bims-auttor 2025-11-16 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–11–16
thirty-two papers selected by
Viktor Korolchuk, Newcastle University

Piecemeal mitochondrial degradation in plants: a coordination between mitochondrial dynamics and mitophagosome formation.
Autophagy-dependent modulation of ER calcium release drives KCNMA1/BKCa signaling and seizure susceptibility.
mTORC1 regulates autophagosomal components recycling through SNX16 phosphorylation.
Palmitate impairs autophagic degradation via oxidative stress-perilysosomal Ca2+ overload-mTORC1 activation in pancreatic β-cells.
The bridge-like lipid transfer protein Vps13 are required for NVJ integrity and nucleophagy.
Autophagy is dispensable in germline stem cells but is required in the cap cells for their maintenance in the Drosophila ovarian niche.
Lactylation of mTOR enhances autophagy in skeletal muscle during exercise.
Cell Type-Specific mTORC1 Signaling and Translational Control in Synaptic Plasticity and Memory.
Biomolecular condensation of ERC1 recruits ATG8 and NBR1 to drive autophagosome formation for plant heat tolerance.
Autophagy Reprogramming in Cancer.
Responses to nutrient starvation in the fission yeast Schizosaccharomyces pombe.
Inhibition or genetic reduction of ASAH1/acid ceramidase restore α-synuclein clearance in mutant GBA1 dopamine neurons from Parkinson's patients.
Autophagy modulates the mechanism of flow-mediated dilation upstream of telomerase.
OR2T6 modulates autophagy through the PPP3CA-mediated pathways to suppress gastric cancer.
IRF7 drives macrophages to kill bacteria and improves septic outcomes via autophagy.
Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
Autophagosome marker, LC3, is released extracellularly via several distinct pathways.
DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans.
Research progress on the mutual regulatory mechanism of circadian clock genes and autophagy.
SQSTM1/p62 Post-Translational Modifications and Reverse Processes Modulate Disease Pathogenesis via KEAP1-NRF2 Signaling and Selective Autophagy.
Uncomplexed-TSC1 deploys novel mTORC1-independent pathway to exacerbate the liver glycogen storage in TSC.
Comparative Analysis of Two Autophagy-Enhancing Small Molecules (AUTEN-67 and -99) in a Drosophila Model of Spinocerebellar Ataxia Type 1.
CARMN loss promotes VSMC-derived foam cell formation and atherosclerosis through transcriptional downregulation of autophagy.
Irisin-mediated hepatic autophagy remodels nutritional metabolism to prevent cognitive dysfunction.
Autophagy regulates the maternal-to-zygotic transition through MAP1LC3B-mediated maternal mRNA decay.
ERLIN1: A central regulator of protein quality control, lipid homeostasis, and cellular signaling at the endoplasmic reticulum.
ALLO-1a is a ubiquitin-binding adaptor for allophagy in Caenorhabditis elegans.
The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
Coupling of USP10 de-ubiquitination and chaperone-mediated autophagy causes cardiac sodium channel degradation and cardiac arrhythmias.
Current Understanding of Protein Aggregation in Neurodegenerative Diseases.
TGF-β2 increases eHSP90α secretion via upregulating secretory autophagy pathway.

Autophagy. 2025 Nov 10.

Piecemeal mitochondrial degradation in plants: a coordination between mitochondrial dynamics and mitophagosome formation.

Juncai Ma, Chaorui Li, Xiaohong Zhuang.

  Mitochondrial dynamics play critical roles in mitochondrial quality control to maintain mitochondrial function. In plants, mitochondria are typically discrete rather than networked, but how damaged mitochondrial contents can be efficiently removed remains unclear. In a recent study, we demonstrate that the plant-specific fission regulator ELM1, together with DRP3 and the autophagic adaptor SH3P2, orchestrates mitochondrial dynamics and mitophagosome assembly for piecemeal mitophagy under heat stress condition. Deficiency in mitochondrial fission activity delays mitophagosome formation and leads to an accumulation of megamitochondria that are partially sequestered by phagophore intermediates positive for ATG8 and NBR1. Further 3D electron tomography analysis reveals that phagophore fragments expand toward the constriction sites of the abnormal protrusions from the mitochondrial body. These findings highlight an unappreciated role of plant mitochondrial fission machinery in coupling with autophagy machinery for mitochondrial segregation and mitophagosome assembly, establishing a mechanistic framework for plant mitophagy in stress resilience.

Keywords:  ELM1; SH3P2; mitochondrial dynamics; mitochondrial fission; piecemeal mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2587051
Autophagy. 2025 Nov 10. 1-3

Autophagy-dependent modulation of ER calcium release drives KCNMA1/BKCa signaling and seizure susceptibility.

Gaga Kochlamazashvili, Marijn Kuijpers.

  Macroautophagy/autophagy is best known for its role in maintaining cellular homeostasis through degradation of damaged proteins and organelles. In neurons, autophagy also contributes to the regulation of activity by adjusting the availability of cellular components to physiological demand. In a recent study, we show that autophagy shapes neuronal excitability by restraining a calcium-dependent pathway that couples endoplasmic reticulum calcium release to KCNMA1/BKCa activity at the plasma membrane. When autophagy is lost, this pathway is enhanced, and seizure susceptibility increases.

Keywords:  Autophagy; BKCa; ERphagy; axon; calcium; endoplasmic reticulum; epilepsy; excitability; neuron; ryanodine receptor

DOI:  https://doi.org/10.1080/15548627.2025.2580436
Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2511069122

mTORC1 regulates autophagosomal components recycling through SNX16 phosphorylation.

Huilin Que, Fengping Liu, Yang Chen, Wenmin Tian, Shuaixin Gao, Catherine C L Wong, Yan Li, Shixuan Wang, Xianbin Meng, Yueguang Rong.

  During autophagy, the contents enclosed within autophagosomes are degraded, while the outer membrane components are recycled from autolysosomes by the recycler complex through the recently discovered autophagosomal components recycling (ACR) process. This recycling is essential for maintaining autophagic activity. However, the molecular machinery and upstream regulatory mechanisms driving this recycling process remain poorly understood. Here, we identify SNX16 as a key component of the recycler complex, which localizes to autolysosomes and is required for ACR. SNX16 functions in ACR by regulating recycler complex formation, facilitating cargo recognition, and mediating the connection between STX17-SNX4-SNX5 and dynein-dynactin complexes. In addition, SNX16-cargo interactions are regulated by two ACR-related small GTPases, Rab32 and Rab38. Importantly, mTORC1 phosphorylates SNX16 to regulate ACR by inhibiting its interactions with STX17 and other recycler components, thus preventing recycler complex formation. Taken together, our findings identify SNX16 as a recycler component and establish a link between mTORC1 and ACR.

Keywords:  SNX16; autophagosomal components recycling; autophagy

DOI:  https://doi.org/10.1073/pnas.2511069122
JCI Insight. 2025 Nov 11. pii: e192827. [Epub ahead of print]

Palmitate impairs autophagic degradation via oxidative stress-perilysosomal Ca2+ overload-mTORC1 activation in pancreatic β-cells.

