bims-auttor 2026-01-25 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–01–25
28 papers selected by
Viktor Korolchuk, Newcastle University

Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired.
ER membrane receptors engage core autophagy machinery to initiate ER-phagy.
Autophagy in lipid metabolism.
Acetyl-CoA as a metabolic switch for selective mitophagy.
Hyperactivation of mTORC1 blocks stem cell fate transitions through TFE3-NuRD association.
[Autophagy and Neurological Diseases].
Regulatory role of mTORC1 signaling in osteoblasts in acute myeloid leukemia progression and steady-state hematopoiesis.
Deletion of the Saccharomyces cerevisiae RACK1 homolog, ASC1, enhances autophagy which mitigates TDP-43 toxicity.
C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
Nrf2 shapes response to lysosomal inhibition of radiation-induced senescent thyroid cancer cells.
α-Synuclein Deletion Leads to Hyposmia: due to Defective Autophagy Induced by Abnormal PI3K/mTOR Signaling Pathway in Olfactory Bulb.
CLN3 mediates chloride efflux from lysosomes.
Rapamycin Differentially Impacts Germline Stem Cell Quiescence Across Diverse Genetic Backgrounds of Drosophila Melanogaster.
The mTOR Pathway in Hearing Disorders: Mechanistic Links to Aging, Regeneration, and Neurodegeneration.
DNA nanodevices detect an acidic nanolayer on the lysosomal surface.
ATG gene duplication in vertebrates: evolutionary divergence and its functional implications.
Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.
The Atg2-Atg18 complex interacts with the Atg1 complex to localize to the pre-autophagosomal structure in Saccharomyces cerevisiae.
Geniposide Attenuates Post-Myocardial Infarction Cardiac Remodeling via Parkin-Dependent Suppression of Hyperactivated Mitophagy.
Editorial: The role of autophagy in infectious diseases, volume II.
The lysosomal LAMTOR-Rag complex functions as a checkpoint for antiviral interferon production.
Neddylation Regulates Mitochondrial Dynamics and Turnover in the Adult Heart.
Proteomic Landscape of Sweat Glands in Neuronal Intranuclear Inclusion Disease Reveals a Pathogenic Triad of Abnormal Autophagy, Mitochondrial Dysfunction, and a Failed Oxidative Stress Response.
Upregulated GBP2 exacerbates Parkinson's disease pathogenesis by impairing NIX-dependent mitophagy.
The PI4K2A-OSBPL6/ORP6-PS axis mediates lysosomal membrane repair to restore neuronal lipid homeostasis and promote neuronal survival after spinal cord injury.
New perspective on neurodegenerative diseases: Focusing on the interaction between autophagy and oxidative stress and targeted strategies.
Ageing promotes microglial accumulation of slow-degrading synaptic proteins.
Molecular engineering of lysosome-based degraders unveils a rapidly expanding therapeutic strategy.

Cell Commun Signal. 2026 Jan 20.

Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired.

Huy Quang Dang, Therése Forssén, Spyridon Pantelios, Aisegkioul Nteli Chatzioglou, Ewa Kurzejamska, C Theresa Vincent, Yasir Ibrahim, Anders P Mutvei.

  The mechanistic target of rapamycin complex 1 (mTORC1) is a central driver of cell growth that is frequently hyperactivated in cancer. While mTORC1 is activated at the lysosomal surface in response to growth factors and amino acids, the processes governing its inactivation are not fully understood. Here, we report that sustained mTORC1 suppression during leucine or arginine starvation requires the translocation of peripheral lysosomes to the perinuclear region. Our data suggest that a pool of mTOR remains active at peripheral lysosomes during starvation, and that increased spatial separation between lysosomes and the plasma membrane attenuates PI3K/Akt signaling-thereby reducing inputs that otherwise maintain mTORC1 activity. Consequently, preventing lysosome translocation and increasing peripheral lysosome levels sustains mTORC1 signaling during prolonged starvation in a PI3K/Akt-dependent manner independently of autophagy. Under these conditions, mTORC1 signaling persists even when lysosomal catabolism is perturbed by chloroquine or concanamycin A. Collectively, these data indicate that the peripheral lysosome pool, even when catabolically impaired, can sustain mTORC1 signaling under nutrient scarcity, by modulating PI3K/Akt signaling input to the pathway. These observations identify peripheral lysosome levels as a critical determinant of mTORC1 inactivation during nutrient stress and may have implications for diseases with aberrant mTORC1 signaling, including cancer.

