bims-auttor 2026-09-20 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–09–20
27 papers selected by
Viktor Korolchuk, Newcastle University

Multilayered interplay between the cGAS-STING pathway and autophagy.
Autophagy-lysosomal pathway in neurodegeneration.
Marked for destruction? When S-nitrosylation writes protein fate through metabolic rewiring.
DFCP1-containing ER microdomains mediate lysosomal membrane repair.
Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.
Mitochondria-Lysosome Quality Flux in Aging Mesenchymal Stem/Stromal Cells: Quality-Control Bottlenecks and Therapeutic Opportunities for Regenerative Decline.
Spatial control of mitochondrial ubiquitination by the AMBRA1-RMC1-HUWE1 axis.
Structure and function of TM6SF1 reveals role in mTORC1 signaling.
A de novo VPS16 missense variant blocks autophagic flux and extends DYT-VPS16 into infancy.
The crosstalk of autophagy and metabolism in plants.
Phosphorylation of OTUB1 promotes autophagy initiation under starvation.
Species-dependent activities of the PINK1-parkin axis.
Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation.
Gomisin N ameliorates autophagy-neuroinflammation imbalance in Parkinson's disease models via modulating the ATG16L1/NLRP3 axis.
5-Fluorouracil-based chemotherapy disrupts autophagy flux and protein synthesis in cultured myotubes: a role for mTORC1 signaling.
Demethylase FTO attenuates atherosclerotic plaque via upregulating ABCA1 and ABCG1 expression by targeting ATG5.
Quality control of glycogen through direct ubiquitylation by RNF213.
Regulatory mechanisms and interactions of mitophagy and ketone body metabolism in cardiac metabolism.
Inhibition of RhoA-mediated secretory autophagy in megakaryocytes mitigates myelofibrosis in mice.
Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway.
Visualizing the Golgi apparatus and Golgiphagy in vivo.
Itaconic acid dissolves TFEB liquid-liquid phase separation to alleviate hyperoxia-induced bronchopulmonary dysplasia.
APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics.
Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.
Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.
Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?
Mitophagy as an active regulator of cardiac metabolic reprogramming.

Autophagy Rep. 2026 ;5(1): 2728537

Multilayered interplay between the cGAS-STING pathway and autophagy.

Ze-Bo Huang, Xiang-Zheng Gao, Jin-Yi Lin, Du Feng, Guang Lu.

  The cGAS-STING pathway detects cytosolic dsDNA to initiate innate immune responses, serving as a critical surveillance system against infection and cellular stress. Autophagy is an evolutionarily conserved catabolic process that maintains homeostasis by degrading cytoplasmic components. Although these two systems operate through distinct mechanisms, recent studies have uncovered a complex bidirectional regulatory network that intimately links them. On the one hand, STING has an evolutionarily conserved capacity to induce TBK1-independent noncanonical autophagy, and recent studies further link this activity to TFEB-dependent lysosome biogenesis, expanding its functional repertoire beyond classical interferon induction. On the other hand, autophagy restricts cGAS-STING signaling by clearing cytosolic DNA and selectively degrading pathway components, thereby preventing excessive inflammation. Furthermore, mitophagy curtails the release of mitochondrial DNA, a potent cGAS agonist, and recent studies further implicate lysosomes as active signaling platforms associated with mtDNA release, LRRK2 activation, and STING-dependent NF-κB responses. In this review, we discuss recent advances in understanding how the cGAS-STING pathway and autophagy mutually regulate each other at the cellular level, focusing on the molecular mechanisms of this interplay, both canonical and noncanonical, and highlighting how their crosstalk shapes cellular homeostasis and stress adaptation.

Keywords:  cGAS-STING pathway; innate immunity; lysosome; mitophagy; mtDNA; non-canonical autophagy

DOI:  https://doi.org/10.1080/27694127.2026.2728537
Mol Neurodegener Adv. 2026 ;2(1): 37

Autophagy-lysosomal pathway in neurodegeneration.

Samantha R McDonough, Aditya K Rao, Jacqueline M McAleer, Bergan M Babrowicz, Manu Sharma.

  Autophagy-Lysosomal Pathway (ALP) dysfunction has emerged as a prominent mechanism underlying neurodegenerative disease. Given its central role in facilitating cellular clearance of misfolded proteins, damaged organelles and other cellular debris, the ALP is vital for cellular health and survival. In mature neurons, whose post-mitotic state renders them unable to dilute such materials through cell division, this waste removal pathway takes on an even greater importance. It is therefore unsurprising that ALP dysfunction is increasingly implicated in the context of age-associated neurodegenerative disease, where impaired proteostasis and pathological protein aggregation are common hallmarks. The focus of this review is how dysregulation of ALP-associated processes, including autophagic flux, chaperone-mediated autophagy, endolysosomal trafficking, lysosomal pH and ion balance, and lysosomal metabolic signaling, is implicated in both the pathogenesis and progression of neurodegenerative diseases, with an emphasis on Alzheimer's disease and Parkinson's disease. A more detailed understanding of how these processes, both independently and cooperatively, contribute to the development and progression of neurodegenerative disease will improve our understanding of these debilitating disorders and inform the development of ALP-targeted therapeutic strategies.

Keywords:  Alzheimer’s disease; Autophagy; Lysosome; Neurodegeneration; Parkinson’s disease; Proteostasis

DOI:  https://doi.org/10.1186/s44477-026-00041-0
Autophagy. 2026 Sep 16.

Marked for destruction? When S-nitrosylation writes protein fate through metabolic rewiring.

Chiara Pecorari, Giuseppe Filomeni.

  Metabolism and autophagy are closely interconnected, but whether metabolic alterations can chemically modify proteins and influence their selective autophagic degradation remains poorly understood. Our recent findings show that increased S-nitrosylation resulting from the loss of the denitrosylase AKR1A1/SCoR impairs glycolysis and promotes methylglyoxal accumulation, leading to carbonyl modification and selective autophagic degradation of KEAP1. These findings suggest that metabolic rewiring can influence the fate of specific proteins. In particular, we discuss whether glycation may act as a metabolic "mark" for selective autophagy and how the removal of metabolically modified proteins may, in turn, sustain signaling pathways involved in tumor progression and therapy resistance.

