhat, Rajesh Tamatta, Abhishek Kumar Singh.
      
    Keywords:  Aging; Autophagy; Dietary restriction; Intermittent fasting; Senescence
    DOI:  https://doi.org/10.1007/s10571-026-01709-7
  16. Free Radic Biol Med. 2026 Mar 09. pii: S0891-5849(26)00180-2. [Epub ahead of print]
    TG2 (transglutaminase 2) promotes PINK1/Parkin-dependent mitophagy in pulmonary hypertension by regulating the TRPC6.
    Linqing Li, Bo Liu, Minhao Zhang, Dong Wang, Yuhan Qin, Mingkang Li, Gaoliang Yan, Jiantong Hou, Yong Qiao, Yuyu Yao, Guoqiu Wu, Chengchun Tang.
      Hypoxia pulmonary hypertension (HPH) is a fatal progressive lung vasculopathy for which no efficacious interventions are currently available. This study investigated the potential mechanisms of TG2, a multifunctional enzyme, in HPH progression. The expression of TG2 was significantly upregulated in patients with pulmonary hypertension, HPH mice, and hypoxia-induced human pulmonary smooth muscle cells. Vascular smooth muscle-specific TG2 knockout (TG2VSMCKO) mice significantly ameliorated hypoxia+SU5416 and HPH. TG2 knockdown in human pulmonary smooth muscle cells remarkably decreased transient receptor potential canonical 6 (TRPC6) protein levels and calcium activity. Thus, we hypothesized that TRPC6 may serve as a novel target for TG2 regulation. TG2 deficiency decreased the mitophagy proteins PINK1 and Parkin and autophagy marker LC3 expression, whereas it increased autophagy receptor protein p62/SQSTM expression and inhibited mitophagy flux in human pulmonary smooth muscle cells exposed to hypoxia. Further investigations on mitochondrial function demonstrated that knockdown of TG2 significantly increased reactive oxygen species levels in the mitochondria and impeded depolarization of the mitochondrial membrane. Under conditions of mitochondrial dysfunction, the activation of TG2 engendered hyper-proliferation and an anti-apoptotic phenotype in human pulmonary smooth muscle cells through the process of mitophagy. Furthermore, we confirmed that TG2 regulates TRPC6 expression through serotonylation. Our findings provide a strong molecular explanation for the association between TG2, mitochondrial function, and HPH. This study identified a novel target for the treatment of HPH.
    Keywords:  Hypoxia; Mitophagy; Pulmonary artery smooth muscle cells; Pulmonary vascular remodeling; Serotonylation; Transglutaminase 2; Transient receptor potential cation channel 6
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.002
  17. Int J Mol Sci. 2026 Feb 27. pii: 2234. [Epub ahead of print]27(5):
    Crosstalk Between Autophagy and Paraptosis: A New Frontier in Cancer Therapy.
    Sweata Hanson, Deiviga Murugan, Palli V Jinsha, Anupama Binoy, Bipin G Nair, Nandita Mishra.
      Autophagy and paraptosis are two distinct physiological mechanisms involved in regulating cell fate in cancer. Recent studies have demonstrated that autophagy is a crucial process for maintaining cellular homeostasis by facilitating the removal of misfolded proteins and damaged organelles. However, autophagy is found to play a dual role in cancer. Severe ER and mitochondrial dysfunction can trigger different forms of programmed cell death, including autophagic cell death. In cancer cells that evade apoptosis, paraptosis, a caspase-independent alternate death pathway, is triggered by ER and mitochondrial swelling, leading to extensive cytoplasmic vacuolation. It can be induced by natural compounds, metallic complexes, nanoparticles, or chemotherapeutic agents, primarily through excessive ROS production and disruption of protein, thiol, and calcium/ion homeostasis. Autophagy and paraptosis have been found to be connected through crosstalk. While MAPK activation drives paraptosis, ER stress and the unfolded protein response (UPR) can initiate both paraptosis and autophagy. UPR-mediated PERK activation promotes survival autophagy in ER-stressed melanoma, whereas PERK elimination triggers paraptosis via sec61β with unresolved ER stress. Similarly, CHOP and DDIT4 can enhance ER stress and proteotoxicity, thereby favouring paraptosis. This review is unique in exploring the dynamic interplay between autophagy and paraptosis in cancer cells, highlighting promising therapeutic targets for chemotherapy-resistant cancers.
