bims-auttor 2026-01-18 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–01–18
thirty-two papers selected by
Viktor Korolchuk, Newcastle University

Advances in autophagy for Parkinson's disease pathogenesis and treatment.
SNX-3 confers lysosomal fusion-competence to sustain basal autophagy.
ATG9A-dependent, LC3-independent autophagy curbs the immune system to protect against disease.
Muscle meets Lysosomes: emerging strategies in muscular dystrophy.
Dual-faced PUMA in CRC: A cytoplasmic autophagy repressor and mitochondrial mitophagy promoter.
Cross-regulation of autophagy and pyroptosis: a new perspective on the inflammatory microenvironment of atherosclerosis.
Obestatin Treatment Counteracts Muscle Wasting by Reactivation of Autophagy in Duchenne Muscular Dystrophy.
Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation.
Brain organoid models of SZT2-related disease reveal an overproduction of outer radial glial cells through mTORC1 activation.
Methionine suppresses autophagy in Cryptococcus neoformans: Impact of GPP2 gene deletion on the expression of autophagy-related genes.
MYO5A-mediated stabilization promotes the acquisition of fusion competence in sealed autophagosomes.
Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.
Pioneers: Glucose sensing and control of health-span and lifespan.
Epigenetic H3K4me3 activation of miR-155-5p promotes intervertebral disc degeneration via autophagy and ageing in nucleus pulposus cells.
A GluN2B disease-associated variant promotes the degradation of NMDA receptors via autophagy.
Glycophagy: molecular mechanisms, regulatory signals, and disease associations.
The activation of the mTOR pathway supports lysosome biogenesis in the sea urchin embryo.
Disruption of intracellular iron homeostasis through mitochondrial dysfunction associated with suppression of ATP 13A2 expression.
AMPK Modulates the Interplay Between PINK1/Parkin-Mediated Mitophagy and NLRP3-Driven Inflammation in Diabetic Periodontal Tissue Under Mechanical Loading.
Cholesterol Deficiency Directs Autophagy-Dependent Secretion of Extracellular Vesicles.
Dissociation of the mTOR Protein Interaction Network Following Neuronal Activation Is Altered by Shank3 Mutation.
Disrupted autophagy overactivates TBK1 and results in mitotic defects promoting chromosomal instability.
Autophagy Impacts Dendritic Spines Differently in Proximal and Distal Dendrites of Hippocampus CA1 Neurons.
Chitosan-based nanoparticles for targeted delivery of 17β-estradiol to enhance SIRT1-mediated autophagy and mitigate rotenone-induced Parkinson's disease.
The interplay between autophagy and unconventional secretion in neurodegeneration.
Mitochondrial fission during mitophagy requires both inner and outer mitofissins.
Metabolites released from apoptotic cells in central nervous system orchestrates the pathological process of Alzheimer disease through improving autophagy.
Drp1-mediated mitochondrial fission protects macrophages from mtDNA/ZBP1-mediated inflammation and inhibits post-infarct cardiac remodeling.
mTOR signaling governs the formation of epithelial apical projections via S6K1-RhoA and aPKC-Lgl2 axes.
Protection against myocardial ischemia reperfusion injury by liquiritin: involvement of autophagy restoration targeting PIK3CA.
Tmem110 regulates the conformation of TRPML1 to maintain endolysosomal homeostasis and prevent mitochondrial DNA leakage and pathological self-DNA processing.
Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.

Ageing Neurodegener Dis. 2025 ;pii: 6. [Epub ahead of print]5(1):

Advances in autophagy for Parkinson's disease pathogenesis and treatment.

Xiaojie Zhang, Huan Zhang, Jie Dong, Huaibin Cai, Weidong Le.

  Autophagy is a cellular process essential for maintaining neuronal homeostasis by degrading and recycling damaged organelles and proteins. Impairments in canonical autophagy pathways, such as macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy, are linked to Parkinson's disease (PD) pathogenesis, contributing to α-synuclein aggregation and dopaminergic neuronal loss. Moreover, the recent discovery of noncanonical autophagy highlights the unexpected roles of autophagy-related proteins in protein degradation beyond the canonical autophagy pathways. Advances in understanding the molecular mechanisms of autophagy provide potential therapeutic strategies to modulate this pathway in PD. Key therapeutic targets include mTOR and AMPK, with compounds like rapamycin, trehalose, and resveratrol showing promise in preclinical models. Enhancing lysosomal function and mitophagy also presents a viable strategy to alleviate PD symptoms. This review emphasizes the complex roles of autophagy in PD and highlights the potential of autophagy modulation as a promising therapeutic strategy for treating the disease.

Keywords:  Parkinson’s disease; autophagy; chaperone-mediated autophagy; lysosome; mitophagy

DOI:  https://doi.org/10.20517/and.2024.33
Cell Mol Life Sci. 2026 Jan 15.

SNX-3 confers lysosomal fusion-competence to sustain basal autophagy.

Qiaoju Kang, Zhenyu Liu, Lianyan Xiang, Sai Yang, Ping Yi, Rongying Zhang.

  Autophagy, the process for recycling cytoplasm in the lysosome, relies on tightly regulated membrane trafficking. During autophagy, autophagosomes either fuse with endosomes generating amphisomes and then lysosomes, or directly fuse with lysosomes, in both cases generating autolysosomes that degrade their contents. It remains unclear whether specific mechanisms or conditions determine these alternate routes. Here, we demonstrate that the endosomal regulator SNX3 specifically regulates basal autophagy under nutrient-adequate conditions in both Caenorhabditis elegans (C. elegans) and cultured mammalian cells. In C. elegans, SNX-3 depletion elevates autophagy independently of the UNC-51/ULK1 complex and leads to the accumulation of both autophagosomes and amphisomes, which consequently impairs the clearance of autophagic cargo, including SQST-1/p62 and protein aggregates. Mechanistically, SNX-3 depletion differentially regulates the machineries required for autophagosome-lysosome fusion. In snx-3 mutants, the Q-SNARE components SYX-17 and SNAP-29 translocate to autophagosomes, where they assemble with the endosomal R-SNAREs VAMP-7 and VAMP-8 to promote amphisome formation. Conversely, loss of SNX-3 impairs the lysosomal delivery of VAMP-8 and RAB-7, both essential for autophagosome/amphisome-lysosome fusion, thereby generating fusion-incompetent lysosomes. However, starvation restores the lysosomal fusion capability compromised by snx-3 depletion. Our findings reveal that autophagosome-lysosome fusion is preferentially regulated by nutrient status, and identify an endosomal regulator that tunes membrane trafficking with changing autophagy demands.

Keywords:  Amphisome; Autophagosome–lysosome fusion; Basal autophagy; RAB-7; SNARE

DOI:  https://doi.org/10.1007/s00018-025-06074-0
Autophagy Rep. 2026 ;5(1): 2614147

ATG9A-dependent, LC3-independent autophagy curbs the immune system to protect against disease.

Dario Priem, Mathieu Jm Bertrand.

  Selective autophagy is generally believed to require the conjugation of microtubule associated protein 1 light chain 3 (LC3) proteins (or other autophagy-related 8 [ATG8] family members) on the inner phagophore leaflet to enable the recruitment of cargo-bound selective autophagy receptors. However, this paradigm is challenged by the discovery that cytosolic cargoes can still be selectively targeted by phagophores even in the absence of LC3 proteins. In a recent study published in Immunity, we discovered that ATG9A-dependent, LC3-independent autophagy facilitates the degradation of multiple inflammatory signaling complexes to prevent an inflammatory skin disease.