Keywords:  Amino acid deprivation; Catabolically impaired lysosomes; Lysosome positioning; MTORC1; PI3K-Akt signaling; Rab7; Rap1

DOI:  https://doi.org/10.1186/s12964-026-02659-9
Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2523465123

ER membrane receptors engage core autophagy machinery to initiate ER-phagy.

Cha Wu, Haixia Yang, Chen Wang, Peiqi Huang, Ning Yan, Ruobing Ren, Wei Liu, Yi Lu, Chunmei Chang.

  Endoplasmic reticulum (ER) phagy is the form of selective autophagy that governs ER abundance and integrity by targeting dysfunctional ER fragments for degradation. How the recognition of ER fragments as autophagy substrates is coupled to engagement of the core autophagic machinery is largely unknown. Here, using a combination of in vitro reconstitution systems, structural modeling, and cell biology, we demonstrate that ER membrane receptors directly engage the core autophagy component ATG9A, as well as the PI3P-binding protein WIPI2, to initiate ER-associated autophagosome biogenesis. ER-phagy receptor-ATG9A association nucleates the recruitment of the other key autophagy proteins required to initiate ER-phagy. In parallel, ER-phagy receptor-WIPI2 engagement promotes rapid LC3 lipidation for autophagic membrane expansion. These data show how ER-phagy receptors trigger the cascade of events leading to ER autophagosome formation.

Keywords:  ER-phagy; ER-phagy receptor; autophagosome biogenesis; autophagy machinery; in vitro reconstitution

DOI:  https://doi.org/10.1073/pnas.2523465123
Adv Clin Chem. 2026 ;pii: S0065-2423(25)00103-9. [Epub ahead of print]130 99-132

Autophagy in lipid metabolism.

Mouliganesh Sekar, Kavitha Thirumurugan.

  Autophagy is a complex and highly regulated cellular process essential for maintaining homeostasis in adipose tissue by modulating adipocyte differentiation, lipogenesis, and lipolysis. Although lipids are primarily known as energy-storage compounds, they also play a role in triglyceride transport, intracellular communication via steroid hormones, organ protection, and thermoregulation. Lipid metabolism relies on the dynamic balance between synthesis, storage and degradation of key lipid classes such as: triglycerides, sterols and phospholipids. Among the pathways controlling lipid metabolism, autophagy plays a critical role by facilitating lipid degradation via enzymatic lipolysis and lipophagy. The latter emerges as a central mechanism in selectively degrading lipid droplets (LD), thus preventing lipid overload and lipotoxicity. Dysregulation of autophagy contributes to the onset and progression of various metabolic disorders, including obesity, non-alcoholic fatty liver disease, and lysosomal storage diseases. This review provides a comprehensive overview of the molecular mechanisms underpinning autophagy, its role in lipid metabolism, and its pathological relevance in lipid-associated disorders, offering insights into potential therapeutic strategies targeting autophagic pathways for restoring lipid balance.

Keywords:  Adipose tissue; Autophagy; Lipid metabolism; Lipids; Lysosomal storage disease; Non-alcoholic fatty liver disease; Obesity

DOI:  https://doi.org/10.1016/bs.acc.2025.10.007
Autophagy. 2026 Feb;22(2): 235-237

Acetyl-CoA as a metabolic switch for selective mitophagy.

Daolin Tang, Rui Kang, Daniel J Klionsky.

  A recent study published in Nature by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.

Keywords:  Acetyl-CoA; KRAS inhibitor; NLRX1; metabolic signaling; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2593032
EMBO Rep. 2026 Jan 20.

Hyperactivation of mTORC1 blocks stem cell fate transitions through TFE3-NuRD association.

Peizhi Li, Shuhui Xu, Xinyu Wu, Yin Gao, Tanveer Ahmed, Yinghua Huang, Dajiang Qin, Baoming Qin, Lulu Wang, Xueting Xu.