    Keywords:  ER stress; autophagy; cancer; crosstalk; mitochondrial dysfunction; paraptosis
    DOI:  https://doi.org/10.3390/ijms27052234
  18. J Cell Biol. 2026 May 04. pii: e202509180. [Epub ahead of print]225(5):
    Mechanoresilience of lysosomes conferred by TMEM63A.
    Angelina S Kim, Jing Ze Wu, Ruiqi Cai, Spencer A Freeman.
      Lysosomes are subject to perturbations that can cause damage to their limiting membrane. Osmotic shifts, pore-forming toxins, and the growth of luminal polymers or pathogens all stand to increase lysosomal membrane tension and/or disrupt the bilayer. In some contexts, this leads to lysosomal rupture and cell death. Here, we describe a mechanism that enables lysosomes to sense and respond to acute increases in tension of their limiting membrane. We report that the lysosome-resident nonselective cation channel, TMEM63A, can drive the directional flux of monovalent cations, major osmoticants, out of the lumen when gated by mechanical tension on the organelle. This results in the ability for lysosomes to relieve hydrostatic pressure and, proportionally, membrane tension, affording lysosomes the time to acquire additional lipids. Lysosomes without this mechanism-either because TMEM63A is deleted or in the case when cells express disease-causing variants of TMEM63A-are an order of magnitude more sensitive to lysis upon increases to their membrane tension when compared with their WT counterparts. These findings suggest that lysosomes are capable of regulating hydrostatic pressure and volume in response to high tension.
    DOI:  https://doi.org/10.1083/jcb.202509180
  19. Autophagy. 2026 Mar 09.
    Impaired mitophagy contributes to osteogenesis and mineralization disorders in fibrous dysplasia.
    Ziji Ling, Lingran Hu, Shenghao Jin, Feng Ling, Chengyu Jin, Xiaodie Yuan, Xingyu Chen, Hanyu Xie, Hongbing Jiang, Yu Fu.
      Fibrous dysplasia (FD) is a bone mesenchymal stromal cells (BMSCs)-derived disorder caused by GNAS gene mutation, characterized by excessive fibrous tissue proliferation in bone and the formation of immature trabecular bone. Although impaired osteogenesis of BMSCs is central to FD pathogenesis, the underlying mechanism remains largely elusive. Here we demonstrate that hyperactivation of the cAMP-PRKA/PKA signaling axis disrupts mitochondrial homeostasis through impaired mitophagy, ultimately leading to diminished amorphous calcium phosphate (ACP) secretion and consequent mineralization failure in FD. Mechanistically, in FD BMSCs, PRKA activation inhibits DNM1L/DRP1 recruitment to mitochondria through phosphorylation at S637, thereby suppressing mitochondrial fission. Consequently, excessive mitochondrial fusion leads to an elevated mitochondrial membrane potential, impaired mitophagy, and diminished ACP release. Collectively, our findings reveal a novel signaling nexus linking cAMP-PRKA signaling, mitochondrial dynamics, and biomineralization processes in FD pathogenesis, providing critical insights into the molecular basis of this disorder.
    Keywords:  Amorphous calcium phosphate; biomineralization; cAMP-PRKA pathway; fibrous dysplasia; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2643409
  20. J Alzheimers Dis. 2026 Mar 13. 13872877261422775
    USP14 inhibitor IU1 alleviates amyloid-β mediated toxicity in Alzheimer's disease cell and worm models.
    Ajish Ariyath, Eugene Hone, W M A D Binosha Fernando, Steve Pedrini, Ralph Martins, Prashant Bharadwaj.