Keywords:  AKR1A1; KEAP1; NRF2; SCoR; cancer metabolism; glycation; glycolysis; methylglyoxal; nitric oxide; pyruvate kinase

DOI:  https://doi.org/10.1080/15548627.2026.2735183
Nat Cell Biol. 2026 Sep 15.

DFCP1-containing ER microdomains mediate lysosomal membrane repair.

Maja Radulovic, Sascha Pust, Athanasios Kournoutis, Di Chen, M Isabel Giner, Qijian Liang, Santosh Phuyal, Thomas J Böddeker, Katy McCarron, Eric Herrmann, Kevin Rose, Sebastian W Schultz, Andreas Brech, James H Hurley, Claudio Bussi, Luis Bonet-Ponce, Maximiliano G Gutierrez, Camilla Raiborg, Harald Stenmark.

Lysosomal membrane integrity is essential for preserving cellular homeostasis in response to different stressors. Upon lysosomal membrane permeabilization, cells activate several mechanisms for lysosomal membrane repair, including ESCRT proteins, phosphatidylinositol 4-phosphate (PI4P)-dependent lipid transfer from the endoplasmic reticulum (ER) and conjugation of ATG8 family proteins to single membranes (CASM). The interplay between these pathways and the regulation of the lipid transfer machinery remain incompletely understood. Here we show that phosphatidylinositol 3-phosphate (PI3P)-containing ER domains play a major role in lysosomal membrane repair. PI3P is formed on lysosome-proximal ER domains by the phosphatidylinositol 3-kinase PIK3C3/VPS34 in response to membrane damage, and inhibition or depletion of PIK3C3 inhibits lysosome repair. Mechanistically, the ATPase DFCP1/ZFYVE1 accumulates on lysosome-proximal ER domains by its PI3P binding, triggered by Ca2+ efflux from lysosomes and requiring the ULK1 kinase complex and ER proteins of the VAP family. Downstream of CASM, PI4P, ESCRTs and PI3P, DFCP1 promotes focal accumulation of the lipid channel VPS13C on ER domains proximal to damaged lysosomes to promote their repair. The function and dynamics of DFCP1 depend on its ability to bind and hydrolyse ATP, and absence of DFCP1 compromises cellular resistance to vacuolar damage induced by Listeria monocytogenes. We conclude that DFCP1 mediates concentration of the ER-associated lipid transport machinery at damaged lysosomes to promote their sealing in response to Ca2+ flux and PIK3C3 activation.

DOI: https://doi.org/10.1038/s41556-026-02062-z
Nat Commun. 2026 09 16. pii: 9647. [Epub ahead of print]17(1):

Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.

Haoning Yang, Koji Matsuhisa, Meng Wei, Wataru Nishi, Dylan Hong Zheng Koh, Aik Yong Sim, Isabelle Bonne, Yasunori Saheki.

Efficient clearance and recycling of dysfunctional mitochondria through the robust catabolic activity of lysosomes are essential for cellular health. However, how membrane lipids contribute to maintaining the degradative capacity of lysosomes remains poorly understood. Here, we show that cholesterol plays a critical role in preserving the functional integrity of degradative lysosomes. Clearance of damaged mitochondria by degradative lysosomes is tightly coupled with the acute accumulation of phosphatidylinositol 4-phosphate (PI4P) on the lysosomal surface via PI4KIIα activity. This PI4P accumulation activates oxysterol-binding protein (OSBP)-mediated cholesterol transport from the endoplasmic reticulum (ER) to lysosomal membranes. The resulting efflux of cholesterol from the ER activates sterol regulatory element-binding protein 2 (SREBP-2), enhancing cholesterol production. Sustained cholesterol accumulation on lysosomal membranes maintains lysosomal acidity and membrane integrity for efficient mitochondrial degradation. This degradation process then leads to the release of free fatty acids and their recycling and storage through the formation of DGAT1-dependent lipid droplets. These findings uncover a key phosphoinositide-regulated cholesterol transport pathway that promotes the clearance and recycling of dysfunctional mitochondria, a process whose impairment is closely linked to neurodegeneration.

DOI: https://doi.org/10.1038/s41467-026-77423-1
Cells. 2026 Aug 27. pii: 1548. [Epub ahead of print]15(17):

Mitochondria-Lysosome Quality Flux in Aging Mesenchymal Stem/Stromal Cells: Quality-Control Bottlenecks and Therapeutic Opportunities for Regenerative Decline.

Lingling Cheng, Gaojie Song.

  Aging mesenchymal stem/stromal cells (MSCs) lose regenerative capacity as redox imbalance, mitochondrial damage, defective organelle quality control and chronic inflammation converge. Yet these processes are commonly considered in isolation, obscuring whether damaged mitochondrial cargo reaches lysosomes and is ultimately degraded. Here, we define mitochondria-lysosome quality flux (MLQF) as an author-proposed, evidence-graded framework that tracks mitochondrial damage from recognition and sorting through lysosomal delivery to terminal lysosomal degradation in aging MSCs. The framework explicitly separates delivery to an acidic compartment from completed degradation and distinguishes direct MSC evidence from cross-model mechanisms and candidate pathways. MSC studies most strongly support macroautophagy-dependent mitophagy, particularly when assessed using dynamic flux reporters. By contrast, mitochondria-derived vesicles and microautophagy-like or piecemeal routes remain incompletely validated in MSCs. Studies in non-MSC systems further show that mitochondria-lysosome contact sites can support lysosomal acidification, although their contribution to natural MSC aging remains unresolved. By locating rate-limiting defects across this continuum, MLQF provides a testable basis for linking incomplete mitochondrial clearance to inflammatory signaling, lineage drift and regenerative decline, and for selecting bottleneck-matched interventions.