  Mechanistic target of rapamycin complex 1 (mTORC1) integrates signals from nutrients, growth factors, and cellular stress to regulate biosynthesis and maintain homeostasis. Dysregulated mTORC1 disrupts stem cell homeostasis and impairs cell fate transitions in vivo and in vitro. Previous studies have shown that mTORC1 hyperactivation promotes nuclear translocation of TFE3, blocking pluripotency exit in both mouse and human naïve embryonic stem cells. Similarly, our earlier work has demonstrated that sustained mTORC1 activation impedes somatic cell reprogramming via the transcriptional coactivator PGC1α. This raises the question of how mTORC1 coordinates gene transcription across distinct transitions in pluripotent cells. Here, we show that TFE3 mediates the transcriptional blockade induced by mTORC1 hyperactivation during reprogramming. Notably, during both pluripotency exit and reprogramming, TFE3 recruits the NuRD corepressor complex to repress genes essential for cell fate transitions. These findings uncover a shared mechanism by which mTORC1 and TFE3 regulate stem cell identity, highlighting the dual regulatory role of TFE3 and its potential implications in development, aging, and tumorigenesis.

Keywords:  NuRD Complex; Pluripotency Exit; Somatic Cell Reprogramming; TFE3; mTORC1

DOI:  https://doi.org/10.1038/s44319-025-00544-z
Brain Nerve. 2026 Jan;78(1): 65-72

[Autophagy and Neurological Diseases].

Takahiro Shimizu, Noboru Mizushima.

Autophagy is an essential degradation mechanism that maintains intracellular homeostasis. In recent years, an increasing number of cases with mutations in autophagy-related genes, such as ATG7, have been reported. These findings highlight the crucial role of autophagy in human neurodevelopment. However, the severity of clinical symptoms does not always correlate with the degree of autophagy impairment observed in patient-derived cells, and phenotypic manifestations can vary widely. These findings indicate that autophagy dysfunction alone does not fully explain disease mechanisms, even in neurological disorders directly associated with mutations in autophagy-related genes. Currently, no established methods exist to quantitatively assess autophagy activity in vivo, making it challenging to determine whether autophagy dysfunction serves as a primary driver of disease pathogenesis in adult-onset neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Although several lines of indirect evidence indicate impaired autophagy in these conditions, it remains uncertain whether such changes are causative or secondary to the disease process. Further research is warranted to elucidate the precise role of autophagy in both developmental and degenerative neurological disorders and to determine whether targeting autophagy holds promise as a therapeutic strategy.

DOI: https://doi.org/10.11477/mf.188160960780010065
iScience. 2026 Jan 16. 29(1): 114533

Regulatory role of mTORC1 signaling in osteoblasts in acute myeloid leukemia progression and steady-state hematopoiesis.

Kazuya Fukasawa, Kazuya Tokumura, Makoto Yoshimoto, Koki Sadamori, Ioanna Mosialou, Yoshiaki Harakawa, Kazuto Isawa, Shohei Tsuji, Haruhiko Inufusa, Atsushi Hirao, Stavroula Kousteni, Eiichi Hinoi.

  Acute myeloid leukemia (AML) is widely recognized for its intrinsic leukemic-cell-driven regulation as well as its extrinsic niche-driven regulation. Despite mounting evidence that bone-forming osteoblasts provide an endosteal niche for AML cells, the precise mechanism remains to be elucidated. The cell-autonomous mammalian target of rapamycin complex 1 (mTORC1) is involved in the onset and progression of AML. Here, we found that mTORC1 signaling was activated in the osteoblasts of an AML murine model and clinical AML specimens. Osteoblast-specific mTORC1 activation in mice promotes AML growth, whereas mTORC1 inactivation suppresses it. Interleukin-6 (IL-6) was identified through screening as a downstream factor in mTORC1-regulated AML progression. Genetic ablation of the IL-6 receptor in AML cells significantly attenuated AML growth in osteoblast-specific mTORC1-activated mice. Collectively, our results suggest that the mTORC1/IL-6 axis in osteoblastic niche non-autonomously contributes to the AML progression, suggesting a viable therapeutic target for AML.

Keywords:  cancer; cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.114533
Genetics. 2026 Jan 19. pii: iyag014. [Epub ahead of print]

Deletion of the Saccharomyces cerevisiae RACK1 homolog, ASC1, enhances autophagy which mitigates TDP-43 toxicity.

Sei-Kyoung Park, Sangeun Park, Susan W Liebman.