      BackgroundProteostasis dysfunction plays a central role in Alzheimer's disease (AD), where aberrant accumulation of amyloid precursor protein (APP)-derived peptides, including APP-C99 and amyloid-β (Aβ), contributes to neurotoxicity. Previous work with an APP-C99 neuronal cell model revealed impaired proteasome activity, lysosomal dysfunction, and increased autophagic markers LC3 and p62.ObjectiveTo identify small molecule modulators of proteostasis that reduce Aβ-mediated toxicity and to evaluate their mechanism of action in both cellular and C. elegans models of AD.MethodsWe screened a library of small molecule proteostasis modulators in the APP-C99 cell model to identify compounds that reduce Aβ-mediated cell death. Hits were further analyzed for their effects on APP-C99/Aβ clearance, autophagy, and proteasomal function. Neuroprotective effects were validated in an AD C. elegans model.ResultsThe USP14 deubiquitinase inhibitor IU1 increased cell survival by 40%, reduced APP-C99 and Aβ accumulation, restored proteasomal activity, LC3 and p62 levels to control. IU1 also decreased neuronal loss and improved survival and behavior in AD worms. Notably, autophagy activators, including mTOR inhibitors rapamycin, everolimus, and temsirolimus, worsened Aβ toxicity. Conversely, autophagy inhibitors such as Bafilomycin A and chloroquine reduced APP-C99/Aβ accumulation, enhanced proteasomal activity, decreased cell death, and improved neurodegeneration and behavior in the worm model.ConclusionsThis study reveals that, under Aβ-mediated proteostasis dysfunction, autophagy activation exacerbates toxicity, whereas proteasome activation via allosteric inhibition of USP14 using IU1 was neuroprotective. These findings provide evidence to suggest that targeting proteasome stimulation via pharmacological inhibition of USP14 offers a promising therapeutic strategy for AD.
    Keywords:  Alzheimer’s disease; C. elegans; amyloid precursor protein; amyloid-β protein; autophagy; ubiquitin-proteasome systems
    DOI:  https://doi.org/10.1177/13872877261422775
  21. J Cell Biol. 2026 May 04. pii: e202507166. [Epub ahead of print]225(5):
    Distinct TRAPP complexes activate Ypt/Rab GTPases in secretion and autophagy.
    Valeriya Gyurkovska, Rakhilya Murtazina, Sarah F Zhao, Christopher B Huppenbauer, Vadim Gaponenko, Nava Segev.
      The conserved Ypt/Rab GTPases regulate all steps of the intracellular transport pathways. In yeast and human cells, Ypt1/Rab1 regulate early steps of secretion and autophagy, whereas Ypt31/Rab11 regulate a late step in secretion, and the TRAPP complexes act as their activators. The Ypt and transport step specificity of TRAPP complexes is currently controversial. Here, we use in vivo analyses of mutations in subunits of yeast TRAPP complexes to determine these specificities. First, deletion of the TRAPPIII-specific subunit Trs85 does not affect transport through the Golgi nor the localization of TRAPPI or Ypt1 to the Golgi. Second, conditional depletion of essential subunits of TRAPPI and TRAPPII shows that they are required for early and late secretion steps, respectively. Thus, TRAPPI and TRAPPII activate Ypt1 and Ypt31 in early- and late-Golgi, respectively, ascribing TRAPPIII in Ypt1 activation only in autophagy. This distinct activator assignment provides a mechanism for the dual function of Ypt1/Rab1 in secretion and autophagy, where Rab1 has been implicated in disease.
    DOI:  https://doi.org/10.1083/jcb.202507166
  22. iScience. 2026 Mar 20. 29(3): 115056
    Loss of DDI2 rewires proteostasis through CCN1-driven compensatory autophagy.
    Nayyerehalsadat Hosseini, Ahmed M Elshazly, Holly A Byers, Madison A Ward, Amy N Brooks, Janakiram R Vangala, Senthil K Radhakrishnan.