Keywords:  cellular senescence; mesenchymal stem/stromal cells; mitochondrial quality control; mitochondria–lysosome quality flux; mitophagy

DOI:  https://doi.org/10.3390/cells15171548
Autophagy. 2026 Sep 16.

Spatial control of mitochondrial ubiquitination by the AMBRA1-RMC1-HUWE1 axis.

Jiamin Yi, Xin Yong, Da Jia.

  Mitochondrial ubiquitination is a central component of mitochondrial quality control. The PINK1 (PTEN induced kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway established how loss of mitochondrial membrane potential can trigger a phospho-ubiquitin feed-forward cascade on the outer mitochondrial membrane (OMM). It remains less clear how mitochondrial ubiquitination is achieved when PRKN is absent or inactivated. In our recent work, we identify a recruitment platform organized by AMBRA1 (autophagy and beclin 1 regulator 1), in which RMC1 (regulator of MON1-CCZ1) positions HUWE1 (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1) at mitochondria. This spatial arrangement promotes HUWE1-dependent ubiquitination and turnover of OMM proteins, including MFN2 (mitofusin 2), VDAC1 (voltage-dependent anion channel 1), and VDAC2 (voltage-dependent anion channel 2). Our findings raise the question of how cells select among distinct mitochondrial ubiquitination pathways and whether these pathways function independently, sequentially, or cooperatively.

Keywords:  AMBRA1; HUWE1; PINK1-PRKN; RMC1; mitochondrial quality control; ubiquitination

DOI:  https://doi.org/10.1080/15548627.2026.2735210
Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2622424123

Structure and function of TM6SF1 reveals role in mTORC1 signaling.

Sen Hong, Liangjie Jia, Rong Wang, Nadia Elghobashi-Meinhardt, Helen H Hobbs, Xiaochun Li.

  The transmembrane 6 superfamily (TM6SF) comprises two members: TM6SF1, a ubiquitously expressed lysosomal membrane protein of unknown function, and TM6SF2, an endoplasmic reticulum protein required for bulk lipidation of Apolipoprotein B-containing lipoproteins. Here, we used cryo-electron microscopy (cryo-EM) to determine the structure of human TM6SF1 at 2.9-Å resolution. TM6SF1 forms a polytopic homodimer, with each protomer comprising 10 transmembrane helices (TMs). TMs 1-6 form a pocket that accommodates a cholesterol molecule. Cell-based assays revealed that loss of TM6SF1 perturbs mTORC1 signaling, resulting in reduced phosphorylation of S6 kinase 1 and 4E-BP1 and constitutive activation of transcription factor EB (TFEB), and that cholesterol is required for these effects. Biochemical analyses support the model that TM6SF1 directly engages LAMTOR1, a component of Ragulator complex, in a cholesterol-dependent manner. Together, these findings identify TM6SF1 as a lysosomal cholesterol binding protein involved in regulating mTORC1 signaling.

Keywords:  LAMTOR1; TM6SF1; cryo-EM; mTORC1; transcription factor EB

DOI:  https://doi.org/10.1073/pnas.2622424123
Autophagy Rep. 2026 ;5(1): 2728539

A de novo VPS16 missense variant blocks autophagic flux and extends DYT-VPS16 into infancy.

Enrique Gonzalez Saez-Diez, Xutong Xue, Darius Ebrahimi-Fakhari.

  Autophagy terminates in the degradation of cargo delivered by fusion of the autophagosome with the lysosome, a step tethered by the homotypic fusion and vacuole protein sorting (HOPS) complex. Heterozygous loss-of-function variants in VPS16, which encodes a core HOPS subunit, cause autosomal dominant DYT-VPS16 dystonia. The pathogenicity of missense alleles has remained uncertain due to a lack of mechanistic data from patient-derived cells. We summarize our recent report of the youngest individual with DYT-VPS16 described to date. This child presented with infantile-onset generalized dystonia caused by a de novo VPS16 missense variant, p. Ala466Thr. Patient-derived fibroblasts accumulate enlarged, stalled autolysosomes and show concurrent elevation of SQSTM1/p62 and the MAP1LC3B/LC3B-II:LC3B-I ratio, consistent with a block in autophagic flux. We discuss the consequences for variant interpretation, describe a previously unrecognized caudate-predominant neuroimaging correlate, and speculate on why striatal neurons are selectively vulnerable to HOPS dysfunction. Abbreviations: HOPS: homotypic fusion and vacuole protein sorting; LOF: loss-of-function; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; SQSTM1: sequestosome 1.

Keywords:  Autolysosome; DYT-VPS16; HOPS complex; MAP1LC3B; SQSTM1; VPS16; autophagic flux; caudate nucleus; dystonia

DOI:  https://doi.org/10.1080/27694127.2026.2728539
Curr Opin Plant Biol. 2026 Sep 17. pii: S1369-5266(26)00107-X. [Epub ahead of print]94 102964

The crosstalk of autophagy and metabolism in plants.

Jaishri Rubina Das, Louis Lambret, Anne Marmagne, Céline Masclaux-Daubresse.

Autophagy in plants promotes cellular longevity and nutrient recycling by degrading unwanted organelles and damaged cytoplasmic components. This process is essential for plant stress tolerance and nutrient management. In all plant organs, autophagy plays a critical role in maintaining cellular homeostasis, and defects in autophagy lead to severe metabolic disorders. Conversely, metabolic signals regulate autophagic activity at multiple levels. Here, we review how autophagy contributes to nutrient management at different organizational levels and how metabolism modulates autophagy across plant organs.

DOI: https://doi.org/10.1016/j.pbi.2026.102964
Nat Commun. 2026 Aug 15. pii: 9820. [Epub ahead of print]17(1):

Phosphorylation of OTUB1 promotes autophagy initiation under starvation.