  Cytoplasmic aggregation of nuclear proteins such as TDP-43 (TAR DNA-binding protein 43) and FUS (fused in sarcoma) is associated with several neurodegenerative diseases. Studies in higher cells suggest that aggregates of TDP-43 and FUS sequester polysomes by binding RACK1 (receptor for activated C kinase 1), a ribosomal protein, thereby inhibiting global translation and contributing to toxicity. However, RACK1 is also a scaffold protein with a role in many other cellular processes including autophagy. Using yeast, we find that deletion of the RACK1 ortholog, ribosomal protein ASC1, reduces TDP-43 toxicity, but not FUS toxicity. TDP-43 foci remain liquid like in the absence of ASC1 but they become smaller. This is consistent with findings in mammalian cells. However, using double label fluorescent tags and co-immunoprecipitation we establish that ASC1 does not co-localize with TDP-43 foci, challenging the polysome sequestration hypothesis. Instead, ASC1 appears to influence toxicity through regulation of autophagy. We previously showed that TDP-43 expression inhibits autophagy and TOROID (TORC1 Organized in Inhibited Domains) formation and that genetic modifiers that rescue yeast from TDP-43 toxicity reverse these effects. Here we show that FUS does not inhibit autophagy. Deletion of ASC1 enhances a non-canonical form of autophagy that effectively counteracts TDP-43 induced autophagy inhibition despite reduced TOROID formation. Our findings highlight autophagy-not polysome sequestration-as a key mechanism underlying ASC1-mediated modulation of TDP-43 toxicity and suggest autophagy as a promising therapeutic target.

Keywords:  ASC1/RACK1; FUS (fused in sarcoma); TDP-43 (TAR DNA-binding protein 43); TOROID; autophagy

DOI:  https://doi.org/10.1093/genetics/iyag014
Autophagy. 2026 Jan 22.

C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.

Jianshuang Li, Wenjun Wang, Li He, Qinghua Zhou.

  Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in Drosophila and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.

Keywords:  Homeostasis; MISO; SMEM; mitochondrial subdomains; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2621110
Endocr Relat Cancer. 2026 Jan 19. pii: ERC-25-0291. [Epub ahead of print]

Nrf2 shapes response to lysosomal inhibition of radiation-induced senescent thyroid cancer cells.

Beatrice Mazzoleni, Mara Mazzoni, Debora Vergaro, Tiziana Di Marco, Sonia Pagliardini, Angela Greco.

  Therapy-induced senescence (TIS) is a potential outcome of anti-cancer treatments, characterized by a stable cell cycle arrest. However, it is now widely accepted that this process acts as a double-edged sword: in facts, senescent cells are active drivers of cancer relapse, aggressiveness and metastasis, through the release of pro-inflammatory factors and the ability to resume proliferation. Therefore, selectively targeting TIS cells, a strategy named one-two punch approach, is crucial to avoid their harmful effects. This may become particularly important for those aggressive tumors that currently lack effective therapeutic options, such as dedifferentiated thyroid tumors. To this purpose, identifying targetable characteristics of TIS cells is essential for the development of new senotherapeutics. TIS is often associated with variations of the autophagic flux, therefore, we investigated the interplay between autophagy and therapy-induced senescence in thyroid cancer cells, to explore a new potential target for senotherapy. We demonstrate that TIS thyroid cancer cells do not always exhibit a sufficient enlargement of the lysosomal compartment to maintain autophagy function. The deficiency in lysosomal biogenesis is driven by the inability of TFEB, this process' master regulator, to properly enter and remain inside the nucleus. The disruption of the autophagic flux leads to the accumulation of SQSTM1/p62, which in turn activates the Nrf2 pathway. In contrast to cells with functional autophagy, Nrf2-activated cells display a higher tolerance to oxidative stress, making them resistant to the senolytic activity of lysosomal inhibitors.

Keywords:  Nrf2; anaplastic thyroid cancer; lysosomes; therapy-induced senescence

DOI:  https://doi.org/10.1530/ERC-25-0291
Mol Neurobiol. 2026 Jan 20. 63(1): 378

α-Synuclein Deletion Leads to Hyposmia: due to Defective Autophagy Induced by Abnormal PI3K/mTOR Signaling Pathway in Olfactory Bulb.