Keywords:  ATG9A; LC3-independent autophagy; STING; TNF; ZBP1; cGAS; cell death; inflammation; inflammatory skin disease; nucleic acid immunity

DOI:  https://doi.org/10.1080/27694127.2026.2614147
Autophagy. 2026 Jan 14. 1-3

Muscle meets Lysosomes: emerging strategies in muscular dystrophy.

Abbass Jaber, David Israeli.

  Duchenne muscular dystrophy (DMD) is caused by the loss of DMD (dystrophin), leading to sarcolemmal fragility and progressive muscle degeneration. Although adeno-associated viral (AAV) microdystrophin (µDMD) therapies have advanced clinically, their benefits remain partial, highlighting the need to identify secondary cellular defects that limit therapeutic efficacy. In our recent study, we demonstrated that lysosomal dysfunction is a conserved, intrinsic, and persistent feature of DMD pathology. Using mouse, canine, and human dystrophic muscle, we show marked lysosomal membrane permeabilization (LMP), impaired acidification, defective proteolysis, and inefficient membrane repair, all hallmarks of compromised lysosomal integrity. Cholesterol accumulation within dystrophic myofibers further exacerbates these defects, linking lipid dysregulation to lysosomal injury and accelerated muscle degeneration. We find macroautophagy/autophagy impairment in DMD stems in part from reduced autophagosome-lysosome fusion, reframing autophagy failure as a downstream consequence of lysosomal damage. µDMD gene therapy only partially corrects these abnormalities and does not fully restore lysosomal stability. In contrast, combining µDMD with the lysosome-activating disaccharide trehalose produces synergistic benefits, improving muscle strength, architecture, and molecular signatures beyond either treatment alone. These findings position lysosomal dysfunction as a central driver of DMD pathophysiology and support therapeutic strategies that pair gene restoration with lysosomal enhancement.Abbreviation: AAV: adeno-associated virus; DAGC: DMD-associated glycoprotein complex; DMD: Duchenne muscular dystrophy; FDA: Food and Drug Administration; LMP: lysosome membrane permeabilization; MTOR: mechanistic target of rapamycin kinase; µDMD: microdystrophin.

Keywords:  Autophagy; Duchenne muscular dystrophy; galectin-3; lysosome; microdystrophin

DOI:  https://doi.org/10.1080/15548627.2026.2615985
Cell Signal. 2026 Jan 10. pii: S0898-6568(26)00012-4. [Epub ahead of print]140 112363

Dual-faced PUMA in CRC: A cytoplasmic autophagy repressor and mitochondrial mitophagy promoter.

Meimei Jiang, Mingyi Zhao, Yeying Liu, Jing Liu, Nannan Liu, Jiehan Li, Wunan Mi, Guiyun Jia, Yang Fu, Lingling Zhang, Yingjie Zhang, Feng Wang.

  As Bcl-2 family members, PUMA and Bcl-XL played critical roles in mitochondrial apoptosis. However, whether they can regulate autophagy, especially mitophagy, is not understood at all. In this study, we explore the interaction among PUMA and Bcl-XL in different subcellular localizations, and their functions in autophagy and mitophagy respectively. The detailed mechanisms were determined by mitochondria purification, Co-IP, and western blot analysis. Moreover, living cell imaging was performed to determine the occurrence of mitophagy. We found that PUMA inhibited autophagy by interacting with Ulk1 and Beclin1 in the cytoplasm. Six mutants of PUMA were constructed to further study which part is responsible for the interaction, and the BH3 domain shows indispensability. When PUMA moved to mitochondria and formed a complex with Ulk1 and Bcl-XL, which played opposite roles, in promoting mitophagy. During this process, Ser96 of PUMA was indispensable for activating mitophagy. Besides, over-expressed PUMA or Bcl-XL promotes obvious mitophagy, and the real-time detection of lysosome and mitochondria shows fusion. Our results identified new functions and molecular mechanisms of PUMA and Bcl-XL in autophagy and mitophagy, which supplied theoretical bases for CRC therapy and other diseases.

Keywords:  Bcl-X(L); CCCP; Macro-autophagy; Mitophagy; PUMA; Ulk1

DOI:  https://doi.org/10.1016/j.cellsig.2026.112363
Apoptosis. 2026 Jan 10. 31(1): 18

Cross-regulation of autophagy and pyroptosis: a new perspective on the inflammatory microenvironment of atherosclerosis.

Yu-Mei Gan, Nai-Shen Qin, Jun Ouyang, Yu-Ming Tang, Jia-Hui Qin, Shu-Min Wei, Hui Wang, Jiang-Nan Huang.

  The pathogenesis of atherosclerosis (AS) is a chronic disease marked by inflammation, and there are intimate associations with various forms of programmed cell death (PCD). Recently, the mechanisms of pyroptosis and autophagy in AS have attracted much attention. Pyroptosis is a form of PCD mediated by inflammasomes, which worsens local inflammatory responses by releasing proinflammatory factors (e.g., IL-18 and IL-1β) and favors plaque instability and thrombosis. Autophagy is a process that helps to keep cells healthy by breaking down damaged cell structures and abnormal proteins. Mitophagy, a specialized form of autophagy, is of major importance to redox homeostasis and the regulation of inflammation. However, the dysregulation of autophagy may disturb the cellular homeostasis, which then accelerates the progression of AS. Studies have found a complex mutual regulation between pyroptosis and autophagy. Autophagy can block the occurrence of pyroptosis by degrading the components of such as NLRP3. The inflammatory mediators released during pyroptosis may cause the disorder of autophagy, which aggravates the cell death and inflammatory response. The disorder of autophagy will also promote pyroptosis' occurrence and progress. Both of them play a vital role in AS. This study is mainly focused on clarifying the relationship and molecular mechanism between pyroptosis and autophagy in the context of AS. These findings pave the way for new avenues for understanding its pathogenesis and potentially therapeutic decision-making.

Keywords:  Atherosclerosis; Autophagy; Inflammation; Mitophagy; Pyroptosis

DOI:  https://doi.org/10.1007/s10495-025-02221-x
MedComm (2020). 2026 Jan;7(1): e70563

Obestatin Treatment Counteracts Muscle Wasting by Reactivation of Autophagy in Duchenne Muscular Dystrophy.

Icía Santos-Zas, Silvia Costas-Abalde, Andrea C Lodeiro, Fátima Fernández-Barreiro, Tania Cid-Díaz, Saúl Leal-López, Jessica González-Sánchez, Mar García-Lamela, Lucía Debasa-Corral, Carlos S Mosteiro, Kamel Mamchaoui, Vincent Mouly, Xesús Casabiell, Rosalía Gallego, José Luis Relova, Yolanda Pazos, Jesus P Camiña.