      The ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP) are the primary mechanisms for protein degradation, yet the molecular mechanisms linking them remain unclear. We show that loss of the UPS shuttle-protease DDI2 in diverse human and murine cells leads to a proteotoxic stress response driven by the intracellular accumulation of the secretory protein CCN1. Misfolded CCN1 is normally extracted from the endoplasmic reticulum by a DDI2-p97 complex and directed to lysosomes for degradation. In the absence of DDI2, CCN1 builds up, produces reactive oxygen species, and triggers compensatory autophagy; CCN1 knockout or ROS scavenging attenuates this response. Loss of DDI2 also impairs CCN1-LAMP1 colocalization, suggesting that DDI2 functions as a selective cargo receptor linking the UPS and ALP. These findings reveal a stress-responsive DDI2-CCN1 axis that reshapes proteostasis and highlight DDI2 as a potential therapeutic vulnerability in proteasome-dependent cancers.
    Keywords:  Biochemistry; Biological sciences; Cancer; Cancer systems biology; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2026.115056
  23. FASEB J. 2026 Mar 31. 40(6): e71655
    ORMDL Proteins Turnover via Proteasome and Autophagy Is Cell-Type Dependent and Tied to Ceramide Homeostasis.
    Michal Mrkacek, Magda Tumova, Alex Puskasu, Pavol Utekal, Marek Vrbacky, Ladislav Kuchar, Petr Draber, Viktor Bugajev.
      ORMDL proteins are essential negative regulators of the serine palmitoyltransferase (SPT) complex, thereby controlling the rate of de novo sphingolipid synthesis. Although mammalian ORMDLs undergo rapid turnover, the mechanisms regulating their stability remain unclear, with conflicting observations across studies. Here, we combined lipidomics, proteomics, and biochemical assays to investigate ORMDL regulation in HEK293, RPE-1, and primary mouse bone marrow-derived mast cells (BMMCs). Inhibition of SPT by myriocin or of ceramide synthases by fumonisin B1 (FB1) profoundly altered sphingolipid composition but induced minimal global proteomic changes while consistently reducing ORMDL protein levels. In contrast, overexpression of a single-chain SPT increased ORMDLs alongside elevated sphingolipids, an effect reversed by myriocin or FB1. ORMDL loss closely correlated with ceramide depletion and, in HEK293 and RPE-1 cells, was prevented by proteasome inhibition, whereas autophagy inhibition had no effect. In BMMCs, both pathways contributed to ORMDL regulation, consistent with high basal autophagy reflected by elevated LC3-II. The p97/valosin-containing protein ATPase was involved in the regulation of ORMDL turnover in all tested cell lines. Mutation of conserved asparagines (N11/N13) in ORMDL3, which mediate ceramide binding and stabilization of the inhibitory conformation, disrupted association with SPTLC1 and SPTLC2, mimicking myriocin-induced complex dissociation, while FB1 had a weaker effect. Together, these findings suggest that ceramide depletion is the primary trigger for ORMDL degradation in HEK293, RPE-1, and BMMCs and reveal a proteasome-dependent pathway that can be supplemented by autophagy in cells with high basal autophagic activity.
    Keywords:  LC3; ORMDL3; RRID; autophagy; fumonisin B1; myriocin; proteasome degradation; sphingolipid
    DOI:  https://doi.org/10.1096/fj.202502924RR
  24. Mech Ageing Dev. 2026 Mar 05. pii: S0047-6374(26)00019-9. [Epub ahead of print]231 112167
    Mitochondrial quality in aging and neurodegeneration: The emerging role of mitochondria-derived vesicles.
    Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Hélio José Coelho-Júnior, Ettore D'Argento, Vito Pesce, Francesco Landi, Cecilia Bucci, Flora Guerra, Anna Picca.