Yuqing Shi, Huizhi Wang, Jing Chen, Jing Ren, Xiaohong Sun, Mingqin Qu, Tongfei Zhao, Chunlei Han, Junliang Yuan, Fangang Meng, Lingling Lu.

  α-Synuclein has been the center of focus in understanding synucleinopathies such as Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, dementia with Lewy bodies, for decades. Most researches focus on its pathology. However, its physiological function remains elusive, especially in olfactory system, one of the original sites to find α-synuclein accumulation in Parkinson's disease. In the present study, α-synuclein knockout (KO) mice were employed to study its physiological function. KO mice exhibited olfaction impairment with cell apoptosis in olfactory bulb. To identify molecules underlying olfactory dysfunction, we employed proteomics based on isobaric tags for relative and absolute quantification (iTRAQ). 188 differentially expressed proteins were identified between KO mice and its littermate control of wildtype mice. Bioinformatic analysis highlighted Phosphatidyl-inositol-3-kinase (PI3K) pathway. Hence, we examined its activation and found that both PI3K and its downstream, protein kinase B(AKT) is hyperactivated with α-synuclein deficiency. Mammalian target of Rapamycin (mTOR), a switch of autophagy, was activated followed by uncoordinated 51-like kinase 1, the autophagy initiator, inhibition. The specific substrate of autophagy, P62 was accumulated, indicating that autophagy was blocked. This blockade of autophagy led to Caspase 8 mediated apoptosis characterized by an increased ratio of B-cell lymphoma-2 (BCL-2)-associated X protein (BAX) to BCL-2 (BAX/BCL-2), reduced mitochondrial complex I activity, and decreased mitochondrial membrane potential. To summarize, α-synuclein played roles in maintaining the normal structure and function of olfactory system. α-Synuclein deletion induced Caspase 8 mediated apoptosis due to the defective autophagy by PI3K/mTOR hyperactivation.

Keywords:  Apoptosis; Autophagy; Hyposmia; Parkinson’s disease; Synucleinopathy; α-Synuclein

DOI:  https://doi.org/10.1007/s12035-026-05686-2
Neuron. 2026 Jan 19. pii: S0896-6273(25)00886-4. [Epub ahead of print]

CLN3 mediates chloride efflux from lysosomes.

Yayu Wang, Kai Li, Wei Chen, Chao Chen, Adeline J H Yong, Xiaofan Zhang, Marena Tynan-La Fontaine, Yuh Nung Jan, Lily Yeh Jan.

  Neurodegenerative diseases, which pose significant challenges for effective treatment, often involve risk variants of lysosomal gene products that disrupt lysosomal function, leading to the accumulation of indigestible materials and damage to brain cells. The lysosome is a degradative organelle and a signaling hub that senses nutrient availability. How lysosomal dysfunction contributes to neurodegenerative diseases is an important open question. In this study, we identified CLN3 (ceroid lipofuscinosis, neuronal 3), an endolysosomal protein that is linked to Batten disease, as an evolutionarily conserved protein that facilitates lysosomal chloride efflux. Additionally, we report that a natural compound with anti-inflammatory properties-the curcumin analog C1, which is a TFEB (transcription factor EB) activator-could enhance CLN3 activity and improve lysosomal function. These findings provide new insight into the role of CLN3 in lysosomal ion homeostasis and raise the possibility that modulation of the TFEB-CLN3 signaling axis may hold therapeutic potential for lysosomal storage disorders.

Keywords:  Batten disease; CLN3; chloride channel; lysosome; neurodegenerative disease

DOI:  https://doi.org/10.1016/j.neuron.2025.11.013
bioRxiv. 2025 Dec 04. pii: 2025.12.03.689791. [Epub ahead of print]

Rapamycin Differentially Impacts Germline Stem Cell Quiescence Across Diverse Genetic Backgrounds of Drosophila Melanogaster.

Sahiti Peddibhotla, Miriam Gonzaga, Tricia Zhang, Yasha Goel, Jun Sun, Benjamin R Harrison, Daniel E L Promislow, Hannele Ruohola-Baker.