  The mechanisms by which muscular dystrophy-related stress is transduced to the autophagic machinery remain poorly characterized. The formulation of strategies should be based on how disruption of these processes results in the deregulation of signaling pathways that contribute to many pathological effects of the disease. In this study, we investigated the molecular mechanism by which the obestatin/GPR39 system, an autocrine signaling with anabolic impact on normal skeletal muscle, restores autophagy in Duchenne muscular dystrophy (DMD). We report that obestatin integrates 5' AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) signaling to control ubiquitin proteasome system (UPS), autophagy-lysosome system, and protein synthesis under dystrophic context. The posttranslational modifications of the E3 ligase NEDD4-L emerges as the main switch to activate the autophagy in response to obestatin. This includes NEDD4-L tyrosine phosphorylation and autoubiquitination, which is critical for recruiting the ubiquitin-specific protease 10 to assemble a deubiquitination complex, that orchestrates the unc-51 like autophagy activating kinase 1 (ULK1) and class III PI3K (VPS34) complexes. Reactivation of autophagy through obestatin signaling promotes the recovery of physiological skeletal muscle function. Thus, DMD conditions determine permissiveness to the activation of AMPK that sustain autophagy under anabolic conditions stablished by obestatin signaling through mTORC1.

Keywords:  Duchenne muscular dystrophy; autophagy; neural precursor cell expressed developmentally downregulated protein 4; obestatin; ubiquitin‐specific protease 10

DOI:  https://doi.org/10.1002/mco2.70563
Nat Commun. 2026 Jan 15.

Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation.

Tim Vervliet, Jens Loncke, Marko Sever, Karan Ahuja, Chris Van den Haute, Tomas Luyten, Grace E Stutzmann, Catherine Verfaillie, Tihomir Tomašič, Geert Bultynck.

Lysosomal and endoplasmic reticulum (ER) Ca2+ release mutually influence each other's functions. Recent work revealed that ER-located ryanodine receptor(s) (RyR(s)) Ca2+ release channels suppress autophagosome turnover by the lysosomes. In familial Alzheimer's disease, inhibiting RyR hyperactivity restored autophagic flux by normalizing lysosomal vacuolar H+-ATPase (vATPase) levels. However, the mechanisms by which RyRs control lysosomal function and how this involves the vATPase remain unknown. Here, we show that RyRs interact with the ATP6v0a1 subunit of the vATPase, contributing to ER-lysosomal contact site formation. This interaction suppresses RyR-mediated Ca²⁺ release, leading to reduced lysosomal exocytosis. Pharmacological inhibition of RyR activity mimics these effects on lysosomal exocytosis. Retaining lysosomes inside cells via RyR inhibition increases ER-lysosomal contact site formation, rendering lysosomes more available for autophagic flux. In summary, these findings establish RyR/ATP6v0a1 complexes as ER-lysosomal tethers that dynamically and Ca2+ dependently regulate the intracellular availability of lysosomes to participate in autophagic flux.

DOI: https://doi.org/10.1038/s41467-025-68054-z
Sci Rep. 2026 Jan 14.

Brain organoid models of SZT2-related disease reveal an overproduction of outer radial glial cells through mTORC1 activation.

Emi Sato, Yuji Nakamura, Masanori Fujimoto, Issei S Shimada, Toshihiko Iwaki, Daisuke Ieda, Yutaka Negishi, Ayako Hattori, Yoichi Kato, Shinji Saitoh.

  Biallelic loss-of-function variants of Seizure Threshold 2 (SZT2) cause neurodevelopmental diseases with developmental delay, epilepsy, and macrocephaly. SZT2 forms the KICSTOR complex, which represses the mechanistic target of rapamycin complex 1 (mTORC1) amino acid-sensitive pathway. SZT2 dysfunction is thought to cause abnormal activation of the mTOR pathway, underlying the pathogenesis of SZT2-related diseases. We previously reported constitutive activation of mTORC1 in lymphoblastoid cell lines derived from patients with SZT2-related disease. However, the impact of SZT2 dysfunction on human brain development remains unclear. In this study, we examined the effects of SZT2 dysfunction on brain development using human brain organoids. We generated pluripotent stem cell-derived brain organoids and found a significantly greater number of outer radial glial cells (oRGCs) in the subventricular zone-like layer (SVZ) of SZT2 mutant (MT) brain organoids compared to control (WT) brain organoids. The number of upper-layer neurons, which generally originate from oRGCs, was also significantly greater in SZT2 MT brain organoids. Mechanistically, SZT2 MT brain organoids showed higher mTORC1 activity in the SVZ, where neural stem/progenitor cells amplify for cortical expansion in response to mTORC1 activity. Our data suggest that SZT2 dysfunction may cause macrocephaly through dysregulation of mTORC1 in early neural development.

Keywords:  Basal radial glia; Cerebral organoids; Developmental and epileptic encephalopathy 18 (DEE18); Neurogenesis; Outer radial glia

DOI:  https://doi.org/10.1038/s41598-026-35733-w
Folia Microbiol (Praha). 2026 Jan 17.

Methionine suppresses autophagy in Cryptococcus neoformans: Impact of GPP2 gene deletion on the expression of autophagy-related genes.

Adrián Adolfo Álvarez Padilla, Kevin Felipe Cruz Martho, Gabrielle Felizardo, Renata Castiglioni Pascon, Marcelo Afonso Vallim.

  Autophagy is an essential intracellular degradation and recycling system for macromolecules and organelles, crucial for cell survival under nutrient stress conditions. In fungi, the genes involved in vesicle assembly during autophagy have been extensively characterized. However, in the pathogen Cryptococcus neoformans, the autophagy pathway remains less understood, particularly regarding its potential connections with virulence and pathogenicity. Our previous work identified Gpp2 as a key player in the biosynthesis of the sulfur-containing amino acid methionine. Through transcriptomic analysis, we observed that through transcriptomic analysis, we observed that deletion of GPP2 in C. neoformans leads to the repression of several core autophagy genes (ATG1, ATG2, ATG4, ATG15, VPS15, and VPS30), likely as an indirect consequence of altered methionine metabolism, while upregulating PEP4 expression. Since methionine is known to repress autophagy in Saccharomyces cerevisiae, we hypothesized that this amino acid might similarly regulate autophagy in C. neoformans. Our experiments demonstrated that both endogenous and exogenous methionine inhibit the expression of autophagy-related genes not only in the wild-type H99 strain but also in gpp2Δ and gpr4Δ mutant strains. Intriguingly, we found that GPR4 deletion creates a mutant unable to sense exogenous methionine, consequently releasing the repression of autophagy genes. Furthermore, microscopic analyses revealed that methionine supplementation substantially reduces autophagosome formation compared to methionine-deprived conditions. These results lead us to conclude that methionine biosynthesis regulation in gpp2Δ strains affects autophagy similarly to S. cerevisiae; GPR4 encodes a functional methionine receptor in C. neoformans; and methionine availability directly impacts autophagic flux, where the methionine receptor Gpr4 links extracellular amino acid availability to the intracellular control of autophagy likely via the Cys3/Gpp2 regulatory axis. This work provides crucial insights into the metabolic regulation of autophagy in pathogenic fungi and opens new avenues for understanding fungal pathogenesis mechanisms.

Keywords:   GPR4 ; Amino acid uptake; Autophagy; Methionine; PMSF

DOI:  https://doi.org/10.1007/s12223-025-01411-z
EMBO J. 2026 Jan 15.

MYO5A-mediated stabilization promotes the acquisition of fusion competence in sealed autophagosomes.

Akshaya Nambiar, René Martin, Kamakshi Tomar, Hans-Joachim Knölker, Sandhya P Koushika, Subramaniam K, Ravi Manjithaya.