Liangbo Sun, Meng He, Dong Liu, Jiahong Liu, Meihua Shan, Mingzhen Yang, Yan Zhang, Xufang Dai, Jie Yao, Yanhao Zhang, Haojun Xiong, Fengtian He, Jiqin Lian.

Eukaryotes initiate autophagy in response to environmental challenges such as nutrient deprivation. However, the mechanisms governing autophagy initiation remain incompletely understood. Here, we demonstrated that OTUB1 phosphorylation plays a key role in starvation-induced autophagy initiation. Specifically, ERK phosphorylates OTUB1 at S118 during starvation. This phosphorylation enables competitive binding of ANXA2 to OTUB1, disrupting its interaction with TRIM29 and enhancing OTUB1 stability. Stabilized OTUB1 upregulated DEPTOR, thereby inhibiting mTOR and inducing autophagy. Furthermore, in vivo studies reveal that fasting-induced OTUB1-mTOR-autophagy axis counteracted Western diet-mediated mTOR activation by restoring ERK-dependent OTUB1 phosphorylation, ultimately ameliorating MASLD progression. Collectively, this study uncovers a phosphorylation-dependent regulatory mechanism controlling OTUB1's function in nutrient deficiency-triggered autophagy initiation, providing cellular and molecular evidence supporting the therapeutic potential of fasting in alleviating MASLD.

DOI: https://doi.org/10.1038/s41467-026-76796-7
Transl Neurodegener. 2026 Sep 18. pii: 48. [Epub ahead of print]15(1):

Species-dependent activities of the PINK1-parkin axis.

Wei Huang, Kecheng Chen, Jiayi Wen, Tong Zhang, Shihua Li, Xiao-Jiang Li, Weili Yang.

  In vitro studies have established that PTEN-induced putative kinase 1 (PINK1) and parkin are central regulators of mitophagy, and loss-of-function mutations in either gene can cause early-onset Parkinson's disease (PD). Although various animal models, including mice and pigs with PINK1 or PRKN knockout, have largely failed to recapitulate the neurodegeneration seen in PD patients, effective knockdown of PINK1 or PRKN in non-human primates, when achieving substantial protein depletion, does induce dopaminergic neuron loss in the substantia nigra and α‑synuclein pathology, suggesting that both the degree of protein loss and the species-dependent PINK1-parkin axis activity contribute to PD pathogenesis. This review compares pathological and behavioral outcomes of PINK1- and parkin-deficient animal models across species, illustrates diverse functions of the PINK1-parkin axis beyond mitophagy, discusses mechanisms underlying the species-dependent differences, and highlights the therapeutic potential of targeting this pathway. The review also underscores the necessity of considering species-specific mechanisms when investigating the PINK1/parkin pathway.

Keywords:  Animal models; Non-human primate; PINK1; Parkinson’s disease; Species specificity; parkin

DOI:  https://doi.org/10.1186/s40035-026-00586-w
PLoS Biol. 2026 Sep 18. 24(9): e3003555

Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation.

Mona Nazemi, Bian Yanes, Eric Vancauwenberghe, Ifeoluwa Oyelade, Heather Walker, Elena Rainero.

Invasive breast and pancreatic cancer cells thrive within a collagen I-rich, poorly perfused extracellular matrix (ECM) network, necessitating robust metabolic adaptation to endure nutrient deficiency, such as glucose starvation. Here we demonstrate that collagen I is critical for the survival and growth of breast and pancreatic cancer cells. Mechanistically, collagen I promotes α2 β1 integrin-dependent S6 phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) and drives the membrane localisation of the (LAT1)-4F2hc amino acid transporter. This process ensures a sustained intracellular essential amino acid supply, further fuelling mTORC1 signalling and limiting autophagy. This collagen I-driven pathway is essential for cancer cell survival, as inhibiting the activity of α2 β1 integrin or the LAT1-4F2hc transporter significantly reduces cell growth and invasion in both 2D and 3D models. Finally, the clinical relevance of these transporters is underscored by the significant upregulation of LAT1-4F2hc expression in basal-like breast and pancreatic cancer patients, correlating with poor prognosis and drug resistance. Collectively, our findings highlight that targeting the LAT1-4F2hc transporter might represent a highly promising therapeutic strategy to limit cancer cell growth and invasion in highly fibrotic and nutrient-deprived tumours.

DOI: https://doi.org/10.1371/journal.pbio.3003555
Phytomedicine. 2026 Sep 10. pii: S0944-7113(26)01025-1. [Epub ahead of print]162 158795

Gomisin N ameliorates autophagy-neuroinflammation imbalance in Parkinson's disease models via modulating the ATG16L1/NLRP3 axis.

Chengfu Su, Zhiqiang Deng, Ka Yee Ying, Jia Liu, Xinjie Guan, Yuxuan Kan, Xiaogang Xu, Ashok Iyaswamy, Kejia Lu, Jing Lu, Jiaxi Wu, Jianguang Zhu, King-Ho Cheung, Min Li, Juxian Song.

   BACKGROUND: Parkinson's disease (PD) is characterized by dopaminergic neuron loss, α-synuclein accumulation, and sustained neuroinflammation. Autophagy can remove pathogenic α-synuclein and restrain NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Gomisin N (GN), a lignan from Schisandra chinensis, is neuroprotective, but its mechanism in PD remains incompletely defined.
PURPOSE: To determine whether GN protects against PD-like pathology by coordinating autophagy and neuroinflammation through autophagy related 16 like 1 (ATG16L1).
METHODS: Neuronal and microglial cell models, as well as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice with ATG16L1 knockdown, were assessed through pharmacological, behavioral, biochemical, and immunohistochemical analyses.
RESULTS: GN crossed the blood-brain barrier, improved motor performance, preserved dopaminergic neurons, reduced α-synuclein oligomers, and suppressed NLRP3/caspase-1/interleukin-1β signaling in MPTP-treated mice. Mechanistically, GN increased the mRNA and protein levels of ATG16L1, enhanced ATG16L1-ATG5 complex formation, and promoted autophagic flux and lysosomal function without canonical mTORC1 inhibition Notably, we uncovered a vicious cycle where α-synuclein overexpression suppressed ATG16L1, impairing autophagy; GN effectively rescued this compromised ATG16L1 expression, facilitating targeted α-synuclein degradation. In microglia, GN blunted NLRP3 inflammasome activation by promoting the ATG16L1-dependent autophagic degradation of essential inflammasome components. Crucially, ATG16L1 knockdown completely abrogated the neuroprotective and anti-inflammatory effects of GN both in vitro and in vivo.
CONCLUSION: GN is a brain-penetrant preclinical candidate that links ATG16L1-dependent autophagy with α-synuclein clearance and NLRP3 inflammasome suppression in PD models.