Ha Thu Nguyen, Luong Dai Ly, Thuy Thi Thanh Ngo, Soo Kyung Lee, Carlos Noriega Polo, Subo Lee, Taesic Lee, Seung-Kuy Cha, Xaviera Riani Yasasilka, Kae Won Cho, Myung-Shik Lee, Andreas Wiederkehr, Claes B Wollheim, Kyu-Sang Park.

  Saturated fatty acids impose lipotoxic stress on pancreatic β-cells, leading to β-cell failure and diabetes. In this study, we investigate the critical role of organellar Ca2+ disturbance on defective autophagy and β-cell lipotoxicity. Palmitate, a saturated fatty acid, induced perilysosomal Ca2+ elevation, sustained mTORC1 activation on the lysosomal membrane, suppression of the lysosomal transient receptor potential mucolipin 1 (TRPML1) channel, and accumulation of undigested autophagosomes in β-cells. These Ca2+ aberrations with autophagy defects by palmitate were prevented by an mTORC1 inhibitor or a mitochondrial superoxide scavenger. To alleviate perilysosomal Ca2+ overload, strategies such as lowering extracellular Ca2+, employing voltage-gated Ca2+ channel blocker or ATP-sensitive K+ channel opener effectively abrogated mTORC1 activation and preserved autophagy. Furthermore, redirecting perilysosomal Ca2+ into the endoplasmic reticulum (ER) with an ER Ca2+ ATPase activator, restores TRPML1 activity, promotes autophagic flux, and improves survival of β-cells exposed to palmitate-induced lipotoxicity. Our findings suggest oxidative stress-Ca2+ overload-mTORC1 pathway involvement in TRPML1 suppression and defective autophagy during β-cell lipotoxicity. Restoring perilysosomal Ca2+ homeostasis emerges as a promising therapeutic strategy for metabolic diseases.

Keywords:  Aging; Autophagy; Calcium signaling; Diabetes; Endocrinology

DOI:  https://doi.org/10.1172/jci.insight.192827
Biochem Biophys Res Commun. 2025 Nov 06. pii: S0006-291X(25)01648-1. [Epub ahead of print]791 152932

The bridge-like lipid transfer protein Vps13 are required for NVJ integrity and nucleophagy.

Tsuneyuki Takuma, Takashi Ushimaru.

  Bridge-like lipid transfer proteins (BLTPs) constitute a superfamily of proteins localized at various intracellular membrane contact sites (MCSs). Members of this family have been implicated in human neurological disorders. Among them, the BLTP Atg2 is essential for the expansion of isolation membranes in macroautophagy. In this study, we demonstrate that another BLTP, Vps13, is involved in microautophagy in budding yeast. Nucleophagy-the autophagic degradation of nuclear components-is crucial for maintaining nuclear proteostasis, and its dysfunction has been linked to neurodegenerative diseases. In micronucleophagy, a portion of the nucleus is directly engulfed by the vacuolar membrane at the nucleus-vacuole junction (NVJ), followed by degradation within the vacuole. Vps13 accumulates at the NVJ upon inactivation of the target of rapamycin complex 1 (TORC1), a process necessary for NVJ integrity. Vps13 is essential for both micronucleophagy and cell viability under nutrient-deprived conditions. Its localization to the NVJ and lipid transfer activity are both critical for nucleophagy. Taken together, these findings suggest that the bridging and lipid transfer functions of Vps13 are both required for effective nucleophagy. This study uncovers novel physiological roles of Vps13 during starvation.

Keywords:  Autophagy; NVJ; Nucleophagy; TORC1; Vps13; rDNA

DOI:  https://doi.org/10.1016/j.bbrc.2025.152932
Stem Cell Reports. 2025 Nov 13. pii: S2213-6711(25)00316-9. [Epub ahead of print] 102712

Autophagy is dispensable in germline stem cells but is required in the cap cells for their maintenance in the Drosophila ovarian niche.

Kiran Suhas Nilangekar, Bhupendra V Shravage.

  Autophagy is a cytoprotective mechanism responsible for the maintenance and long-term survival of various cell types, including stem cells. However, its role in the germline stem cell (GSC) niche remains unexplored. We demonstrate that autophagy flux in female Drosophila GSCs is low and dependent on the core autophagy gene, Atg5. However, the maintenance of Atg5-/- GSCs within the GSC niche was unaffected even under nutrient stress. In contrast, disruption of autophagy within the cap cells (niche cells) leads to the loss of both cap cells and GSCs during aging. Further, reduced autophagy in cap cells severely impairs the crucial GSC self-renewal signal mediated by BMP-pMad emanating from the cap cells at the onset of midlife. Autophagy was essential for the long-term survival of cap cells. Our study reveals a differential role for autophagy, which is dispensable in GSCs but necessary in niche cells, where it supports signaling and survival to maintain GSCs.

Keywords:  Atg5; Drosophila; aging; autophagy; germline stem cells; niche

DOI:  https://doi.org/10.1016/j.stemcr.2025.102712
Cell Chem Biol. 2025 Nov 11. pii: S2451-9456(25)00344-7. [Epub ahead of print]

Lactylation of mTOR enhances autophagy in skeletal muscle during exercise.

Yan Li, Lamei Xue, Feijie Wang, Yu Wang, Yujie Sun, Zhoumin Niu, Shengnan Liu, Ying Yan, Siyi Shen, Kuiliang Zhang, Chenzhipeng Nie, Mingcong Fan, Mei Ma, Yuting Wu, Binrui Yang, Jun Du, Ben Zhou, Duo Zhang, Billy K C Chow, Li Zhang, Haifeng Qian, Liang Chen, Hao Ying, Li Wang.

  Emerging evidence suggests that autophagy is activated during exercise, mediating the benefits of exercise. However, the molecular mechanisms underlying the regulation of skeletal muscle autophagy during exercise are incompletely understood. Here, we show lactate severs as a positive regulator of autophagy in myocytes and its levels increase rapidly in response to a single bout of exercise. Mice with low lactate levels due to the lack of myocyte lactate dehydrogenase A exhibit significant abnormalities in skeletal muscle, including impaired autophagy. Our mechanistic study demonstrates that lactate enhances autophagy by inactivating mTOR complex 1 (mTORC1) through promoting mTOR lactylation at lysine 921 (K921) in myocytes. Accordingly, mutation of mTOR at K921 site causes sustained mTORC1 activation, leading to defects in skeletal muscle autophagy. Thus, our work uncovers a previously undescribed physiological action of lactate in the regulation of mTORC1-controlled skeletal muscle autophagy during acute exercise, which involves a lactylation-based post-translational modification mechanism.

Keywords:  autophagy; exercise; lactylation; mTOR; skeletal muscle

DOI:  https://doi.org/10.1016/j.chembiol.2025.10.007
J Neurochem. 2025 Nov;169(11): e70281

Cell Type-Specific mTORC1 Signaling and Translational Control in Synaptic Plasticity and Memory.

Ziying Huang, Niaz Mahmood, Shane Wiebe, Arkady Khoutorsky, Jean-Claude Lacaille, Nahum Sonenberg.