  Autophagy requires precise regulation of autophagosome-lysosome fusion, yet the molecular details of this process remain incompletely understood. Here, we identify the class V myosin MYO5A as a critical regulator of autophagic flux. The genetic or pharmacological inhibition of MYO5A in Saccharomyces cerevisiae, mammalian cells, or Caenorhabditis elegans blocked autophagic flux by preventing autophagosome-lysosome fusion. MYO5A facilitates the maturation of autophagosomes into fusion-competent intermediates as its loss altered the localization of fusion machinery on autophagosomes and reduced the pool of stationary autophagosomes, a step that proved critical for subsequent fusion with lysosomes. Domain mapping and targeted mutagenesis revealed that two LIR motifs (PAYRVL and QAYIGL) within the coiled-coil and globular tail domains of MYO5A mediate its direct interaction with LC3 on autophagosomes. Live imaging in mammalian cells and C. elegans added support for this role, revealing how MYO5A regulates autophagic flux to ensure fusion. Together, these findings establish MYO5A as a regulator of autophagy and highlight its potential as a target for fine-tuning autophagic flux.

Keywords:  Actomyosin Dynamics; Autophagic Flux; Autophagosome–Lysosome Fusion; MYO5A; Unconventional Myosins

DOI:  https://doi.org/10.1038/s44318-025-00686-9
Nat Cell Biol. 2026 Jan 12.

Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.

Siddharthan B Thendral, Sasha Bacot, Ian T Ryde, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.

The quality of mitochondria inherited from the oocyte determines embryonic viability, lifelong metabolic health of the progeny and lineage endurance. High levels of endogenous reactive oxygen species and exogenous toxicants pose threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in mature oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here, we discover that in Caenorhabditis elegans, the onset of oocyte-to-zygote transition developmentally triggers a rapid mitophagy event. We show that mitophagy at oocyte-to-zygote transition (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. MOZT reduces the transmission of deleterious mtDNA and as a result, protects embryonic survival. Impaired MOZT drives the increased accumulation of mtDNA mutations across generations, leading to the extinction of descendant populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and safeguards lineage continuity.

DOI: https://doi.org/10.1038/s41556-025-01854-z
J Mol Biol. 2026 Jan 09. pii: S0022-2836(26)00007-0. [Epub ahead of print] 169634

Pioneers: Glucose sensing and control of health-span and lifespan.

Sheng-Cai Lin.

  My independent career started based on a simple doctrine of protein multifunctionality, by intuitively choosing the protein called AXIN, which has turned out to be the protagonist of my scientific life. This led us to discover the sensing pathway for glucose which links to AMPK and mTORC1, two master metabolic controllers. We found that AXIN binds LKB1, an upstream kinase of AMPK, and that the AXIN:LKB1 complex translocates to the lysosomal surface after the lysosomal aldolase senses low glucose (fructose-1,6-bisphosphate as the direct signal) to activate AMPK and concomitantly inhibit mTORC1. Remarkably, we found that the lysosomal glucose-sensing AMPK pathway is shared by metformin, a glucose-lowering drug known to also extend lifespan and reduce cancer risk. In search of metabolites enriched in calorie-restricted mice and able to activate AMPK via the lysosomal pathway, we identified that lithocholic acid (LCA) as such a factor. We also identified TULP3 as the LCA receptor, which signals to activate sirtuins, increase NAD+, activate AMPK and inhibit mTORC1. In translation, we have identified an aldolase inhibitor termed aldometanib, which mimics glucose starvation to activate AMPK. Aldometanib can alleviate fatty liver, lower blood glucose, and extend lifespan in animals. Surprisingly, aldometanib can also mobilize tumoricidal CD8+ T cells to infiltrate and contain hepatocellular carcinomas (HCC), enabling HCC-bearing mice to live to ripe ages, the endpoint of cancer therapy. Our work has thus revealed that glucose acts as a messenger that signals through a specialized route to control health-span and lifespan. We will continue to explore the teleological meaning of glucose as a "chosen" molecule.

Keywords:  AMPK; AXIN; and lifespan; glucose sensing; health-span; lysosome

DOI:  https://doi.org/10.1016/j.jmb.2026.169634
Noncoding RNA Res. 2026 Apr;17 112-127

Epigenetic H3K4me3 activation of miR-155-5p promotes intervertebral disc degeneration via autophagy and ageing in nucleus pulposus cells.

Ximeng Wang, Hanqiu Sun, Wenbiao Xiao, Yuxuan Zhang, Xiao Lu, Zhaoyang Gong, Dachuan Li, Siyang Liu, Xinlei Xia, Hongli Wang, Minghao Shao, Guangyu Xu, Xiaosheng Ma.

  Nucleus pulposus (NP) cell ageing and impaired autophagy - lysosome biogenesis (ALB) are key drivers of intervertebral disc degeneration (IVDD). The upstream epigenetic regulation of transcription factor EB (TFEB), a major ALB regulator, remains elusive. Our study identifies a H3K4me3-associated miRNA pathway that modulates TFEB activity and IVDD progression. Using in vivo and in vitro models, we found that methyltransferase MLL3 knockdown reduces H3K4me3 methylation at the miR-155-5p promoter, suppressing miR-155-5p transcription. MiR-155-5p directly targets FBXO22, indirectly repressing TFEB transcription and exacerbating NP cells ageing and IVDD. Notably, experiments confirmed MLL3 binds specifically to the miR-155-5p promoter, with no interaction detected at the TFEB or FBXO22 promoters. Our data establish a linear H3K4me3/miR-155-5p/FBXO22/TFEB axis in IVDD pathogenesis. We reveal a novel epigenetic crosstalk where H3K4me3 methylation mediates miRNA-driven TFEB regulation, independent of canonical mTOR signaling. These findings enhance understanding of epigenetic mechanisms in autophagy and ageing control and highlight MLL3 and miR-155-5p as potential IVDD therapeutic targets.

Keywords:  Autophagy; H3K4me3 methylation modification; Intervertebral disc degeneration; MLL3; TFEB; miR-155-5p

DOI:  https://doi.org/10.1016/j.ncrna.2025.12.001
J Biol Chem. 2026 Jan 10. pii: S0021-9258(26)00017-7. [Epub ahead of print] 111147

A GluN2B disease-associated variant promotes the degradation of NMDA receptors via autophagy.

Taylor M Benske, Marnie P Williams, Pei-Pei Zhang, Adrian J Palumbo, Ting-Wei Mu.

  N-methyl-D-aspartate receptors (NMDARs) are essential for excitatory neurotransmission, and missense mutations can severely disrupt their function. Pathogenic variants often lead to proteostasis defects, including improper folding, impaired assembly, and reduced trafficking to the plasma membrane, ultimately compromising the physiological function of NMDARs and thereby contributing to neurological diseases. However, mechanisms by which the proteostasis network recognizes and degrades aggregated, misfolded, and trafficking-deficient pathogenic NMDARs remain poorly understood. Here, we demonstrate that the R519Q GluN2B variant is retained in the endoplasmic reticulum (ER) and fails to traffic to the cell surface to form functional NMDARs. Pharmacological and genetic inhibition of autophagy resulted in the accumulation of this variant, indicating that it is degraded by the autophagy-lysosomal proteolysis pathway. Since GluN2B subunit has a cytosolic LC3-interacting region (LIR) motif, disruption of the LIR motif via mutagenesis similarly impairs the autophagic clearance of this variant. Furthermore, we demonstrate that this variant is recognized by the ER-phagy receptor CCPG1 and that the LIR domain plays a facilitative role in strengthening this interaction. Our results provide a novel molecular mechanism for the ER-to-lysosome associated degradation of NMDAR variants and identify a pathway for targeted therapeutic intervention for neurological disorders with dysfunctional NMDARs.