Keywords:  ATG16L1/NLRP3; Autophagy; Gomisin N; Neuroinflammation; Parkinson's disease

DOI:  https://doi.org/10.1016/j.phymed.2026.158795
Am J Physiol Cell Physiol. 2026 Sep 14.

5-Fluorouracil-based chemotherapy disrupts autophagy flux and protein synthesis in cultured myotubes: a role for mTORC1 signaling.

Jessica L Halle, Quan Zhang, Tanner Jenkins, James A Carson.

  5-Fluorouracil-based chemotherapies, such as FOLFOX (5-fluorouracil, leucovorin, oxaliplatin), are used to treat colon cancer but also induce skeletal muscle toxicities. While FOLFOX can disrupt muscle autophagy signaling in vivo, the upstream mechanisms underlying this effect, as well as the roles of mTORC1 and AMPK signaling, require further investigation. We investigated whether 5-FU, 5-FU + leucovorin, oxaliplatin, or the combined FOLFOX regimen disrupts protein synthesis or autophagy flux through altered mTORC1/AMPK signaling in C2C12 myotubes with or without tumor cell-conditioned media, and whether these effects were readily reversible. We also examined the effects of rapamycin or metformin administration on FOLFOX-induced disruptions to muscle protein synthesis and autophagy. FOLFOX was added to myotube cultures for 24 hours; recovery was assessed by removing FOLFOX from the culture media for an additional 24 hours. Cultured Colon-26 tumor cells (CT26) were used for conditioned media. Autophagy flux was assessed using Bafilomycin A1 and LC3BII/I immunoblotting. FOLFOX and CT26 each decreased myotube diameter and protein synthesis compared to the vehicle. CT26, but not FOLFOX, increased STAT3 phosphorylation. FOLFOX, but not CT26, increased Atrogin-1 protein, while MURF-1 protein was increased by both CT26 and FOLFOX. FOLFOX reduced autophagy flux, AMPK, and ULK1(S555) phosphorylation, which did not recover upon FOLFOX removal. Rapamycin, but not metformin, altered autophagy flux in FOLFOX-treated myotubes and restored suppressed AMPK phosphorylation without increasing protein synthesis. We report that FOLFOX and oxaliplatin disrupt myotube mTORC1/AMPK regulation of autophagy flux, which was not easily reversible. However, rapamycin treatment increased autophagy flux in FOLFOX-treated myotubes.

Keywords:  Colon Cancer; FOLFOX; Muscle; Oxaliplatin; Rapamycin; metformin

DOI:  https://doi.org/10.1152/ajpcell.00321.2026
Mol Med Rep. 2026 Nov;pii: 314. [Epub ahead of print]34(5):

Demethylase FTO attenuates atherosclerotic plaque via upregulating ABCA1 and ABCG1 expression by targeting ATG5.

Fengxia Guo, Mei He, Yaonan Li, Kangning Zhu, Bing Hu.

  N6‑methyladenosine (m6A), the predominant internal modification in eukaryotic mRNAs, has emerged as a significant epigenetic regulator in atherosclerosis; however, its precise mechanistic contributions remain inadequately elucidated. The present study demonstrated that the m6A demethylase fat mass and obesity‑associated (FTO) regulates autophagy, lipid metabolism and plaque vulnerability by targeting autophagy related 5 (ATG5). FTO knockdown resulted in reduced ATG5 expression, thereby suppressing autophagy and downregulating ATP‑binding cassette transporter A1 (ABCA1) and ATP‑binding cassette sub‑family G member 1 (ABCG1). The regulation of ATG5 expression by FTO occurs through direct binding to its transcripts as well as m6A‑mediated mechanisms. Increased m6A modification on ATG5 mRNA following FTO silencing enhanced its recognition by YTH domain‑containing family 1, leading to transcript degradation and diminished protein levels. Consequently, autophagy and cholesterol efflux pathways were inhibited. In vivo experiments revealed that specific FTO knockdown compromised plaque stability and impaired ATG5‑mediated autophagy, in addition to downregulating ABCA1 and ABCG1. These findings highlighted the FTO‑ATG5‑ABCA1/ABCG1 axis as a critical regulator of autophagy and lipid homeostasis in atherosclerosis.

Keywords:  atherosclerotic plaque; autophagy; fat mass and obesity‑associated

DOI:  https://doi.org/10.3892/mmr.2026.14025
Nature. 2026 Sep 15.

Quality control of glycogen through direct ubiquitylation by RNF213.

Matthew C J Yip, Katerina Naydenova, Elsje G Otten, Alexander Heatley, Agnes Moe, Leonie Anton, Lucía de Los Reyes-Ramírez, Helen E Jolin, Frederic Langevin, Michal Wiacek, Catarina Franco, Anne Bertolotti, Wanda Kukulski, Andrew N J McKenzie, Felix Randow.