      Mitochondria are central to cellular energy metabolism, redox balance, and signaling, and their integrity is maintained by a multilayered mitochondrial quality control (MQC) system. This system includes proteostasis, dynamics, biogenesis, and mitophagy, which together repair or remove damaged organelles. Mitochondria-derived vesicles (MDVs) have emerged as an additional MQC component. MDVs are small vesicles that bud from mitochondria and selectively transport damaged mitochondrial proteins, lipids, and nucleic acids to endolysosomal compartments or other intracellular destinations, enabling rapid and localized responses to mitochondrial stress. Acting upstream of or in parallel with mitophagy, MDVs can avoid or delay irreversible mitochondrial damage and help preserve cellular homeostasis. Aging and age-associated disorders are characterized by progressive mitochondrial dysfunction and chronic inflammation. Age-related changes in intracellular trafficking, lysosomal function, and vesicle dynamics may impair MDV formation, cargo selection, and targeting. Under conditions of defective degradation, mitochondrial components may also appear in extracellular vesicles, potentially contributing to altered intercellular signaling and inflammation. In the nervous system, where energetic demands are high and mitochondrial turnover requires tight regulation, such alterations may be especially harmful. This review summarizes MQC mechanisms in neurons, with a focus on MDVs, their dysregulation during aging and neurodegeneration, and implications for biomarkers and therapeutic strategies.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; Tau protein, α-synuclein
    DOI:  https://doi.org/10.1016/j.mad.2026.112167
  25. Cell Rep. 2026 Mar 11. pii: S2211-1247(26)00253-6. [Epub ahead of print]45(3): 117175
    Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy.
    Changyoun Kim, Edward Rockenstein, Brian Spencer, Hyung-Koo Kim, Anthony Adame, Margarita Trejo, Klodjan Stafa, He-Jin Lee, Seung-Jae Lee, Eliezer Masliah.
      
    DOI:  https://doi.org/10.1016/j.celrep.2026.117175
  26. Trends Cancer. 2026 Mar 11. pii: S2405-8033(26)00025-7. [Epub ahead of print]
    A lysosomal requiem for glioblastoma cells.
    Laura Merlet, Margaux Le Guyon, Julie Gavard.
      Once viewed solely as degradative compartments, lysosomes shape cell fate through signaling, metabolism, and communication. In glioblastoma, their rewiring underlies plasticity, invasion, and resistance to therapies. This forum explores lysosomal dynamics in brain tumors and therapeutic strategies targeting lysosomal vulnerabilities, offering fresh perspectives for precision approaches in this lethal cancer.
    Keywords:  autophagy; cell death; endolysosome; glioma; organelles
    DOI:  https://doi.org/10.1016/j.trecan.2026.01.012
  27. Autophagy. 2026 Mar 11. 1-18
    Lipophagy fuels phosphatidylcholine synthesis for Newcastle disease virus replication.
    Mengqing Yang, Juan Chen, Xiang Su, Xianjin Kan, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Shengqing Yu, Chan Ding, Yingjie Sun.
      Lipid droplets (LDs) are dynamic organelles that store neutral lipids and maintain lipid homeostasis. Many viruses exploit LDs as replication platforms or lipid sources, but their role in supplying membrane lipids for viral assembly remains unclear. Newcastle disease virus (NDV), an enveloped RNA virus with oncolytic potential, extensively remodels host metabolism, yet its impact on LD lipid mobilization is unknown. Here, we show that NDV reprograms host lipid metabolism via SQSTM1/p62-dependent lipophagy, selectively degrading triglycerides (TAGs) enriched in unsaturated fatty acids (UFAs). Lipidomics revealed concurrent depletion of UFA-containing triglycerides (UFA-TAGs) and UFA-containing phosphatidylcholines (UFA-PCs) during infection. Inhibition of lipophagy blocked LD degradation, reduced viral replication, and suppressed UFA-PC formation. Isotope tracing demonstrated that lipophagy-derived UFAs are incorporated into phosphatidylcholines (PCs) via the Kennedy pathway, whereas β-oxidation was dispensable. UFA supplementation rescued viral replication under lipophagy blockade and promoted virus-like particle (VLP) release, indicating that UFA-PCs facilitate viral budding. These findings uncover a distinct NDV strategy linking lipophagy-driven UFA release to phospholipid synthesis and membrane remodeling, revealing a lipid-based metabolic vulnerability for antiviral and oncolytic interventions.Abbreviations: AP: autophagosome; ATG: autophagy related; ATP: adenosine triphosphate; CQ: chloroquine; EGFP: enhance green fluorescent protein; FFA: free fatty acid; HN: Hemagglutinin-Neuraminidase; LA: linoleic acid; LD: lipid droplet; LIPA: lipase A, lysosomal acid type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NDV: newcastle disease virus; NP: nucleoprotein; OA: oleic acid; PA: palmitic acid; PC: phosphatidylcholine; PLIN2/ADRP: perilipin 2; PNPLA2/ATGL: patatin like phospholipase domain containing 2; POA: palmitoleic acid; SFA: saturated fatty acid; TAG: triglyceride; UFA: unsaturated fatty acid; UFA-PC: UFA-containing phosphatidylcholine; VLP: virus-like particle.