Keywords:  CCPG1; ER-phagy; LC3-interacting region (LIR); NMDAR; proteostasis

DOI:  https://doi.org/10.1016/j.jbc.2026.111147
Autophagy Rep. 2026 ;5(1): 2595375

Glycophagy: molecular mechanisms, regulatory signals, and disease associations.

Lei Chen, Jinyong Jiang, Meiqing Liu, Linxi Chen.

  Glycophagy is a process of selective degradation of glycogen through the autophagy pathway. It relies on key proteins, such as STBD1 (glycogen-specific autophagy receptor), GABARAPL1 (member of the ATG8 family), and acid α-glucosidase (GAA), and proceeds through the steps of "glycogen recognition - autophagosome encapsulation - lysosomal degradation" to release glucose, thereby maintaining energy homeostasis. This process is regulated by multiple signaling pathways, such as AMPK, mTOR, CAMP/PKA, and calcium signaling pathways, which jointly respond to cellular energy demands and metabolic states. Glycophagy occurs under conditions, such as starvation, exercise, and energy metabolism disorders, and plays a role in diseases with glycogen metabolism disorders. Its functions include energy supply, blood sugar regulation, maintenance of cellular homeostasis, and influencing cellular aging. Dysfunction of glycophagy can lead to various diseases, such as glycogen storage diseases and diabetic cardiomyopathy. In-depth study of the regulatory mechanisms of glycophagy is helpful for developing therapeutic strategies for related diseases.

Keywords:  GABARAPL1; Glycophagy; STBD1; autophagy regulation; metabolic disorders

DOI:  https://doi.org/10.1080/27694127.2025.2595375
Development. 2026 Jan 13. pii: dev.205162. [Epub ahead of print]

The activation of the mTOR pathway supports lysosome biogenesis in the sea urchin embryo.

Sonia Dufour, Sandrine Boulben, Maïwenn M Petit-Jamin, Patrick Cormier, Julia Morales, Fernando Roch.

  The mTOR pathway controls the balance between anabolic and catabolic activities in animal cells, acting as a key coordinator of metabolic homeostasis. In fact, the activation of this conserved regulatory circuit promotes the biosynthesis of different macromolecules, including proteins, lipids and nucleic acids, and blocks simultaneously catabolic processes such as lysosome biogenesis. In this work we describe a biological system in which these two aspects of the mTOR function are uncoupled. Studying the sea urchin Paracentrotus lividus, we have found that the activation of the mTOR pathway in the fertilised egg, besides stimulating protein synthesis, contributes to the development of a dense array of acidic vesicles that behave as lysosomes. We present evidence indicating that mTOR could operate in this context enhancing the translation of the maternal transcripts that code for the multiple components of these organelles. We argue that the mTOR-mediated implementation of a typical catabolic process may in fact support the biosynthetic vocation of this pathway, providing energy and recycled blocks for construction.

Keywords:  Lysosome biogenesis; MTOR signalling; Metabolic homeostasis; Oocyte-to-embryo transition; mRNA translation

DOI:  https://doi.org/10.1242/dev.205162
Sci Rep. 2026 Jan 10.

Disruption of intracellular iron homeostasis through mitochondrial dysfunction associated with suppression of ATP 13A2 expression.

Takanori Murakami, Kazuki Ohuchi, Masanori Kiuchi, Hisaka Kurita, Kanta Kawai, Ryo Kakiuchi, Tasuku Hirayama, Hideko Nagasawa, Zhiliang Wu, Yoichi Maekawa, Isao Hozumi, Masatoshi Inden.

  Elevated iron in the SNpc may play a key role in Parkinson's disease (PD) neurodegeneration, yet the underlying mechanism accounting for this iron accumulation is unclear. Although iron is an essential element, excessive amounts produce toxicity. Here, we focused on the role of iron and ATP13A2, the causative gene of PARK9 neurodegeneration with brain iron accumulation, using a cellular model. ATP13A2 deficiency resulted in impaired lysosomal function and iron accumulation in cell organelles. Further, we found dysfunction of mitophagy, which is involved in managing mitochondrial quality, as well as mitochondrial damage. Furthermore, we confirmed a decreased heme synthesis capacity, which is important to maintain intracellular iron homeostasis. Overall, our study indicates that lysosome-derived mitochondrial impairment can disrupt intracellular iron homeostasis in a cell model of PD pathology. This could help better understand the mechanisms underlying PD.

Keywords:  ATP13A2; Heme; IRP2; Intracellular iron homeostasis; Lysosome; Mitochondria; Mitophagy; PARK9; Parkinson’s disease; Transferrin receptor

DOI:  https://doi.org/10.1038/s41598-026-35368-x
FASEB J. 2026 Jan 31. 40(2): e71460

AMPK Modulates the Interplay Between PINK1/Parkin-Mediated Mitophagy and NLRP3-Driven Inflammation in Diabetic Periodontal Tissue Under Mechanical Loading.

Shuo Chen, Ruijiao Yan, Yiling Chen, Shushu He, Chenchen Zhou, Shujuan Zou, Yuyu Li.

  Mechanical force induces a series of biological responses such as inflammation in force-loaded tissues and cells. The periodontal ligament (PDL) fibroblasts act as vital sensors and transducers in response to mechanical loading within periodontium. Studies have shown that PDL fibroblasts also participate in mediating periodontal inflammatory responses under physiological or pathological conditions. Mitophagy is a selective form of autophagy that eliminates damaged or dysfunctional mitochondria to maintain cellular health. It plays a vital role in inflammation alleviation, cell survival, and tissue homeostasis. However, whether mitophagy is involved in mechanical force-related inflammation and the precise mechanisms remain unclear. In addition, the elucidation of the interplay between mitophagy and periodontal inflammation during mechanical loading is of great significance for maintaining periodontal homeostasis under systemic conditions. In our study, we first focused on validating the crosstalk between mitophagy and inflammation in PDL fibroblasts under mechanical loading and aimed to elucidate the upstream regulatory role of adenosine monophosphate-activated protein kinase (AMPK). Moreover, based on both in vivo and in vitro experiments, we found that high glucose conditions exacerbated inflammation by suppressing mitophagy. Additionally, targeted activation of AMPK enhanced mitochondrial turnover through mitophagy, thereby disrupting proinflammatory cascades and offering a promising strategy for inflammation resolution in periodontal diseases, especially those combined with diabetic conditions.

Keywords:  AMPK activation; inflammation; mechanical loading; mitophagy; periodontal ligament fibroblasts

DOI:  https://doi.org/10.1096/fj.202502330R
J Extracell Vesicles. 2026 Jan;15(1): e70218

Cholesterol Deficiency Directs Autophagy-Dependent Secretion of Extracellular Vesicles.

Jazmine D W Yaeger, Sonali Sengupta, Austin L Walz, Mayu Morita, Terry K Morgan, Paola D Vermeer, Kevin R Francis.