  Synaptic plasticity and memory formation require de novo protein synthesis. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) promotes mRNA translation initiation in the central nervous system. Recent research has uncovered that excitatory neurons, inhibitory neurons, and glia play distinct roles in modulating synaptic strength and encoding long-term memory via mTORC1 signaling. In this review, we discuss the mechanisms by which mTORC1 regulates translation initiation in the brain and its cell type-specific roles in shaping distinct forms of synaptic plasticity and memory. We also consider how dysregulated translational control contributes to neurological disorders and explore emerging technologies for therapeutic modulation of the mTORC1 pathway.

Keywords:  excitatory neurons; glia; interneurons; mTORC1; memory; synaptic plasticity; translation

DOI:  https://doi.org/10.1111/jnc.70281
Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2425689122

Biomolecular condensation of ERC1 recruits ATG8 and NBR1 to drive autophagosome formation for plant heat tolerance.

Ka Kit Chung, Kai Ching Law, Ziwei Zhao, Juncai Ma, Xiao-Tong Zhan, Cheuk Him Chiang, Kwan Ho Leung, Ruben Shrestha, Yixin Wu, Chaorui Li, Ka Ming Lee, Lei Feng, Xibao Li, Kam Bo Wong, Shou-Ling Xu, Caiji Gao, Xiaohong Zhuang.

  Macroautophagy (hereafter autophagy) is essential for cells to respond to nutrient deficiency by delivering cytosolic contents to vacuoles for degradation via the formation of a multilayer organelle named an autophagosome. A set of autophagy-related (ATG) regulators are recruited to the phagophore assembly site for phagophore initiation, including its expansion and closure, and subsequent delivery into the vacuole. However, it remains elusive how the phagophore assembly is regulated under different stress conditions. Here, we described an uncharacterized Arabidopsis (Arabidopsis thaliana) ERC (ELKS/Rab6-interacting/CAST) protein family as an interacting partner of ATG8. ERC1 proteins translocate to the phagophore membrane and develop into ring-like autophagosomes upon autophagic induction. Notably, we found that ERC1 proteins possess the ability to assemble into substantial droplets together with ATG8e proteins prior to ATG8 conjugation to the membrane. Through multiscale characterization, we demonstrated that the ERC1 membraneless droplet represents a distinct type of plant condensate. Additionally, ERC1 directly binds to NBR1 to promote NBR1 degradation. ERC1 dysfunction suppresses the turnover of ubiquitinated substrates and compromises plant tolerance to heat stress. Our study suggests a model for autophagic degradation in response to heat stress by the action of ERC1-mediated biomolecular condensation in Arabidopsis.

Keywords:  ATG8; ERC protein family; NBR1; autophagosome formation; biomolecular condensation

DOI:  https://doi.org/10.1073/pnas.2425689122
J Cell Physiol. 2025 Nov;240(11): e70107

Autophagy Reprogramming in Cancer.

Annie D Fuller, Travis H Bordner, Abigail J Staub, Jazmyne L Jackson, No'ad Shanas, John M Crespo, William A Nazario-Lugo, Mazen Rukhsar, Alex Tufano, Courtney Worrell, Zachary Wilmer Reichenbach, Kelly A Whelan.

  During malignancy, metabolic reprogramming is critical for cancer cells to survive and thrive in nutrient- and oxygen-poor conditions. Autophagy is a catabolic process through which intracellular components are degraded to support cells upon exposure to stressful conditions. While autophagy is protective during early cancer initiation, tumor cells may initiate cell-intrinsic and cell-extrinsic autophagy to support their survival in later stages of cancer. As autophagy is present at low levels in most tissues under homeostasis and upregulated in malignancy, there has been great interest in targeting the autophagy pathway for cancer therapy. Here, we discuss the mechanisms through which autophagy and autophagy-related proteins act to limit carcinogenesis. We then review pro-tumor roles for autophagy in tumor cells as well as in components of the tumor microenvironment. Finally, we discuss autophagy-targeted approaches for cancer therapy. This review article highlights autophagy as a key player in cell metabolism that is often leveraged to support cancer progression and as a potential therapeutic target in a variety of cancer types.

Keywords:  autophagy; cancer; metabolism

DOI:  https://doi.org/10.1002/jcp.70107
Microbiol Res. 2025 Nov 07. pii: S0944-5013(25)00346-5. [Epub ahead of print]303 128387

Responses to nutrient starvation in the fission yeast Schizosaccharomyces pombe.

Hokuto Ohtsuka, Takafumi Shimasaki, Hirofumi Aiba.

  In nature, nutrient-poor environments are more common than exposure to nutrient-rich environments, and living organisms have developed countermeasures to survive nutrient starvation. Increasing research has revealed beneficial aspects of starvation for an individual's life, including lifespan extension. The fission yeast Schizosaccharomyces pombe is a model unicellular eukaryotic organism and has greatly contributed to the understanding of various cellular processes, including the cell cycle, cell morphology, sexual development, cell lifespan, and nutritional responses. Traditionally, research on starvation in fission yeast has focused on glucose starvation and nitrogen starvation. Recently, studies on cellular responses to the starvation of various nutrients, such as phosphorus, sulfur, iron, zinc, copper, and amino acids have been reported, revealing similarities and differences among the various types of nutrient starvation. In fission yeast, Ecl proteins, which are conserved among fungi, can sense the starvation of multiple nutrients. These proteins also repress the target of rapamycin complex 1 (TORC1), which is conserved across eukaryotes. They channel a variety of starvation signals into common cellular responses, such as growth arrest, sexual differentiation, autophagy, and lifespan extension. This review summarizes and discusses the signaling mechanisms involved in the initial cellular responses of fission yeast to the starvation of various nutrients.

Keywords:  Cell signaling; Fission yeast; Nutrition; Schizosaccharomyces pombe; Starvation

DOI:  https://doi.org/10.1016/j.micres.2025.128387
Hum Mol Genet. 2025 Nov 13. pii: ddaf166. [Epub ahead of print]

Inhibition or genetic reduction of ASAH1/acid ceramidase restore α-synuclein clearance in mutant GBA1 dopamine neurons from Parkinson's patients.

Manoj Kumar, Ricardo A Feldman.

  Bi-allelic mutations in GBA1, a gene that encodes the lysosomal enzyme β-glucocerebrosidase (GCase), cause Gaucher disease (GD). Although GD carriers do not exhibit clinical manifestations, GBA1 mutations are the highest risk factor for Parkinson's disease (PD) in GD patients and carriers of the disease [1-5]. GCase breaks down glucosylceramide (GluCer), a sphingolipid that accumulates in GD. GluCer is deacylated by the lysosomal enzyme acid ceramidase (ACDase) to glucosylsphingosine (GluSph) [6-8]. GluSph is neurotoxic and accumulates to high levels in neuronopathic GD brains [9, 10]. However, whether this metabolic pathway involving ACDase plays a role in GBA1-associated PD (GBA1/PD) is not known. In this report we used induced pluripotent stem cells (hiPSCs) from PD patients harboring heterozygote GBA1 mutations to examine the role of ACDase in promoting α-synuclein accumulation and aggregation, a hallmark of PD. Compared to isogenic controls, hiPSC-derived PD dopamine (DA) neurons had elevated levels of pathogenic α-synuclein species. There was also reduced nuclear localization of transcription factor EB (TFEB), impaired autophagy, and decreased levels of cathepsin D (CathD), a lysosomal protease involved in α-synuclein degradation [11]. Treatment of the mutant DA neurons with a number of different ACDase inhibitors, or CRISPR/Cas9 knockdown (KD) of the ASAH1 gene, reversed all the phenotypic abnormalities of the mutant DA neurons. We conclude that in GBA1/PD-DA neurons, ACDase contributes to deregulation of key nodes of the autophagy/lysosomal pathway (ALP) involved in α-synuclein clearance. Our results suggest that ACDase is a potential therapeutic target for treating GBA1-associated PD.