    Keywords:  Newcastle disease virus; SQSTM1/p62; lipid droplets; lipophagy; phosphatidylcholine; unsaturated fatty acids
    DOI:  https://doi.org/10.1080/15548627.2026.2642980
  28. Nutrients. 2026 Mar 07. pii: 863. [Epub ahead of print]18(5):
    Mechanistic Modulation of Autophagy by Bioactive Natural Products: Implications for Human Aging and Longevity.
    Maroua Jalouli, Abdel Halim Harrath, Mohammed Al-Zharani, Md Ataur Rahman.
      Autophagy is an evolutionarily preserved intracellular degradation process pivotal in maintaining proteostasis, mitochondrial homeostasis, and metabolic equilibrium, all of which are dysregulated with aging. Aberrant autophagy has been recognized as a hallmark of human aging and age-related diseases, including neurodegeneration, metabolic dysfunction, cardiovascular diseases, and cancer. Bioactive natural compounds derived from plants, foods, and marine organisms have emerged as potent modulators of autophagy, offering a promising strategy to counteract aging and promote healthy lifespan. Mechanistically, these compounds regulate autophagy by modulating key signaling pathways, such as AMPK, PI3K/AKT/mTOR, SIRT1, and FOXO, while also alleviating oxidative stress, inflammation, and mitochondrial dysfunction. Natural compounds like polyphenols, flavonoids, alkaloids, terpenoids, and carotenoids exhibit dual roles by restoring age-related suppressed autophagic flux and inhibiting excessive autophagy-induced cell death. In this review, we provide a comprehensive overview of the molecular mechanisms through which bioactive natural compounds modulate autophagy and impact human aging and longevity. We discuss both experimental and clinical evidence supporting their geroprotective effects, limitations regarding bioavailability and dose-dependent effects, and prospects for the utilization of autophagy-targeting natural products in aging intervention strategies.
    Keywords:  autophagy modulation; bioactive natural products; cellular homeostasis; human aging; longevity; oxidative stress
    DOI:  https://doi.org/10.3390/nu18050863
  29. Science. 2026 Mar 12. 391(6790): eaec1778
    Autophagolysosomal exocytosis inverts Src kinase onto the cell surface in cancer.
    Corleone S Delaveris, Rita P Loudermilk, Apurva Pandey, Soumya G Remesh, Trenton M Peters-Clarke, Snehal D Ganjave, William J N Dougherty, Henry M Delavan, Chunyue Wang, Jesse Ling, Juan Antonio Camara Serrano, Fernando Salangsang, Chien-Kuang Cornelia Ding, Nancy Greenland, Carissa E Chu, Sima Porten, Veronica Steri, Jonathan Chou, Michael J Evans, Kevin K Leung, James A Wells.
      Overexpression of the proto-oncogene Src is common to a wide variety of cancers. In this work, we found that Src is noncanonically translocated and inverted onto the cell surface in cancer, both in vitro and in vivo. We identified autophagolysosomal exocytosis (ALE) as a secretory mechanism prominent in cancer cell lines. Src represents the prototypical example of a family of membrane-anchored proteins that are transported by this process. Furthermore, this extracellular membrane-associated Src (eSrc) was found in primary tumors, and anti-Src antibody-based therapies mediated tumor cell killing in cell culture systems and in mouse xenograft models. Thus, intracellular N-myristoylated proteins, prototypically Src, can be topologically inverted onto the cell surface in cancer and targeted with antibody therapeutics.
    DOI:  https://doi.org/10.1126/science.aec1778
  30. Aging Cell. 2026 Mar;25(3): e70444
    Glycative Stress Disrupts the Mitochondrial-Lysosome Axis and Promotes Geroconversion in Aging Cardiomyocytes.