  Extracellular vesicle (EV) secretion is an important, though not fully understood, intercellular communication process. Lipid metabolism has been shown to regulate EV activity, though the impact of specific lipid classes is unclear. Through analysis of small EVs (sEVs), we observe aberrant increases in sEV release within genetic models of cholesterol biosynthesis disorders, where cellular cholesterol is diminished. Inhibition of cholesterol synthesis at multiple synthetic steps mimics genetic models in terms of cholesterol reduction and sEVs secreted. Further analyses of sEVs from cholesterol-depleted cells revealed structural deficits and altered surface marker expression, though these sEVs were also more easily internalized by recipient cells. Transmission electron microscopy of cells with impaired cholesterol biosynthesis demonstrated multivesicular and multilamellar structures potentially associated with autophagic defects. We further found autophagic vesicles being redirected towards late endosomes at the expense of autophagolysosomes. These findings were subsequently validated in cellular models of head and neck cancer, where cholesterol depletion induced sEV release and promoted late endosome-autophagosome fusion. Through CRISPR-mediated inhibition of autophagosome formation, we mechanistically determined that release of sEVs after cholesterol depletion is autophagy dependent. We conclude that cholesterol imbalance initiates autophagosome-dependent secretion of sEVs, which may have pathological relevance in diseases of cholesterol disequilibrium.

Keywords:  Smith–Lemli–Opitz; cancer; cholesterol; exosome; extracellular vesicle

DOI:  https://doi.org/10.1002/jev2.70218
J Neurochem. 2026 Jan;170(1): e70353

Dissociation of the mTOR Protein Interaction Network Following Neuronal Activation Is Altered by Shank3 Mutation.

Devin T Wehle, Emily A Brown, Vera Stamenkovic, Breann Gniffen, Felicia M Harsh, Stephen E P Smith.

  The mechanistic target of Rapamycin (mTOR) kinase pathway plays critical roles in neuronal function and synaptic plasticity, and its dysfunction is implicated in numerous neurological and psychiatric disorders. Traditional linear models depict mTOR signaling as a sequential phosphorylation cascade, but accumulating evidence supports a model that includes signaling through dynamic protein-protein interaction networks. To examine how neuronal mTOR signaling networks discriminate between distinct stimuli, we quantified phosphorylation events and protein co-association networks in primary mouse cortical neurons. Unexpectedly, neuronal mTOR activation by IGF or glutamate triggered dissociation-rather than the anticipated assembly-of protein complexes involving mTOR complex 1 (TORC1), mTOR complex 2 (TORC2), and translational machinery, distinguishing neurons from proliferative cells. Applying in vitro homeostatic scaling paradigms revealed distinct combinatorial encoding of synaptic scaling direction: both up- and down-scaling induced dissociation of translational complexes, but downscaling uniquely included dissociation of upstream pathway regulators. Cortical neurons from Shank3B knockout mice, modeling autism-associated Phelan-McDermid Syndrome, displayed baseline hyperactivation of the mTOR network, which reduced the dynamic range of protein interaction network responses to homeostatic synaptic scaling and pharmacological mTOR inhibition. These findings reveal that neuronal mTOR signaling employs stimulus-specific combinations of dissociative protein interaction modules to encode opposing forms of synaptic plasticity.

Keywords:  Shank3; homeostatic scaling; mTOR; protein–protein interaction; signal transduction

DOI:  https://doi.org/10.1111/jnc.70353
Autophagy. 2026 Jan 16.

Disrupted autophagy overactivates TBK1 and results in mitotic defects promoting chromosomal instability.

Swagatika Paul, Porter L Tomsick, Julia P Milner, Sahitya Ranjan Biswas, Samantha Brindley, Nicole DeFoor, Leila Zavar, Grace Wright, Yairis Soto, Alicia M Pickrell.

  Micronuclei are formed during cell division when acentric fragments or lagging chromosomes cannot be incorporated into the primary nucleus. Macroautophagy/autophagy may reduce chromosomal instability (CIN) by clearing isolated, atypical micronuclei. Other studies implicate that the loss of autophagy disrupts DNA repair pathways. However, whether aberrant mitosis contributing to CIN occurs when autophagy is inhibited has yet to be evaluated. We found impaired autophagy initiation contributes to CIN and facilitates the formation of micronuclei and other abnormal nuclear phenotypes either by genetic or pharmacological manipulation in multiple cell lines. We also found that loss of the integral autophagy protein ATG9A resulted in various types of mitotic errors that can contribute to the formation of micronuclei. ATG9A also localizes to centrosomes and midbody during cell division. Autophagy inhibition causes the overactivation and mislocalization of TBK1 (TANK binding kinase 1) into cytoplasmic, punctate structures that colocalize with SQSTM1/p62. This overactivation interferes with its function in cell division as a mitotic kinase and its role at the centrosome. These results indicate that loss of autophagy contributes to genomic instability from multiple angles, one of which being aberrant cell division.

Keywords:  ATG9A; TBK1; cell division; chromosomal instability; micronucleation; mitosis

DOI:  https://doi.org/10.1080/15548627.2026.2617844
Hippocampus. 2026 Jan;36(1): e70069

Autophagy Impacts Dendritic Spines Differently in Proximal and Distal Dendrites of Hippocampus CA1 Neurons.

Kevin M Keary, Ellen Sojka, Melissa Gonzalez, Zheng Li.

  Autophagy is a cellular protein degradation mechanism essential for neuronal function. Recent work has begun to implicate autophagy in cellular functions beyond preserving homeostasis, such as synaptic plasticity and the regulation of dendritic spines. Work from our lab and others demonstrates that synaptic plasticity in distinct dendritic compartments is in part regulated by the uneven distribution of autophagosomes in CA1 apical dendrites. However, it remains unclear whether autophagy contributes to dendritic spine regulation in different dendritic segments. Here, we investigated the role of autophagy and caspase-3, a protein inhibiting autophagy during NMDA receptor-dependent long-term depression, in the regulation of proximal and distal dendritic spines of CA1 pyramidal neurons. We conducted 3D neuron reconstruction of fluorescently labeled dendrites to analyze the volume, density, and subtype proportions of dendritic spines across compartments in ATG5 and caspase-3 knockout mice. ATG5 knockout mice had larger spines in distal dendrites as compared to proximal dendrites. Caspase-3 knockout mice did not display any difference between proximal and distal spine volume. Only ATG5 knockout mice exhibited reduced spine density as compared to controls. Both ATG5 and caspase-3 knockout mice possessed increased spine volume across all three spine subtypes: thin, stubby, and mushroom, along with a shift in spine subtypes with reduced proportions of thin and increased proportions of stubby and mushroom. These findings suggest that both autophagy and caspase-3 contribute to the regulation of spine volume and morphology. However, only autophagy appears to influence spine density. Moreover, autophagy uniquely regulates spine volume differently in proximal versus distal dendrites.

Keywords:  CA1; autophagy; dendritic spines; long‐term depression; structural plasticity

DOI:  https://doi.org/10.1002/hipo.70069
J Mater Chem B. 2026 Jan 14.

Chitosan-based nanoparticles for targeted delivery of 17β-estradiol to enhance SIRT1-mediated autophagy and mitigate rotenone-induced Parkinson's disease.

Liku Biswal, Mohd Ayoub, Devangi Ghosh, Vikas Kumar Sahu, Subhasree Roy Choudhury, Surajit Karmakar.