Quality control of biomolecules is vital for organismal health. While DNA repair and protein quality control are well understood, how cells monitor other important biomolecules such as glycogen remains ill-defined. The accumulation of aberrant, poorly branched glycogen into insoluble polyglucosan bodies causes severe disease1,2. Here, we discover autophagy of ubiquitylated aberrant glycogen as a previously unrecognized quality control mechanism safeguarding the brain from polyglucosan buildup. This mechanism depends on the E3 ubiquitin ligase RNF213. Mice lacking ligase activity in RNF213 accumulate polyglucosan in cerebellum, pons, and hippocampus. Using cells engineered to produce polyglucosan, we show that RNF213 selectively ubiquitylates abnormal glycogen. Cryo-EM analysis of RNF213 bound to glycogen-derived maltoheptaose revealed its CBM20 domain binds linear oligosaccharides. Disrupting carbohydrate binding results in gain of E3 ligase activity towards physiological glycogen, indicating the CBM20 domain limits RNF213 activity towards physiological glycogen. Epistasis analysis places RNF213 upstream of LUBAC, suggesting a hierarchical network of multiple E3 ligases surveying glycogen quality. Ubiquitylated polyglucosan recruits the autophagy receptors SQSTM1, TAX1BP1, and optineurin, thereby triggering uptake into autophagosomes. These findings identify RNF213 as a quality control factor preventing polyglucosan accumulation in astrocytes through direct ubiquitylation of polyglucosan, revealing an essential role for non-protein ubiquitylation in glycogen quality control.

DOI: https://doi.org/10.1038/s41586-026-11139-6
Front Cardiovasc Med. 2026 ;13 1925684

Regulatory mechanisms and interactions of mitophagy and ketone body metabolism in cardiac metabolism.

Shujun Ding, Yuna Hu, Qin Zhang, Xinyi Liu, Xuan Zhao, Yajing Zhao, Wen Zhang.

  Cardiac function depends on tightly regulated energy metabolism, with mitochondria serving as key sites of cellular energy production. Mitophagy, a selective form of autophagy that maintains mitochondrial quality, has received growing attention for its role in cardiomyocyte metabolism. Under specific physiological and pathological conditions, the myocardium increases its use of ketone bodies as energy substrates, and ketone body metabolism is closely linked to mitochondrial function. However, the relationship between mitophagy and ketone body metabolism is incompletely understood, particularly in cardiovascular disease. This review summarizes their roles and regulatory mechanisms in the myocardium and evaluates evidence for a potential bidirectional relationship. Mitophagy may preserve the mitochondrial capacity required for ketone body oxidation, whereas ketone body metabolism and β-hydroxybutyrate-mediated signaling may regulate mitophagy and mitochondrial stress resilience. By integrating these interactions across cardiovascular disease phenotypes, this review highlights their potential therapeutic relevance and identifies priorities for mechanism-based intervention and clinical translation.

Keywords:  ketone body; metabolic flexibility; mitochondria; mitophagy; myocardial metabolism

DOI:  https://doi.org/10.3389/fcvm.2026.1925684
Nat Commun. 2026 Aug 13. pii: 9750. [Epub ahead of print]17(1):

Inhibition of RhoA-mediated secretory autophagy in megakaryocytes mitigates myelofibrosis in mice.

Isabelle C Becker, Siobhan Branfield, Maria N Barrachina, Virginia Camacho, Joshua Lykins, Andrew P Stone, Ethan Walsey, Muhammad Bennani, Bernadette A Chua, Robert A J Signer, Kellie R Machlus, Sidney W Whiteheart, Harvey G Roweth, Joseph E Italiano.

Megakaryocytes (MKs) are polyploid cells that maintain bone marrow homeostasis by secreting cytokines, including transforming growth factor β1 (TGFβ1). During neoplastic transformation, MKs accumulate in the bone marrow, promoting fibrotic remodeling that leads to myelofibrosis. However, the therapeutic potential of targeting MK cytokine secretion remains poorly understood. Because unconventional secretion of TGFβ1 and interleukin 1β (IL1β) via secretory autophagy occurs in other cell types, we investigated whether MKs may utilize the same mechanism. Disrupting secretory autophagy, or inhibiting the small GTPase RhoA or its downstream effector Rho-associated kinase (ROCK), markedly reduced TGFβ1 and IL1β secretion in vitro. Conditional deletion of the autophagy gene Atg5 in the hematopoietic system limited megakaryocytosis and aberrant cytokine secretion in an MPLW515L-driven transplant model, while MK-specific deletion of Rhoa protected mice from fibrosis. Ultimately, ROCK inhibition, alone or combined with a JAK2 inhibitor, also attenuated disease hallmarks, identifying the RhoA-secretory autophagy axis as a promising therapeutic target in myelofibrosis.

DOI: https://doi.org/10.1038/s41467-026-76615-z
Nat Cell Biol. 2026 Sep 15.

Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway.

Johannes Breithofer, Nermeen Fawzy, Clara Zitta, Martin Tischitz, Dominik Bulfon, Clemens Hofmann, Lennart Hartig, Carina Wagner, Gernot F Grabner, Anita Pirchheim, Achim Lass, Ulrike Taschler, Keira Turner, Kasparas Petkevicius, Ulrich Stelzl, Dagmar Kratky, Rolf Breinbauer, Robert Zimmermann.

According to text book knowledge, de novo glycerophospholipid (GPL) synthesis begins with the acylation of glycerol-3-phosphate to form phosphatidic acid, the precursor of all other GPLs. Here we describe an alternative GPL synthesis pathway that starts with the acyl-CoA-dependent acylation of glycerophosphoglycerol, resulting in the formation of lysophosphatidylglycerol. The acyltransferase reaction is catalysed by the Batten disease-associated protein ceroid lipofuscinosis neuronal 8 (CLN8). Tracer studies revealed that CLN8-derived lysophosphatidylglycerol is selectively converted into bis(monoacylglycero)phosphate (BMP), a GPL essential for lysosomal lipid homeostasis but not into phosphatidylglycerol or cardiolipin. CLN8-knockout cells and mice cannot utilize glycerophosphoglycerol for BMP synthesis, resulting in BMP deficiency and excess accumulation of phospholipids in lysosomes. The lipid synthesis pathway described herein is relevant for understanding lysosomal lipid metabolism and the pathogenesis of neurodegenerative diseases. BMP deficiency may contribute to or even underlie lysosomal cargo accumulation in certain forms of Batten disease and other lysosomal storage disorders.