Keywords:  GBA1; Parkinson’s disease; TFEB; acid ceramidase; ASAH1; α-synuclein

DOI:  https://doi.org/10.1093/hmg/ddaf166
Basic Res Cardiol. 2025 Nov 14.

Autophagy modulates the mechanism of flow-mediated dilation upstream of telomerase.

William E Hughes, Shelby N Hader, Kate Astbury, Lukas Brandt, Karima Ait-Aissa, David D Gutterman, Andreas M Beyer.

  The non-canonical functions of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase play a critical role in maintaining microvascular homeostasis utilizing both human and rodent models. Previously, we have demonstrated that intact autophagic flux is necessary for the beneficial effects of TERT to maintain microvascular function and redox status in human resistance arterioles. The purpose of this investigation was to examine (1) whether loss of TERT function in vivo resulted in reductions in autophagy/mitophagy and concomitant changes in the mediator of microvascular FMD; (2) whether restoration of autophagy can reverse this pathological switch in dilator mechanism, reduce shear-induced mitochondrial H2O2 production while enhancing NO production. TERT mutant rats were generated and compared to their WT counterparts. Rats were given an autophagy activator (2% trehalose) for 28-days. Isolated mesenteric arteries were used for videomicroscopy, and aortic tissue was collected for immunoblotting. FMD and autophagic flux were measured in arteries in all groups. Loss of TERT function resulted in a switch from NOS-dependent to H2O2-dependent FMD, repressed microvascular shear-induced autophagic flux and NO production, and increased mitochondrial H2O2 production. Activation of autophagy restored NO-mediated dilation in TERT mutant rats, and enhanced shear-induced autophagic flux. We provide evidence that autophagy is necessary for the beneficial role of TERT within maintaining microvascular function, positioning this pathway as a modifiable target to maintain microvascular health by rescuing the endothelial dysfunction caused by loss of TERT signaling.

Keywords:  Autophagy; FMD; Microcirculation; Mitochondria; Mitophagy; TERT

DOI:  https://doi.org/10.1007/s00395-025-01146-5
Cell Death Differ. 2025 Nov 10.

OR2T6 modulates autophagy through the PPP3CA-mediated pathways to suppress gastric cancer.

Liping Yan, Wenjie Zhu, Mengqi Wang, Ruinan Zhao, Guohao Zhang, Xiangyu Guo, Chunlan Li, Suxia Wang, Hui Zhang, Peng Gao.

The role of autophagy in gastric cancer (GC) progression remains elusive, warranting further investigation into its mechanisms and therapeutic implications. In this study, we demonstrate that olfactory receptor family 2 subfamily T member 6 (OR2T6) is downregulated and correlates with poorer prognosis in GC tissues. Functionally, OR2T6 induces autophagy initiation while blocking autophagic flux by compromising lysosomal function and inhibits cell proliferation both in vitro and in vivo. Mechanistically, co-immunoprecipitation (Co-IP) and mass spectrometry (MS) analyses reveal that OR2T6 specifically binds to PPP3CA. OR2T6 facilitates the protein stability and enzyme activity of PPP3CA through the ubiquitin-proteasome system and the promotion of calcium ion influx via the Gs/cAMP/PKA channel signaling axis. Our further research demonstrates that OR2T6 binds to PPP3CA, which suppresses the AKT/mTOR signaling pathway, thereby inhibiting tumor proliferation and promoting autophagy initiation. Interestingly, it facilitates the nuclear translocation of TFEB, a key regulator of lysosomal biogenesis, which leads to the transcriptional inactivation of lysosomal target genes (LAMP1, MCOLN1, ATP6V1H, CTSB, and CTSD), impairing lysosomal function and blocking autophagic flux. Collectively, we report that OR2T6 binds to and promotes PPP3CA, which subsequently initiates autophagy, inhibits proliferation by suppressing the AKT/mTOR pathway, and then blocks autophagic flux through TFEB-mediated lysosomal dysfunction. These findings suggest that OR2T6 may be a potential therapeutic target for GC.

DOI: https://doi.org/10.1038/s41418-025-01611-7
JCI Insight. 2025 Nov 10. pii: e189420. [Epub ahead of print]10(21):

IRF7 drives macrophages to kill bacteria and improves septic outcomes via autophagy.

Guiming Chen, Kangxin Li, Haihua Luo, Lianxu Zhao, Yong Jiang.

  Sepsis contributes substantially to mortality rates worldwide, yet clinical trials that have focused on its underlying pathogenesis have failed to demonstrate benefits. Recently, enhancing self-defense has been regarded as an emerging therapeutic approach. Autophagy is a self-defense mechanism that protects septic mice, but its regulatory factor is still unknown. Moreover, the role of interferon regulatory factor 7 (IRF7) in sepsis has been debated. Here, we showed that Irf7 deficiency increased mortality during polymicrobial sepsis. Furthermore, IRF7 drove macrophages to protect against sepsis. Mechanistically, IRF7 is a transcription factor that upregulates the expression of autophagy-related genes responsible for autophagosome formation and autolysosome maturation, induces autophagic killing of bacteria, and ultimately reduces septic organ injury. Recombinant adeno-associated virus 9-Irf7-mediated IRF7 overexpression promoted the autophagic clearance of pathogens and improved sepsis outcomes, which may be the mechanism underlying the observed improvement in bacterial clearance. These findings provide evidence that IRF7 is the underlying regulatory factor that drives autophagy to eliminate pathogens in macrophages during sepsis. Collectively, IRF7 overexpression represents a potential host-directed therapeutic strategy for preclinical sepsis models, operating independently of antibiotic mechanisms.

Keywords:  Autophagy; Bacterial infections; Infectious disease; Macrophages; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.189420
Autophagy. 2025 Nov 13.

Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.

Tian Lan, Dantong Shang, Lan Lin, Haoyu Wang, Juan Zou, Mengxin Hu, Hanhua Cheng, Rongjia Zhou.