In response to ionizing radiation, stem cells enter a state of temporary quiescence, safeguarding the stem cell pool for tissue regeneration. Quiescence requires the inhibition of mTORC1, a kinase complex that promotes growth and suppresses autophagy, and cell cycle re-entry requires the reactivation of mTORC1. The pharmacological inhibition of mTORC1 in quiescent stem cells by rapamycin prevents cell cycle re-entry and subsequent tissue regeneration. It is well established that pharmacological responses can vary across genetic backgrounds, however, the extent to which genetic variation can impact the quiescence response to rapamycin is unclear. Here, we tested the sensitivity of stem cell quiescence to rapamycin in different genetic backgrounds within the Drosophila Genetic Reference Panel. These analyses revealed substantial variation across different genetic backgrounds, indicating that genetic variation can modulate drug-induced effects on stem cell dynamics. Our analyses suggest that mitophagy, rather than DNA damage response, is associated with the persistence of quiescence and delayed tissue regeneration by rapamycin. This work underscores the critical role of genetic background in determining drug efficacy, highlighting important implications for the therapeutic application of rapamycin.

DOI: https://doi.org/10.64898/2025.12.03.689791
Mol Neurobiol. 2026 Jan 22. 63(1): 388

The mTOR Pathway in Hearing Disorders: Mechanistic Links to Aging, Regeneration, and Neurodegeneration.

Safura Pournajaf, Maryam Moghbel Baerz, Shahrokh Khoshsirat.

  Hearing loss is a prevalent global health problem that most often arises from aging, noise exposure, ototoxic insults, or genetic defects. In addition to its well‑recognized social and economic burden, mounting evidence links hearing loss to neurological disorders such as Alzheimer's disease and dementia, underscoring the urgent need for effective curative strategies. Progress in regenerative therapies has been hindered by the limited capacity of mammalian auditory hair cells to regenerate, making a deep understanding of the underlying molecular pathology essential. The mechanistic target of rapamycin (mTOR), a master regulator of cell growth, metabolism, autophagy, and aging, has recently emerged as a key player in both auditory and neurological disorders. In this review, we summarize the current knowledge on how mTOR signaling shapes auditory cellular physiology, contributes to hearing disorder pathogenesis, and offers novel therapeutic entry points. We further explored the possibility that dysregulated mTOR activity may represent a missing mechanistic link between hearing loss and broader neurological disease processes.

Keywords:  Auditory system; Autophagy; Hair cell regeneration; Hair cells; Hearing loss; MTOR signaling

DOI:  https://doi.org/10.1007/s12035-025-05653-3
Nat Cell Biol. 2026 Jan 21.

DNA nanodevices detect an acidic nanolayer on the lysosomal surface.

Yutong Zhang, Meiqin Hu, Yaping Meng, Xin Wang, Fangqian Huang, Ping Li, Yuting Zhuo, Danzhen Chen, Zhimin Wang, Qiang Zhang, Hui Wu, Yao He, Yulin Du, Haoxing Xu, Liping Qiu, Weihong Tan.

Lysosomes maintain a highly acidic lumen to regulate H+-dependent hydrolase-mediated degradation, but how protons are 'leaked' out to regulate organellar functions through cytosolic effectors remains unknown. Here we developed DNA nanodevices on the cytosolic leaflet of lysosomal membranes to monitor juxta-organellar pH in cells. Unexpectedly, we revealed a radiating acidic layer (up to 21 nm in thickness) on the outer surface of all lysosomes, typically 0.2-0.7 pH units more acidic than the neutral cytosol. This acidic nanolayer is established and maintained primarily by TMEM175, a lysosomal H+ efflux channel associated with Parkinson's disease. Activation of TMEM175 causes opposite pH changes on both sides of lysosomes; however, it is the juxta-lysosomal, not the luminal, acidity that determines lysosome positioning in cells with dynein adaptor RILP acting as a juxta-lysosomal pH sensor. Hence, through inside-out proton conduits, lysosomes create a steady acidic surrounding that acts as a nano-interface for cytosolic machineries to regulate organellar activities.

DOI: https://doi.org/10.1038/s41556-025-01855-y
Autophagy. 2026 Jan 18.

ATG gene duplication in vertebrates: evolutionary divergence and its functional implications.

Sidi Zhang, Ikuko Koyama-Honda, Daiki Hiratsuka, Noboru Mizushima.