    Diana Bou-Teen, Simonas Valiuska, Elisabet Miro-Casas, Chiara Rubeo, Elena Bonzon-Kulichenko, Zuzana Nichtova, Celia Fernandez-Sanz, Javier Inserte, Antonio Rodriguez-Sinovas, Begoña Benito, Eduard Ródenas-Alesina, Jesús Vázquez, Ignacio Ferreira-González, Marisol Ruiz-Meana.
      Aging is a major risk factor for heart failure, yet the molecular mechanisms linking cardiac aging to the inflammatory pathophysiology of heart failure remain elusive. Mitochondrial dysfunction and defective organelle quality control are emerging hallmarks of the aging heart, but their biochemical underpinnings are poorly defined. Using comprehensive glycomics, we found that cardiac mitochondria from physiologically aged mice (≥ 20 months) are the major intracellular reservoirs of advanced glycation end products (AGEs), derived primarily from the chemical attack of some α-oxoaldehydes on proteins. This was associated with mild mitochondrial dysfunction and structural remodeling. Lysosomes in aged hearts were enlarged, more abundant, less acidic, and frequently loaded with lipofuscin. Notably, ~7% of cardiomyocytes showed proinflammatory senescence traits. In vitro, glycative stress in H9c2 myoblasts reproduced mitochondrial AGE buildup, dysfunction, and activation of the mitochondria-lysosome axis. However, AGE-modified mitochondria impaired lysosomal acidification and proteolysis, hindering mitophagic clearance and contributing to lipofuscin accumulation. This sequence of events ultimately led to proinflammatory senescence in a subset of cells. These findings identify mitochondrial AGE accumulation as a novel mechanism of sublethal nonsolved aging-associated stress that eventually triggers geroconversion in cardiomyocytes. This mechanism could facilitate the transition of the aging heart towards a failing phenotype.
    Keywords:  AGEs; aging; cardiomyocytes; lipofuscin; methylglyoxal; mitochondria; senescence
    DOI:  https://doi.org/10.1111/acel.70444
  31. EMBO Rep. 2026 Mar 11.
    Sirtuin 2 inhibits global protein synthesis via Rheb-GTPase degradation.
    Amarjeet Shrama, Yanlin Zi, Anwit Shriniwas Pandit, Kirtika Jha, Vikrant Kumar Sinha, Dimple Nagesh, Bhoomika Shivanaiah, Venkatraman Ravi, Souvik Ghosh, Danish Khan, Arathi Bangalore Prabhashankar, Thoniparambil Sunil Sumi, Satish Rajpurohit, Sunayana Ningaraju, Sukanya Raghu, Anand Srivastava, Mahavir Singh, Hening Lin, Nagalingam R Sundaresan.
      Increased global protein synthesis is associated with the development and progression of several aging-related diseases and disorders. Strategies like calorie restriction and pharmacological inhibition of protein synthesis have exhibited health-promoting effects. However, the complex molecular events that regulate global protein synthesis are not completely understood. Here, we report that SIRT2, a histone deacetylase, negatively regulates global protein synthesis by inhibiting the mTORC1 pathway via deacetylating Rheb and promoting its degradation. Our in vitro results suggest that SIRT2 deficiency increases protein synthesis, whereas SIRT2 overexpression suppresses protein synthesis. SIRT2-deficient mice exhibit increased global protein synthesis in the hearts, which may contribute to the development of cardiac hypertrophy. Conversely, cardiac-specific overexpression reduces global protein synthesis in the hearts of SIRT2 transgenic mice. Mechanistically, SIRT2 binds to and deacetylates Rheb at K151 residue to enhance ubiquitin-proteosome-mediated degradation of Rheb. Depletion of Rheb rescues increased protein synthesis in SIRT2-inhibited conditions. Our findings suggest that SIRT2 activation could be a potential therapeutic strategy for treating diseases associated with increased protein synthesis.