  Mitochondrial nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, yet its roles and mechanisms in mitophagy and innate immunity remain poorly understood. In this study, we identify mitochondrial NAD+ depletion that causes mitophagy dysfunction and inflammation. We find that depletion of mitochondrial NAD+ owing to deficiency of the mitochondrial NAD+ transporter SLC25A51 impairs BNIP3-mediated mitophagy. Loss of mitochondrial NAD+ inhibits SIRT3-mediated deacetylation of FOXO3, leading to transcriptional downregulation of BNIP3 and subsequent disruption of MAP1LC3B/LC3B recruitment. Notably, mitochondrial NAD+ depletion promotes mitochondrial DNA (mtDNA) release from mitochondria to the cytosol upon oxidative stress, thereby exacerbating the type I interferon response to free cytosolic mtDNA via activation of the CGAS-STING1 signaling pathway. Our findings reveal a novel mechanistic link among mitochondrial NAD+, mitophagy, and mtDNA-induced inflammation by genetic manipulation of cell lines, highlighting mitochondrial NAD+ as a potential therapeutic target for mitigating sterile inflammation triggered by free cytosolic mtDNA. Thus, the study provides new insights into the crosstalk among mitochondrial homeostasis, inflammation, and innate immunity.

Keywords:  Cytosolic mtDNA; SLC25A51; inflammation; innate immunity; mitochondrial NAD+; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2589909
FEBS Open Bio. 2025 Nov 10.

Autophagosome marker, LC3, is released extracellularly via several distinct pathways.

Koki Saito, Masashi Arakawa, Koki Maeda, Eiji Morita.

  Autophagy-mediated secretion contributes to the maintenance of intracellular homeostasis by releasing cytoplasmic components into the extracellular space. However, several aspects of the process remain unclear. In this study, we developed an ultrasensitive detection system using HiBiT tag/NanoBiT technology to analyze the conditions that trigger the secretion of LC3, an autophagosome marker. In HiBiT-tagged knock-in cells, a detectable amount of HiBiT-dependent NanoLuc luciferase activity (HiBiT activity) from HiBiT-fused LC3 was observed in the culture supernatants. However, the levels were lower than those of CD63. HiBiT activity was detected only in the presence of detergent, indicating that LC3 was released from the lipid membranes. Treatment with bafilomycin A1 significantly increased the extracellular HiBiT activity, which was diminished in ATG5 or FIP200 knockout cells, suggesting that this release depends on autophagosome formation. However, some HiBiT-LC3 was detected in these knockout cells, indicating that LC3 may be released via an autophagy-independent mechanism. The introduction of a C-terminal truncation (ΔG) or the K51A/L53A mutation also reduced LC3 release, but did not completely inhibit it, suggesting that multiple pathways exist for LC3 release. This system is expected to elucidate the mechanisms underlying autophagy-mediated secretion.

Keywords:  HiBiT tag; LC3 family; autophagic secretion; autophagy; knock‐in cells; lysosome

DOI:  https://doi.org/10.1002/2211-5463.70150
Nat Commun. 2025 Nov 10. 16(1): 9878

DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans.

Cristian Ricaurte-Perez, Joshua P Gill, P Kerr Wall, Olga Dubuisson, Kathryn R DeLeo, K Adam Bohnert, Alyssa E Johnson.

Transcription factors DAF-16/FOXO and HLH-30/TFEB have been linked to aging regulation, but how they synergize to promote longevity is not fully understood. Here, we reveal a functional interaction between these two transcription factors that supports healthier aging in Caenorhabditis elegans. Namely, DAF-16 and HLH-30 cooperate to trigger robust lysosomal tubulation under various contexts, which contributes to systemic health benefits in late age. Remarkably, lysosome tubulation can be artificially induced via overexpression of a small lysosomal gene, dSVIP, in the absence of one transcription factor, but not both. Mechanistically, intestinal overexpression of dSVIP leads to nuclear accumulation of DAF-16 and HLH-30 in gut and non-gut tissues and triggers global gene expression changes, including induction of vps-34 and related lipid-metabolism genes, that promote tubular-lysosome activity. Collectively, our work reveals a cellular process under control of DAF-16 and HLH-30 that elicits pro-health effects in aging.

DOI: https://doi.org/10.1038/s41467-025-64832-x
Front Cell Dev Biol. 2025 ;13 1696985

Research progress on the mutual regulatory mechanism of circadian clock genes and autophagy.

Yueqi Ma, Ran Yu, Xueqing Zheng, Jiahui Rao, Gaiping Shi, Yumei Ding.

  Recent studies have highlighted the intricate relationship between the circadian rhythm, a natural biological process responsive to light and darkness, and autophagy, a mechanism crucial for maintaining cellular homeostasis. Circadian clock genes, which are pivotal in regulating our internal body clock, appear to be closely intertwined with autophagy. These genes can directly influence the expression of autophagy-related genes or modulate signalling pathways that govern autophagic processes. Conversely, autophagy also controls the expression and activity of circadian clock genes. Investigating these interactions will help elucidate how autophagy and circadian rhythms maintain cellular equilibrium and regulate physiological functions. Moreover, such studies help reveal disease mechanisms and develop potential therapeutic strategies.

Keywords:  autophagy; bmal1; circadian clock genes; circadian rhythm; molecular mechanisms

DOI:  https://doi.org/10.3389/fcell.2025.1696985
Antioxid Redox Signal. 2025 Nov;43(13-15): 745-764

SQSTM1/p62 Post-Translational Modifications and Reverse Processes Modulate Disease Pathogenesis via KEAP1-NRF2 Signaling and Selective Autophagy.

Dongrong Zhu, Yue Li, Lirong Zhao, Duxiang Pei, Yutong Guo, Liren Liu.

  Significance: Sequestosome 1 (SQSTM1/p62, hereafter referred to as p62) is a multifunctional ubiquitin-binding autophagy receptor that acts as a critical bridge between the kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) pathway and selective autophagy through diverse post-translational modifications (PTMs) and their reverse processes. Recent Advances: As a selective autophagy receptor, p62 facilitates the degradation of ubiquitinated substrates while functioning as a signaling hub to orchestrate cellular responses to oxidative stress. Given its central role in multiple signaling pathways, p62 is subject to tight and intricate regulation. Beyond transcriptional control, p62 activity is finely modulated by diverse PTMs and their reverse processes, including phosphorylation, dephosphorylation, ubiquitination, deubiquitination, acetylation, deacetylation, S-Acylation, and deacylation, which collectively fine-tune its roles in selective autophagy and the KEAP1-NRF2 pathway. Mounting evidence underscores that the PTMs and their reverse processes of p62 are implicated in diverse pathologies through both direct and indirect mechanisms, spanning multiple cancer subtypes, neurodegenerative disorders, inflammatory conditions, non-alcoholic fatty liver disease (NAFLD), and metal-induced toxicity, as well as infectious diseases. Critical Issues: This review synthesizes current knowledge on the PTMs and their reverse processes of p62, its functional implications, its disease-associated mechanisms, and molecular regulators, aiming to provide novel insights for targeting the PTMs and their reverse processes of p62 in therapeutic strategies. Future Directions: Targeting p62 PTMs and their reverse processes may be a promising strategy to ameliorate various diseases, including cancer, neurodegenerative disorders, inflammatory conditions, NAFLD, metal-induced toxicity, and infectious diseases. Antioxid. Redox Signal. 43, 745-764.

Keywords:  KEAP1-NRF2 pathway; SQSTM1/p62; disease pathogenesis; posttranslational modification; selective autophagy

DOI:  https://doi.org/10.1177/15230864251395963
Cell Death Dis. 2025 Nov 14. 16(1): 829

Uncomplexed-TSC1 deploys novel mTORC1-independent pathway to exacerbate the liver glycogen storage in TSC.