The pathogenesis of Parkinson's disease (PD) is closely linked to the dysregulation of the clearance mechanism responsible for degrading misfolded proteins and malfunctioning organelles. Thus, maintaining a balance in autophagy is essential for managing PD. 17β-Estradiol (E2) is a specific calpain inhibitor, where the latter is upregulated in the PD brain and is responsible for inducing apoptosis. However, its peripheral toxicity and hydrophobicity hinder the investigation of its therapeutic potential. To address this, a neuroprotective and biocompatible chitosan nanoparticle, conjugated with DRD3 (Ab-ECSnps), is engineered to enable active targeting. The nanoformulation with immense potential for inhibiting calpain downregulates caspase 3-mediated apoptosis in the rotenone-treated PD model. Neuroprotection conferred by the nanoformulation is not solely due to apoptosis inhibition. Interestingly, the study reveals that the simultaneous induction of SIRT1- and LAMP2-mediated autophagy enhances autophagic flux, as supported by the upregulation of beclin, VPS34, and an increase in the number of lysosomes. The nanoformulation also clears pathological pSer129-synuclein and protects substantia nigra dopaminergic neurons in rotenone-induced Parkinson's disease models. This non-invasive, dopaminergic neuron-targeted delivery system, with its excellent biocompatibility, maintains a balance between apoptosis and autophagy, making it a promising approach for treating and preventing Parkinson's disease.

DOI: https://doi.org/10.1039/d5tb02351c
Cell Chem Biol. 2026 Jan 15. pii: S2451-9456(25)00400-3. [Epub ahead of print]33(1): 10-32

The interplay between autophagy and unconventional secretion in neurodegeneration.

Maurizio Renna, Raffaella Bonavita, Grace Dixon, Luigi Vittorio Verdicchio, Angeleen Fleming.

  Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer's disease) and alpha-synuclein in Parkinson's disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental models. When the flux through these pathways is increased, the levels of aggregate-prone proteins are reduced, resulting in improved cell survival in both cell-based and animal models of ND. More recently, a third strategy for clearing proteins from cells has been identified, via the unconventional secretion of proteins out of the cell. However, secretion may also facilitate the spreading and propagation of disease through a prion-like process. This review explains how the autophagy and unconventional secretion pathways interact and how these impact ND.

Keywords:  alpha-synuclein; autophagy; extracellular vesicles; neurodegeneration; secretory autophagy; tau; unconventional protein secretion

DOI:  https://doi.org/10.1016/j.chembiol.2025.12.007
EMBO Rep. 2026 Jan 13.

Mitochondrial fission during mitophagy requires both inner and outer mitofissins.

Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Shun-Ichi Yamashita, Keiichi Inoue, Tomoyuki Fukuda, Nobuo N Noda, Tomotake Kanki.

  Mitophagy maintains mitochondrial homeostasis through the selective degradation of damaged or excess mitochondria. Recently, we identified mitofissin/Atg44, a mitochondrial intermembrane space-resident fission factor, which directly acts on lipid membranes and drives mitochondrial fission required for mitophagy in yeast. However, it remains unclear whether mitofissin is sufficient for mitophagy-associated mitochondrial fission and whether other factors act from outside mitochondria. Here, we identify a mitochondrial outer membrane-resident mitofissin-like microprotein required for mitophagy, and we name it mitofissin 2/Mfi2 based on the following results. Overexpression of an N-terminal Atg44-like region of Mfi2 induces mitochondrial fragmentation and partially restores mitophagy in atg44Δ cells. Mfi2 binds to lipid membranes and mediates membrane fission in a cardiolipin-dependent manner in vitro, demonstrating its intrinsic mitofissin activity. Coarse-grained molecular dynamics simulations further support the stable interaction of Mfi2 with cardiolipin-containing bilayers. Genetic analyses reveal that Mfi2 and the dynamin-related protein Dnm1 independently facilitate mitochondrial fission during mitophagy. Thus, Atg44 and Mfi2, two mitofissins with distinct localizations, are required for mitophagy-associated mitochondrial fission.

Keywords:  Atg44; Mfi2; Mitochondrial Fission; Mitofissin; Mitophagy

DOI:  https://doi.org/10.1038/s44319-025-00689-x
Autophagy. 2026 Jan 10.

Metabolites released from apoptotic cells in central nervous system orchestrates the pathological process of Alzheimer disease through improving autophagy.

Fan Xiao, Xue Tan, Aojie He, Yulan Zhou, Kaicheng Xu, Ziqi Yuan, Yufei Zhu, Chensi Liang, Dan Can, Jie Zhang, Lige Leng.

  Apoptosis, a programmed cell death process activated in Alzheimer disease (AD), is not limited to neurons but extends to all cell types within the central nervous system (CNS). However, how apoptotic cells mediate their impact on surrounding cells and contribute to the pathological progression of AD remains largely unclear. Here, we report that in 5×FAD mice, cells surrounding amyloid-β (Aβ) plaques undergo apoptosis, which occurs concurrently with elevated macroautophagy/autophagy. The autophagic flux, nevertheless, is impaired in AD, as evidenced by the simultaneous accumulation of MAP1LC3/LC3 and SQSTM1/p62. As a result, although there is an increased formation of autophagosomes, misfolded proteins fail to undergo proper degradation in the subsequent process. By profiling the "metabolomic secretome" of primary neurons and glial cells under different apoptotic stimuli, we identified spermidine as a conserved apoptotic metabolite messenger in the CNS. Spermidine is actively released from apoptotic neurons or glia cells and functions in a paracrine manner to induce autophagy activation in neighboring cells. Such an effect of enhancing autophagic flux promotes both the cargo encapsulation within autophagosomes and degradation in autolysosomes in nearby cells. Conversely, the blockade of spermidine release impairs autophagic flux, thereby exacerbating cognitive impairment and pathological progression in AD. These findings reveal a link between cell apoptosis and autophagy in AD, suggesting that spermidine supplementation could serve as a promising therapeutic strategy.

Keywords:  Alzheimer disease; apoptosis; autophagy; metabolism; secretome; spermidine

DOI:  https://doi.org/10.1080/15548627.2026.2615978
Cardiovasc Res. 2026 Jan 16. pii: cvag006. [Epub ahead of print]

Drp1-mediated mitochondrial fission protects macrophages from mtDNA/ZBP1-mediated inflammation and inhibits post-infarct cardiac remodeling.

Yuki Kondo, Jun-Ichiro Koga, Nasanbadrakh Orkhonselenge, Lixiang Wang, Nao Hasuzawa, Shunsuke Katsuki, Tetsuya Matoba, Yosuke Nishimura, Masatoshi Nomura, Masaharu Kataoka.

AIM: Ischemic heart disease is a leading cause of death worldwide, and heart failure after myocardial infarction (MI) is a growing issue in an ageing society. Macrophages play a central role in left ventricular (LV) remodeling after MI. Mitochondria consistently change their morphology, including fission and fusion; however, the role of these morphological changes, particularly in macrophages, remains unknown. This study investigated the role of dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission, in macrophages and its involvement in the mechanisms of left ventricular remodeling after myocardial infarction (MI).
METHODS AND RESULTS: This study utilized genetically altered mice lacking Drp1 in Lysozyme M-positive cells (Drp1-KO) to elucidate the specific role of macrophage Drp1 in post-infarct LV remodeling. Deletion of Drp1 in macrophages exacerbated LV remodeling, underpinned by reduced ejection fraction and increased LV diameter, which resulted in a poor prognosis after MI. Histological analysis indicated increased fibrosis and sustained macrophage accumulation in the infarcted hearts of Drp1-KO mice. Blockade of Drp1 in macrophages decreased mitochondrial fission and impaired mitophagy, leading to the subsequent release of mitochondrial DNA (mtDNA) into the cytosol and the induction of inflammatory cytokines. This induction was abrogated by the autophagy inducer Tat-beclin1 or siRNA-mediated knockdown of Z-DNA Binding Protein 1 (ZBP1). Deletion of ZBP1 in bone marrow-derived cells abrogated LV remodeling induced by the Drp1 inhibitor Mdivi-1.
CONCLUSION: Macrophage Drp1 plays a critical role in the pathobiology of post-infarct LV remodeling, particularly in mitochondrial quality control mechanisms. Macrophage Drp1 could be a novel therapeutic molecule to mitigate the progression of LV remodeling and consequent heart failure after MI.