    Keywords:  Cardiac Hypertrophy; Protein Synthesis; Rheb; SIRT2; Ubiquitination
    DOI:  https://doi.org/10.1038/s44319-026-00724-5
  32. Bio Protoc. 2026 Mar 05. 16(5): e5619
    Quantifying Lysosomal Degradation of Extracellular Proteins With a Fluorescent Protein-Based Internalization Assay.
    Sayana Bun, Kanna Kamikawa, Akira Matsuura, Eisuke Itakura.
      Endocytosis is an essential membrane transport mechanism that is indispensable for the maintenance of life. It is responsible for the selective internalization and subsequent degradation or recycling of specific extracellular proteins and nutrients, thereby facilitating cellular nutrient supply, modulation of receptor signaling, and clearance of foreign substances. However, methods for the quantitative analysis of lysosomal degradation of extracellular proteins via endocytosis remain limited. This protocol describes a method for purifying the protein-of-interest (POI)-red fluorescent protein (RFP)-green fluorescent protein (GFP) fusion protein, which is modified with specific mammalian cell glycans or other modifications, from the conditioned medium of mammalian cell cultures. Subsequently, the protocol details a quantitative approach for evaluating its internalization and lysosomal degradation within cells using the RFP-GFP tandem fluorescent reporter. Following the addition of POI-RFP-GFP to the medium, cells can be subjected to cell biological assays, such as flow cytometry, as well as biochemical analyses, such as immunoblotting. This protocol is broadly applicable to studies of the internalization of extracellular proteins. Key features • Purification of secreted GFP-RFP-fused POI from mammalian cell culture supernatant. • Quantification of POI-RFP-GFP internalization through measurement of GFP and RFP signals using flow cytometry. • Confirmation of lysosomal degradation of POI-RFP-GFP by immunoblotting.
    Keywords:  Endocytosis; Extracellular protein; Internalization; Lysosome; Protein degradation; Proteostasis; Secreted protein
    DOI:  https://doi.org/10.21769/BioProtoc.5619
  33. Mol Biol Cell. 2026 Mar 11. mbcE25070334
    ATG9B Regulates Mitochondrial Integrity and Apoptotic Tumor Cell Death.
    Hong Cao, Lixia Guo, Jing Chen, Eugene Krueger, Gina Razidlo, Mark A McNiven.
      It is well established that many tumor types possess defective autophagic pathways. Several studies have reported that the transmembrane, autophagic lipid scramblase ATG9B is altered in multiple cancers, suggesting that this dysregulation could contribute to oncogenesis. Therefore, the goal of this study was to define the cellular distribution of ATG9B in two different tumor cell types and to provide insights into its cellular function. Surprisingly, we found that ATG9B shows a modest association with autophagic structures and exhibits a unique and prominent localization to mitochondria, in contrast to its related form ATG9A. Upon expression of tagged ATG9B forms, this mitochondrial distribution was accompanied by aberrant changes in mitochondrial morphology as well as a reduction in the mitochondrial membrane potential and the release of mtDNA. Few indicators for ATG9B-dependent mitophagy were noted. Instead, ATG9B overexpression led to pronounced apoptotic cell death as assessed by a variety of indicators. Further, we find that the N-terminal sequence of ATG9B acts as a mitochondrial targeting domain and that expression of this peptide alone can induce apoptotic cell death. These findings provide new insights into a putative cellular localization and function for ATG9B. [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-07-0334
  34. Adv Sci (Weinh). 2026 Mar 12. e15220
    Restriction of Individual Branched-Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice.
    Reji Babygirija, Cara L Green, Michelle M Sonsalla, Izabelle Marie F Le, Fan Xiao, Sarah Yandell, Mariah F Calubag, Michaela E Trautman, Anna Tobon, Ryan Matoska, Chung-Yang Yeh, Charles I Opara, Isaac Grunow, Diana Vertein, Sophia Schlorf, Bailey A Knopf, Michael J Rigby, David A Harris, Mark P Keller, Alan D Attie, Luigi Puglielli, Cholsoon Jang, Dudley W Lamming.
      Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA-restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA-specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short-term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay AD.
    Keywords:  Alzheimer's disease; autophagy; branched chain amino acids; mTORC1
    DOI:  https://doi.org/10.1002/advs.202515220
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