Xiaoqiao Yue, Yanping Zhang, Na Zhao, Tao Lang, Guangxin Chen, Qiuhong Xiong, Lei Gao, Wenjing Wang, Ping Li, Changxin Wu.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations in TSC1 or TSC2 gene, leading to mTORC1 hyperactivation. However, mTORC1-independent mechanisms in this disorder remain poorly understood. In the study, excess glycogen storage was found in Tsc1-/- cells, Tsc1+/- and Tsc1c.2500-2503delAACA mice, as well as in Tsc2-/- cells, Tsc2+/- and Tsc2c.1113delA mice, with more pronounced accumulation in models with TSC2 defects. Mechanistically, the deficiency of TSC1 or TSC2 gene caused redundant uncomplexed-TSC2 or TSC1 protein, respectively. Strikingly, only uncomplexed-TSC1 downregulated the histone demethylase KDM5A, which in turn increased H3K4me3 levels at the METTL3 promoter to enhance its expression. The upregulated m6A "writer" protein METTL3 cooperated with the "reader" protein IGF2BP2 to stabilize GYS2 mRNA, causing the upregulation of GYS2 resulting in the glycogen storage. Thus, our study uncovered a novel mTORC1 independent pathway (TSC1-KDM5A-METTL3-IGF2BP2-GYS2) that underlies the excess glycogen storage, and that synergy of mTORC1-dependent and independent pathways leads to the more pronounced glycogen storage with TSC2 defects compared to those with TSC1 defects, reflecting the more severer clinical phenotypes in TSC patients with TSC2 mutations. Importantly, the restoration of glycogen homeostasis and significant amelioration of liver lesion in TSC2 defect models after the combination treatment of pharmacological inhibitors targeting mTORC1 and METTL3, unveil a potential clinic intervention for TSC patients to whom mTORC1 inhibitors are less effective or even ineffective.

DOI: https://doi.org/10.1038/s41419-025-08161-3
Int J Mol Sci. 2025 Oct 27. pii: 10443. [Epub ahead of print]26(21):

Comparative Analysis of Two Autophagy-Enhancing Small Molecules (AUTEN-67 and -99) in a Drosophila Model of Spinocerebellar Ataxia Type 1.

Tímea Burján, Maryam Aslam, Fanni Keresztes, Tímea Sigmond, Viktor A Billes, Norbert Bencsik, Katalin Schlett, Tibor Vellai, Tibor Kovács.

  Autophagy is a lysosome-mediated self-degradation process of eukaryotic cells which is critical for the elimination of cellular damage. Its capacity progressively declines with age, and this change can lead to the development of various neurodegenerative pathologies including Spinocerebellar ataxia type 1 (SCA1). SCA1 is mainly caused by mutations in the polyglutamine region of Ataxin 1 protein. In patients affected by the disease, Purkinje neurons of the cerebellum frequently undergo demise and eventually become lost. Here we tested whether two well-characterized autophagy-enhancing small molecules, AUTEN-67 and -99, which antagonize the autophagy complex Vps34 through blocking the myotubularin-related lipid phosphatase MTMR14/EDTP, have the capacity to ameliorate SCA1 symptoms. We found that in a Drosophila model of SCA1, only AUTEN-67 exerts positive effects including improvement in climbing ability and extending life span. Based on these results, we hypothesized that the two compounds influence autophagy in the brain in a neuron-specific manner. Indeed, according to data we obtained, AUTEN-67 and -99 exhibit shared and unique functional domains in the Drosophila brain. AUTENs enhance autophagy in GABAergic and dopaminergic neurons. In addition, AUTEN-67 also affect autophagy in cholinergic neurons, while AUTEN-99 trigger the process in glutaminergic neurons and motoneurons. We also observed varying efficiencies between the two AUTENs among different subtypes of cultured hippocampal neurons of mice. These data suggest that the two compounds display neuron-specific differences in exerting autophagy-enhancing effects, and may lead to a better understanding of which types of neurons autophagy could potentially be activated to treat SCA1 in human patients.

Keywords:  AUTEN-67 2; AUTEN-99 3; Drosophila 5; EDTP 6; MTMR14 7; SCA1 9; aging 1; autophagy 4; neurodegeneration 8

DOI:  https://doi.org/10.3390/ijms262110443
Cell Death Dis. 2025 Nov 10. 16(1): 815

CARMN loss promotes VSMC-derived foam cell formation and atherosclerosis through transcriptional downregulation of autophagy.

Tiegen Huang, Yao Tang, Quanli Su, Chen Su, Jiahao Wang, Lu Fu, Yixin Tang.

Vascular smooth muscle cells (VSMCs) are a significant source of foam cells in atherosclerosis, but the mechanism involved in the formation of VSMC-derived foam cells remains poorly understood. Although long noncoding RNAs (lncRNAs) are dysregulated in lipid metabolism disorder and atherosclerosis, little is known about their involvement in VSMC-derived foam cell formation. Silencing CARMN promoted lipid accumulation and VSMC-derived foam cell formation in high-fat diet-fed ApoE-/- mice. Furthermore, CARMN knockdown reduced cholesterol efflux and promoted VSMC-derived foam cell formation by regulating autophagy. In exploring the mechanism by which CARMN regulates autophagy, our results demonstrated that CARMN knockdown reduced autophagy in VSMCs by modulating the AKT/ATG7 pathway through transcriptional suppression of the adjacent gene casein kinase 1 alpha 1 (CSNK1A1). In vivo, CARMN deficiency led to reduced autophagy in VSMCs and increased atherosclerotic lesions, characterized by increased lipid deposition and necrotic core. Our findings reveal that CARMN plays an essential role in the regulation of VSMC autophagy, which is crucial for the formation of VSMC-derived foam cells and the progression of atherosclerosis. These results provide new insights into the molecular mechanisms underlying VSMC autophagy and suggest that CARMN is a potential therapeutic target for atherosclerosis.

DOI: https://doi.org/10.1038/s41419-025-08157-z
Ageing Res Rev. 2025 Nov 07. pii: S1568-1637(25)00282-X. [Epub ahead of print]113 102936

Irisin-mediated hepatic autophagy remodels nutritional metabolism to prevent cognitive dysfunction.

Xinjie Zhang, Yizhuo Yang, Hanan Song, Xuan Hu, Xiaobing Wang, Yanli Yu.

  Cognitive impairment has emerged as a serious global health challenge and is closely associated with metabolic disorders. Autophagy dysfunction leading to metabolic disorders has become a key factor in neurodegenerative diseases. The liver, as the central organ of systemic metabolism, regulates metabolic homeostasis through hepatic autophagy, thereby affecting the clearance of toxic proteins in the brain and energy supply. Hepatic autophagy dysfunction can increase free fatty acids, which attack the blood-brain barrier and lead to neurodegenerative diseases. Irisin enters the liver via the bloodstream, activates AMPK to promote hepatic autophagy, reduces the production of lipotoxic substances, alleviates neuroinflammation, and ensures effective synaptic signaling. Previous studies have demonstrated that irisin can improve neurodegenerative diseases, but no connection has yet been established between irisin, hepatic autophagy, and cognition. Therefore, this review discusses the positive role of irisin in preventing cognitive impairment through hepatic autophagy. Future studies should employ multi-omics approaches to deeply analyze the metabolic network regulated by irisin and explore its potential in the treatment of neurological diseases. Irisin is expected to serve as a key bridge connecting exercise, metabolic health, and neuroprotection, thus paving the way for the prevention and treatment of cognitive decline and neurodegenerative diseases.