DOI: https://doi.org/10.1038/s41556-026-02059-8
J Cell Biol. 2026 Nov 02. pii: e202508151. [Epub ahead of print]225(11):

Visualizing the Golgi apparatus and Golgiphagy in vivo.

Pengwei Zhao, Mengyuan Zhang, Rongbin Ding, Dandan Song, Wei Liu, Lingling Zhang, Yongjuan Sang, Qiming Sun.

The Golgi apparatus is essential for protein secretion and cellular homeostasis, yet its organization and turnover in living tissues remain poorly understood. Golgiphagy, the selective autophagic degradation of the Golgi, has emerged as a key quality control pathway, but its physiological regulation in vivo remains largely unknown. Here, we generated two reporter mouse lines for constitutive or Cre-dependent visualization of Golgi architecture and Golgiphagy, enabling quantitative single-cell analysis across tissues. These models revealed striking cell type- and tissue-specific heterogeneity in basal Golgiphagy, including higher activity in renal proximal than distal tubules and in cerebellar than cortical neurons. Starvation and lipopolysaccharide-induced inflammation also promoted Golgi remodeling and Golgiphagy in multiple organs, particularly the liver, spleen, and kidney. Together, these reporter mice provide a powerful genetic toolkit for studying Golgi dynamics in vivo and establish that Golgiphagy is a spatially heterogeneous and stress-responsive process under physiological conditions.

DOI: https://doi.org/10.1083/jcb.202508151
Biochem Pharmacol. 2026 Sep 16. pii: S0006-2952(26)00825-7. [Epub ahead of print] 118483

Itaconic acid dissolves TFEB liquid-liquid phase separation to alleviate hyperoxia-induced bronchopulmonary dysplasia.

Tengfei Wang, Fengdan Xu, Hui Shi, Rui Long, Zhenyang Ye, Weineng Xie, Xiaoguang He, Xingyun Wang, Ning Li.

  Supplemental oxygen in premature neonates risks bronchopulmonary dysplasia (BPD). Although the metabolite itaconic acid (ITA) promotes transcription factor EB (TFEB) nuclear translocation to alleviate BPD, the upstream mechanism driving hyperoxia-induced TFEB sequestration remains unclear. Here, we investigated whether hyperoxia exploits liquid-liquid phase separation (LLPS) to trap cytoplasmic TFEB, and if ITA directly dissolves these pathological condensates. Using hyperoxia-induced BPD mice (85 % O2) and MLE12 cells, we analyzed TFEB LLPS via FRAP, fusion, and in vitro phase separation assays. ITA-TFEB binding was evaluated by surface plasmon resonance (SPR). Autophagic/mitophagic flux and apoptosis were assessed, and the necessity of TFEB was validated using shRNA knockdown in vivo and in 3D lung organoids. We found that hyperoxia promoted TFEB accumulation into cytoplasmic condensates with liquid-like properties, which was associated with the blockage of its nuclear import. ITA directly bound TFEB with high affinity (confirmed by SPR) and effectively disrupted these pathological condensates without altering basal expression. Consequently, ITA restored TFEB nuclear translocation, reactivated mitophagy, cleared dysfunctional mitochondria, and reduced AT2 cell apoptosis in BPD lungs. These protective effects of ITA were abolished by TFEB knockdown in vivo and in lung organoids. Collectively, our findings suggest that hyperoxia-triggered TFEB phase-separation-like behavior represents a novel biophysical mechanism of autophagic arrest in BPD. By acting as an endogenous metabolite capable of disrupting biomolecular condensates, ITA alleviates pathological TFEB condensates, restoring mitophagy and alveolar development, thereby proposing a paradigm of targeting aberrant macromolecular condensation for neonatal lung injury.

Keywords:  Bronchopulmonary dysplasia; Itaconic acid; Liquid-liquid phase separation; Lung development; TFEB

DOI:  https://doi.org/10.1016/j.bcp.2026.118483
Nat Commun. 2026 08 19. pii: 9900. [Epub ahead of print]17(1):

APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics.

Carla Cuní-López, Jessica T Root, Ying Hao, Niek Blomberg, Sascha J Koppes-den Hertog, Dylan Sacks, Amber E Trujillo, Rodolfo Ghirlando, Isabelle Kowal, Jacob Epstein, Linda G Yang, Mark R Cookson, Elise Marsan, Rik van der Kant, Martin Giera, Yue Andy Qi, Priyanka S Narayan.

Lipid droplets are dynamic cellular organelles that store neutral lipids and coordinate metabolic and stress-response pathways. In the brain, lipid droplets in glial cells, including astrocytes, have been implicated in Alzheimer's disease, but how genetic risk factors influence their composition and turnover remains poorly understood. APOE is the strongest genetic modulator of late-onset Alzheimer's disease and exists in common variants that confer decreased, neutral, or increased risk. Here we show that APOE genotype shapes the lipid droplet proteome, lipidome, and degradation dynamics in human induced pluripotent stem cell-derived astrocytes. By comparing oleic acid-treated astrocytes carrying APOE2, APOE3, or APOE4, we find that each variant is associated with distinct lipid droplet proteins and lipids. These molecular differences correspond to genotype-dependent changes in lipophagy, an autophagy-mediated pathway for lipid droplet clearance. Lipid droplets in APOE2 astrocytes undergo efficient autophagic turnover, whereas those in APOE4 astrocytes resist degradation. These findings identify impaired lipid droplet clearance as a potential mechanism linking APOE4 to Alzheimer's disease risk.

DOI: https://doi.org/10.1038/s41467-026-76565-6
Nat Commun. 2026 09 16. pii: 9877. [Epub ahead of print]17(1):

Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.

Nádia Da Silva Fernandes, Fridolin Kielisch, Amitkumar Fulzele, Sivarajan Karunanithi, Justus F Gräf, Jia-Xuan Chen, Christian Behl, Helle D Ulrich, Petra Beli.