DOI: https://doi.org/10.1093/cvr/cvag006
Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2501779123

mTOR signaling governs the formation of epithelial apical projections via S6K1-RhoA and aPKC-Lgl2 axes.

Sumit Sen, Prithwish Ghosh, Sudipta Mukherjee, Shreedha Prabhu, Ginni Khurana, Clyde Savio Pinto, Kirti Gupta, Ravindra Venkatramani, Mahendra Sonawane.

  In metazoans, epithelia perform functions of absorption, diffusion, and secretion. The actin-based apical projections on the epithelial cells contribute to these functions and are formed via cell-autonomous mechanisms that control cell polarity, intracellular transport, and the cytoskeleton. However, the cues that function upstream of these cell-autonomous regulators remain poorly known. Using microridges on zebrafish epithelial cells as a paradigm, we show that mTOR, a metabolic sensor, regulates the formation of apical projections. Mechanistically, mTORC1 controls the RhoA-ROCK activity via S6K1 to prevent the overactivation of nonmuscle myosin II (NMII) to restrict microridge elongation. Furthermore, genetic, biochemical, and molecular dynamics simulation analyses reveal that mTORC2 regulates the microridge pattern by modulating the activity of aPKC via its differential phosphorylation at two conserved sites. We propose that mTOR integrates the developmental and/or metabolic status of epithelial cells with cell autonomously acting RhoA and aPKC to regulate tissue-wide formation of apical projections.

Keywords:  RhoA signaling; aPKC signaling; actin cytoskeleton; mTOR signaling; microridges

DOI:  https://doi.org/10.1073/pnas.2501779123
Braz J Med Biol Res. 2026 ;pii: S0100-879X2025000100699. [Epub ahead of print]58 e14964

Protection against myocardial ischemia reperfusion injury by liquiritin: involvement of autophagy restoration targeting PIK3CA.

Huizi Mao, Zhuqing Li, Chengzhi Lu.

The current therapy for myocardial infarction focuses on reestablishing blood flow in the coronary arteries to reduce the ischemic area, but the subsequent damage caused by reperfusion cannot be ignored. Liquiritin, a primary flavonoid compound found in the medicinal plant licorice, exhibits distinct pharmacological properties including neuroprotection, anti-inflammatory, antioxidant, and anti-apoptotic effects. However, further research on its role and mechanism in myocardial ischemia-reperfusion (I/R) injury is needed. The aim of this work was to elucidate the protection of liquiritin against myocardial I/R insult and whether liquiritin-mediated autophagy restoration was associated with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in vivo and in vitro. Liquiritin administration by oral gavage inhibited pathological injury of myocardial I/R injured rats, evidenced by improved cardiac function and reduced infarct size. Moreover, liquiritin restored excessive autophagy by promoting the phosphorylation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR), which was accompanied by PIK3CA upregulation. Mechanistically, silencing PIK3CA in rat H9c2 cardiomyoblasts diminished the beneficial effects against oxygen-glucose deprivation/reoxygenation (OGD/R) injury reflected by exacerbated apoptosis and dysregulated autophagy mediated by the classical PI3K/Akt/mTOR pathway. Liquiritin inhibited excessive autophagic flux via decreasing autophagosome-lysosome fusion, which was similar to the effect of the autophagy inhibitor chloroquine. Moreover, this phenomenon was enhanced when liquiritin and chloroquine were used in combination. Collectively, our work revealed that the protective effect of liquiritin against myocardial I/R injury may be attributed to its autophagy restoration mediated by PIK3CA.

DOI: https://doi.org/10.1590/1414-431X2025e14964
Nat Commun. 2026 Jan 15.

Tmem110 regulates the conformation of TRPML1 to maintain endolysosomal homeostasis and prevent mitochondrial DNA leakage and pathological self-DNA processing.

Zunyong Feng, Yuanbo Pan, Jing Zhou, Liuxi Chu, Qiang Li, Xuanbo Zhang, Ping Wu, Zhiliang Xu, Yanjiao Huang, Jianhua Zou, Xiaokun Li, Xiaoyuan Chen, Zhouguang Wang.

The mechanisms by which phagocytes handle large quantities of internalized organelles, such as mitochondria released during tissue injury, remain unclear. Here we show that the endoplasmic reticulum transmembrane regulator TMEM110 is a key determinant of disease severity in traumatic brain injury-associated multiple organ dysfunction. Loss of TMEM110 impairs the clearance of mitochondria aberrantly released into the circulation, leading to heightened autoimmune-mediated tissue injury and mortality. TMEM110 maintains lysosomal function by controlling the conformational transition of the lysosomal ion channel TRPML1 and generating localized calcium efflux sites, thereby preventing calcium overload, membrane disruption, and leakage of mitochondrial DNA into the cytosol. We further find that TMEM110 expression is restrained by the nucleic acid sensor STING under basal conditions, and that a naturally occurring interface mutation between TMEM110 and STING causes defective lysosomal DNA disposal and aberrant type I interferon activity. These findings identify a feedback pathway linking cytosolic DNA sensing to organelle homeostasis.

DOI: https://doi.org/10.1038/s41467-026-68382-8
Nat Aging. 2026 Jan 16.

Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.

Takuya Kumazawa, Yanxin Xu, Yu Wang, Ji-Won Lee, Tara C O'Brien, Chia-Kang Ho, Murat Cetinbas, Aaron Weiner, Konrad Hochedlinger, Ruslan I Sadreyev, Nabeel Bardeesy, Chia-Wei Cheng, Bin He, Zhixun Dou.

Chronic inflammation promotes aging and age-associated diseases. While metabolic interventions can modulate inflammation, how metabolism and inflammation are connected remains unclear. Cytoplasmic chromatin fragments (CCFs) drive chronic inflammation through the cGAS-STING pathway in senescence and aging. However, CCFs are larger than nuclear pores, and how they translocate from the nucleus to the cytoplasm remains uncharacterized. Here we report that chromatin fragments exit the nucleus via nuclear egress, a membrane trafficking process that shuttles large complexes across the nuclear envelope. Inactivating critical nuclear egress proteins, the ESCRT-III or Torsin complex, traps chromatin fragments at the nuclear membrane and suppresses cGAS-STING activation and senescence-associated inflammation. Glucose limitation or metformin inhibits CCF formation through AMPK-dependent phosphorylation and autophagic degradation of ALIX, an ESCRT-III component. In aged mice, metformin reduces ALIX, CCFs, and cGAS-mediated inflammation in the intestine. Our study identifies a mechanism linking metabolism and inflammation and suggests targeting the nuclear egress of chromatin fragments as a strategy to suppress age-associated inflammation.

DOI: https://doi.org/10.1038/s43587-025-01048-0