Keywords:  Cognitive Dysfunction; Hepatic Autophagy; Irisin; Nutritional Metabolism

DOI:  https://doi.org/10.1016/j.arr.2025.102936
Autophagy. 2025 Nov 13.

Autophagy regulates the maternal-to-zygotic transition through MAP1LC3B-mediated maternal mRNA decay.

Doudou Liu, Shimeng Guo, Jing Hu, Lin Zhu, Jie Wang, Sheng Yang, Yuhan Zhang, Guoning Huang, Shaorong Gao, Qianshu Zhu, Jingyu Li.

  During the maternal-to-zygotic transition (MZT), the programmed decay of maternal mRNAs is critical for successful embryonic development. Although autophagy is known to participate in early embryonic development, its specific role in maternal mRNA clearance remains unclear. MAP1LC3B/LC3B, a key autophagy-related protein, has recently been identified as an RNA-binding protein; however, whether it contributes to maternal mRNA degradation has not been established. Through integrative analyses combining RIP-seq, RNA-seq, and CUT&Tag in early embryos, we identified LC3B as a maternal mRNA-binding protein essential for mRNA degradation. LC3B-mediated mRNA decay exhibited faster kinetics than the classical BTG4-CCR4-NOT pathway. Knockdown of LC3B or inhibition of autophagy significantly delayed maternal mRNA clearance, resulting in impaired zygotic genome activation (ZGA) and developmental arrest. Further analysis revealed the maternal Suv39h2 as a key LC3B-target gene, whose abnormal persistence correlates with developmental failure. Our findings revealed an autophagy-dependent mRNA clearance pathway mediated by LC3B, providing novel mechanistic insights into maternal mRNA decay and developmental regulation during mammalian MZT.

Keywords:  Autophagy; LC3B; Suv39h2; ZGA; embryo development; maternal decay

DOI:  https://doi.org/10.1080/15548627.2025.2589911
Cell Signal. 2025 Nov 06. pii: S0898-6568(25)00639-4. [Epub ahead of print] 112224

ERLIN1: A central regulator of protein quality control, lipid homeostasis, and cellular signaling at the endoplasmic reticulum.

Hyojeong Cho, Beomwoo Lee, Changgyu Son, Jaeseok Choi, Sunho Eom, Jongsun Park.

  Endoplasmic reticulum lipid raft-associated protein 1 (ERLIN1) is an endoplasmic reticulum (ER)-resident stomatin/prohibitin/flotillin/HflK/C (SPFH) family protein that assembles into oligomeric complexes within detergent-resistant membrane domains. ERLIN1 regulates multiple cellular functions, including protein quality control, calcium signaling, and lipid metabolism. Together with ERLIN2, it forms ER-associated degradation (ERAD) nanodomains through interactions with RING finger protein 170 (RNF170) and transmembrane and ubiquitin-like domain-containing 1 (TMUB1). These specialized domains facilitate the degradation of inositol 1,4,5-trisphosphate receptor type 1 (IP3R) via the ERAD pathway. ERLIN1 also controls cholesterol metabolism by inhibiting sterol regulatory element-binding protein (SREBP) activation and promoting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) degradation. In addition, it blocks cholesterol esterification, thereby enhancing cholesterol transport to the Golgi apparatus. ERLIN1 further regulates cell fate by promoting autophagy and suppressing apoptosis; in complex with ERLIN2, it interacts with activating molecule in Beclin 1-regulated autophagy protein 1 (AMBRA1) at mitochondria-associated membranes to initiate autophagy and binds phosphatidylinositol 3-phosphate to stabilize autophagy signaling. Its overexpression enhances tumor progression, whereas silencing triggers apoptosis in colorectal cancer. Mutations in ERLIN1 are linked to neurodegenerative diseases such as hereditary spastic paraplegia type 62 and atypical amyotrophic lateral sclerosis. The ERLIN1/2 complex also influences immune responses and viral replication through cholesterol regulation. Collectively, these diverse and integrated functions highlight the potential of ERLIN1 as a therapeutic target in cancer, metabolic, neurodegenerative, and infectious diseases.

Keywords:  Autophagy; Cellular signaling; Cholesterol metabolism; ERLIN1; Endoplasmic reticulum–associated degradation (ERAD)

DOI:  https://doi.org/10.1016/j.cellsig.2025.112224
J Cell Sci. 2025 Nov 14. pii: jcs.264252. [Epub ahead of print]

ALLO-1a is a ubiquitin-binding adaptor for allophagy in Caenorhabditis elegans.

Takuya Norizuki, Yasuharu Kushida, Takayuki Sekimoto, Taeko Sasaki, Koji Yamano, Noriyuki Matsuda, Ryohei Sasaki, Nobuo N Noda, Ken Sato, Miyuki Sato.

  In the nematode Caenorhabditis elegans, sperm-derived mitochondria and membranous organelles (MOs) are selectively degraded by autophagy in embryos in a process termed allophagy. For this process, ALLO-1 functions as an autophagy adaptor. The allo-1 gene encodes two splice isoforms, ALLO-1a and b, which have different C-terminal sequences and are predominantly targeted to MOs and paternal mitochondria, respectively. However, the mechanism by which ALLO-1 targets the paternal organelles remains unknown. In this study, X-ray crystallography analysis reveals that the C-terminal region of ALLO-1a forms a parallel coiled-coil structure. In addition, Alphafold-Multimer predicts that this region directly interacts with ubiquitin. We showed that ALLO-1a interacts with K48- and K63-linked polyubiquitin in vitro and found that the 355th Asp residue of ALLO-1a at the predicted interface with ubiquitin is important for its ubiquitin binding in vitro and also for its MO-targeting and MO degradation in embryos. These results suggest that ubiquitin is a marker for the recognition of MOs by the autophagy machinery in C. elegans embryos.

Keywords:   Caenorhabditis elegans ; Autophagy; Fertilization; Membranous organelles; Sperm; Ubiquitin

DOI:  https://doi.org/10.1242/jcs.264252
Sci Adv. 2025 Nov 14. 11(46): eaea4660

The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.

Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.

Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.

DOI: https://doi.org/10.1126/sciadv.aea4660
Nature. 2025 Nov 12.

Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.

Yifan Zhang, Xiao Shen, Yuan Shen, Chao Wang, Chengping Yu, Jiangxue Han, Siyi Cao, Lin Qian, Miaolian Ma, Shijing Huang, Wenyu Wen, Miao Yin, Qun-Ying Lei.

Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY), mitochondrial citrate/malate antiporter (encoded by SLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA-NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.

DOI: https://doi.org/10.1038/s41586-025-09745-x
Cardiovasc Res. 2025 Nov 10. pii: cvaf214. [Epub ahead of print]

Coupling of USP10 de-ubiquitination and chaperone-mediated autophagy causes cardiac sodium channel degradation and cardiac arrhythmias.