Cellular senescence is a state of irreversible cell cycle arrest triggered by telomere erosion, persistent DNA damage or chronic stress. The accumulation of senescent cells disrupts tissue function and contributes to aging and disease. Here, we employ mass spectrometry-based proteomics to systematically interrogate dynamic proteome changes at multiple levels during the progression of replicative cellular senescence. We demonstrate that proteome changes during senescence occur in a coordinated manner, characterized by widespread protein depletion on chromatin. Moreover, components of the cytoplasmic translation machinery are depleted, while mitochondrial proteins display increased insolubility. Autophagic and proteasome activity is compromised in senescent cells along with remodeling of ubiquitin linkages and depletion of ubiquitin E3 ligases. Comparison of the senescent proteome with different pathophysiological cellular states reveals a distinctive senescent signature shaped by changes in the proteostasis network. Collectively, we provide a resource for the exploration of temporally resolved changes in the senescent proteome.

DOI: https://doi.org/10.1038/s41467-026-77686-8
Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2616684123

Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.

Baolong Xia, Myeonghoon Han, Isaac Park, Norbert Perrimon.

  Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.

Keywords:  SREBP; de novo lipogenesis; lysosomal enzyme transport; protein myristoylation; proximity labeling

DOI:  https://doi.org/10.1073/pnas.2616684123
Mol Neurodegener Adv. 2026 ;2(1): 38

Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?

Silas A Buck, Sidharth S Madhavan, Laurie H Sanders.

  Many neurodegenerative diseases are characterized by pathological protein aggregation in the brain. Alzheimer's disease displays amyloid-β and tau inclusions in the form of amyloid-β plaques and tau neurofibrillary tangles. Synucleinopathies comprise Parkinson's disease and Dementia with Lewy bodies, which are classified by α-synuclein depositions in the form of Lewy bodies, as well as multiple system atrophy, which displays glial cytoplasmic α-synuclein inclusions. Tar DNA binding protein 43 (TDP-43) inclusions are observed in amyotrophic lateral sclerosis and frontotemporal lobar dementia with TDP-43 inclusions. A separate subgroup of frontotemporal lobar dementias, including Pick's disease, progressive supranuclear palsy and corticobasal degeneration, are characterized by disease-specific patterns of tau pathology and are termed primary tauopathies. Despite these classifications, it is not often appreciated that neurodegenerative diseases commonly display amyloid-β, tau, α-synuclein, and/or TDP-43 co-pathologies not typically associated with that specific disease's pathophysiology. Additionally, in vitro and in vivo proteinopathy models show interactions between pathological forms of these proteins that increase protein aggregation and neurotoxicity, suggesting distinct mechanisms underlying co-pathologies that play a significant role in neurodegeneration. In this review, we describe the frequency of protein co-pathologies across neurodegenerative diseases and preclinical work demonstrating pathological protein synergies that exacerbate protein aggregation and toxicity. We also discuss granulovacuolar degeneration bodies, proteolytically active lysosomal structures that are induced by either pathological tau or α-synuclein accumulation, as an example of a shared cellular response to, and link between, distinct protein pathologies. Finally, we highlight interventional clinical trials which target multiple pathologies and/or specifically target co-pathologies in neurodegenerative diseases, noting that current preclinical and clinical research is limited and this line of investigation should be pursued more vigorously. In all, we find that protein co-pathologies are frequently observed in the brains of common neurodegenerative diseases and serve as important future therapeutic targets for combatting neurodegeneration across clinically distinct diseases.
Graphical abstract:

Keywords:  Alzheimer’s disease; Amyloid; Amyotrophic lateral sclerosis; Co-pathology; Granulovacuolar degeneration bodies; Lewy body disease; Synuclein; TDP-43; Tau; Tauopathy

DOI:  https://doi.org/10.1186/s44477-026-00047-8
Front Cardiovasc Med. 2026 ;13 1884607

Mitophagy as an active regulator of cardiac metabolic reprogramming.

Li Gai, Yan Li, Chen Yang, Mengya Wang.

  Mitophagy is increasingly recognized as a context-dependent regulator of cardiac metabolic adaptation rather than solely as a disposal pathway for damaged mitochondria. By coupling mitochondrial turnover to substrate selection, redox control, and inflammatory signaling, mitophagy can influence fatty acid oxidation (FAO), glycolysis, and oxidative phosphorylation (OXPHOS) in cardiomyocytes, vascular endothelial cells, and immune cells. In this review, the term Mitophagy-Metabolic Rewiring Axis (MMRA) is used as an integrative conceptual framework-not as a newly discovered pathway or theory-to organize evidence for bidirectional interactions between mitophagy and metabolic remodeling. The framework comprises stress inputs, mitophagy machinery and flux, metabolic outputs, and cell- or disease-level consequences, while emphasizing that the biological effect of mitophagy depends on cell type, disease stage, and duration of activation. We critically assess the AMP-activated protein kinase (AMPK)-UNC-51-like kinase 1 (ULK1), sirtuin 3 (SIRT3)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), PTEN-induced kinase 1 (PINK1)-Parkin E3 ubiquitin ligase, and hypoxia-inducible factor 1-alpha (HIF-1α)-BCL2-interacting protein 3 (BNIP3)/FUN14 domain-containing 1 (FUNDC1) modules in atherosclerosis, heart failure, and ischemia/reperfusion injury. Pharmacological, substrate-based, and exercise interventions are evaluated with particular attention to the predominantly preclinical evidence base, methodological limitations in measuring mitophagy flux, and the need for validated human biomarkers. Multi-omics and spatial approaches may improve mechanistic resolution, but clinical translation will require prospective studies that link target engagement to metabolic and cardiovascular outcomes.

Keywords:  AMPK–ULK1; FUNDC1; SIRT3–PGC-1α; cardiovascular disease; metabolic reprogramming; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.3389/fcvm.2026.1884607