Hongbo Xiong, Di Guo, Zhen Zhou, Lilin Xiang, Xiangjie Kong, Tong Zhang, Zhijie Wang, Huanhuan Cai, Di Fan, Qiongxin Wang, Yimei Du, Qing K Wang, Zhibing Lu.

   AIMS: SCN5A encodes cardiac sodium channel Nav1.5 that maintains normal electrophysiological functions of hearts. Loss-of-function variants of Nav1.5 reduce sodium current densities (INa) and cause arrythmias such as cardiac conduction block or Brugada syndrome. The regulatory mechanisms of Nav1.5 functions are not fully understood. The aim of this study was to identify novel proteins that interact with Nav1.5 and characterize their regulatory mechanisms on Nav1.5 and arrhythmias.
METHODS AND RESULTS: GST pull-down coupled with mass spectrometry, co-immunoprecipitation and mutational analysis were used to identify deubiquitinating enzyme USP10 as a novel Nav1.5-interacting protein, and showed that USP10 reduces Nav1.5 protein expression and INa densities in vitro. AAV9-mediated cardiac overexpression of USP10 in mice reduced Nav1.5 protein expression, INa and ICa-L densities, shortened APD, and caused delayed ventricular activation, spontaneous atrioventricular conduction block, sinus pause and ventricular tachycardia (VT) induced with electrical pacing. Cardiac knockdown of USP10 in Scn5a+/- mice restored Nav1.5, INa and ICa-L to levels comparable to wild-type mice, and alleviated the conduction delay and premature ventricular contractions. Mechanistically, USP10 increased Nav1.5 protein degradation through chaperone-mediated autophagy (CMA) as the effect was blocked by lysosome inhibitor CQ and inhibition of CMA using siRNA targeting LAMP2A or HSC70, but not by proteasomal inhibitor MG132. Mutational analysis identified the key CMA degradation motif of Nav1.5 as EKRFQ431-435. USP10 decreased Nav1.5 ubiquitination, and increased binding of Nav1.5 to HSC70. Mutational analysis identified K430 of Nav1.5 as the USP10 de-ubiquitination site, and K430R mutation blocked regulation of Nav1.5 by USP10.
CONCLUSIONS: We identified a novel CMA-mediated pathway regulating degradation of Nav1.5 by coupling with USP10-mediated de-ubiquitination at K430 of Nav1.5, which resulted in reduced INa densities and cardiac conduction defects. Knockdown of USP10 alleviated arrythmias in Scn5a+/- mice, providing a novel therapeutic strategy for treating arrythmias with reduced INa.

Keywords:  Nav1.5/SCN5A; USP10; arrythmia; cardiac conduction block; chaperone-mediated autophagy

DOI:  https://doi.org/10.1093/cvr/cvaf214
Int J Mol Sci. 2025 Oct 30. pii: 10568. [Epub ahead of print]26(21):

Current Understanding of Protein Aggregation in Neurodegenerative Diseases.

Chen Hu, Menghan Lin, Chuangui Wang, Shengping Zhang.

  Protein aggregates are central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. This comprehensive review explores the mechanisms of protein misfolding and aggregation, their prion-like propagation, and the critical role of oligomeric species in neurotoxicity. It further examines cellular clearance pathways, including the ubiquitin-proteasome system and autophagy, alongside the regulatory functions of molecular chaperones. The review also covers advanced diagnostic imaging and biomarker techniques, as well as emerging therapeutic strategies such as pharmacological agents, gene therapy, and immunotherapy. Controversies regarding the toxicity of aggregates and future directions, including novel degradation technologies and targeted therapeutic approaches, are discussed. By integrating current knowledge, this review aims to provide a broad yet detailed overview of the field, highlighting both established concepts and promising avenues for research and treatment.

Keywords:  aggregate clearance; neurodegenerative diseases; oligomers; protein aggregates; therapeutic strategies

DOI:  https://doi.org/10.3390/ijms262110568
Cell Commun Signal. 2025 Nov 12. 23(1): 492

TGF-β2 increases eHSP90α secretion via upregulating secretory autophagy pathway.

Jing Li, Junmin Li, Tong Xie, Shuxin Huang, Haijiao Tian, Mengyun Liu, Xiumei Kong, Dongzhe Zhang, Khan Iqbal Nawaz, Mingli Wang, Hui Li, Jing Zhang, Fengling Yuan, Weikai Guo, Xiukun Cui, Hongmei Mu, Yanzhong Hu.

   BACKGROUND: Extracellular heat shock protein 90α (eHSP90α) regulates diverse cellular processes such as wound healing, tumor metastasis, angiogenesis and cell differentiation etc. Our previous data show that lens epithelial cells can secret eHSP90α, and administration of eHSP90α exerts a critical regulation for lens regeneration by promoting the differentiation of lens epithelial cells (ECs) to lens fiber cells. Autophagy is proposed to regulate the eHSP90α secretion from lens epithelial cells. However, the regulatory mechanism remains unclear.
METHODS: Lens ECs cell line SRA01/04, ex vivo cultured rat lens capsular bags and primary rat lens ECs were used in this study. The immunoblotting and qPCR were used for measuring the expression of proteins and mRNAs. The immunofluorescence staining assay was for testing the autophagosomes or protein co-localization. siRNA or CRISPR-Cas9 were used to knock down genes' expression in cells in vitro. The ChIP assay was used to study the interaction of transcriptional factor to the promoter of target genes. The nuclear and cytoplasmic extraction assay was for testing the nuclear translocation of TFEB and TFE3.
RESULTS: eHSP90α is secreted through the secretory autophagy pathway in lens epithelial cells in vitro or in the residual anterior ECs of capsular bags ex vivo. HSP90α interacts with adaptor protein TRIM16, and was recruited to the R-SNARE protein SEC22B on the surface of secretory autophagosome membrane for secretion. Silencing autophagic ATG7 or components of secretory autophagy pathways, such as TRIM16, SEC22B and Q-SNARE STX3, STX4 and SNAP23 downregulates HSP90α secretion. TGF-β2 upregulates the eHSP90α secretion via upregulating secretory autophagy pathway. TGF-β2 treatment results in the upregulation of the expression of ATG7, Beclin1, LC3B at both protein and mRNA levels through activating p38 and ERK1/2. In addition, TGF-β2 increases SEC22B expression through ERK1/2-induced expression and nuclear translocation of transcriptional factors TFEB and TFE3, which form the heterodimer binding to the promoter of SEC22B. Functionally, the upregulated eHSP90α can trigger TGF-β2-induced differentiation of lens ECs to fiber cells.
CONCLUSIONS: In lens cells, the eHSP90α's secretion undertakes secretory autophagy pathway through interacting with TRIM16 and SEC22B. TGF-β2 elevates eHSP90α secretion through upregulating secretory autophagy pathway, which in turn promote TGF-β2-induced lens epithelial cells' differentiation to lens fiber cells.

Keywords:  Extracellular HSP90α; SEC22B; Secretory autophagy; TGF-β2; Unconventional protein secretion

DOI:  https://doi.org/10.1186/s12964-025-02493-5