  Macroautophagy (hereafter referred to as autophagy) requires the coordinated action of approximately 20 ATG (autophagy related) genes. Duplication of ATG genes has had a major impact on the evolution of the autophagy pathway among major lineages. One duplication hotspot is in vertebrates. However, the exact duplication timing, post-duplication evolutionary divergence patterns, and its relation to functional differences among paralogs have not been investigated in detail. Here, we demonstrate that most ATG genes were likely duplicated by whole-genome duplication events near the root of vertebrates. We compared the sequence and gene expression divergence between paralogs and categorized the evolutionary fates (i.e. how ancestral function is divided between paralogs). Within the paralog pairs that evolved most asymmetrically, namely BECN, WIPI (WIPI1 and WIPI2), and ATG16, one paralog likely retained the ancestral function, allowing the other to evolve under less constraint. While no obvious asymmetry was observed between ATG9A and ATG9B in non-mammalian vertebrates, ATG9B experienced marked sequence divergence and expression level reduction in mammals, suggesting a shift in balance. Expression patterns among the ULK-1 (ULK1 and ULK2), GABARAP (GABARAP and GABARAPL1), and LC3 (LC3A and LC3B) pairs were more consistent with hypofunctionalization/dosage sharing, such that ancestral function depends on both paralogs. We also demonstrate that both ULK1 and ULK2 can support autophagy, whereas only BECN1, but not BECN2, has autophagic function and discuss the relationship between autophagic function and evolutionary divergence. The present detailed analysis of ATG gene duplication in vertebrates provides a critical timeline for interpreting functional differentiation between homologs.

Keywords:  ATG; evolutionary fate; functional difference; gene duplication; ohnolog; vertebrates

DOI:  https://doi.org/10.1080/15548627.2026.2618126
Aging Cell. 2026 Feb;25(2): e70386

Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.

Wagner S Dantas, Elizabeth R M Zunica, Elizabeth C Heintz, Charles L Hoppel, Cristal M Hill, Christopher D Morrison, Christopher L Axelrod, Gangarao Davuluri, John P Kirwan.

  Calorie restriction (CR) is a robust intervention for improving metabolic health and delaying obesity and age-related diseases, yet its translational utility is limited by adherence challenges and diminished effectiveness later in life. Dietary protein restriction (DPR), which reduces dietary protein without decreasing total caloric intake, has emerged as a promising alternative, yet its cardioprotective potential in the context of obesity and aging remains poorly understood. Here, we demonstrate that DPR mitigates obesity-induced cardiac remodeling and inflammaging by activating the AMPK-ULK1 signaling axis and enhancing mitochondrial quality control. In middle-aged male mice with high-fat diet-induced obesity, 4 months of DPR attenuated cardiac hypertrophy and normalized heart failure markers, independently of FGF21 signaling. Transcriptomic and protein analyses revealed that DPR suppressed the activation of the cGAS-STING pathway, reduced mitochondrial DNA release into the cytosol, and blunted expression of pro-inflammatory mediators, including IRF3 and IFN-γ. DPR also restored mitochondrial dynamics, enhanced mitophagy, and maintained ATP content despite reduced respiratory capacity. Mechanistically, DPR increased AMPK-dependent ULK1 phosphorylation while suppressing mTOR signaling, thereby promoting mitochondrial turnover. These effects were confirmed in cardiomyocytes, where AMPK knockdown abrogated ULK1 activation and mitophagy under conditions of low amino acid availability. Together, these findings uncover a novel mechanism by which DPR attenuates cardiac inflammation and supports mitochondrial homeostasis, highlighting its therapeutic potential for enhancing cardiovascular health during obesity-mediated inflammaging.

Keywords:  bioenergetics; fission; fusion; heart; mitochondria; obesity; quality control

DOI:  https://doi.org/10.1111/acel.70386
Mol Biol Cell. 2026 Jan 21. mbcE25060273

The Atg2-Atg18 complex interacts with the Atg1 complex to localize to the pre-autophagosomal structure in Saccharomyces cerevisiae.

Yuri Yasuda, Kanae Hitomi, Nobuo N Noda, Tetsuya Kotani, Hitoshi Nakatogawa.

During autophagy induction in Saccharomyces cerevisiae, over twenty autophagy-related (Atg) proteins localize to the site of autophagosome formation to generate the pre-autophagosomal structure (PAS), where phase-separated condensates of the Atg1 kinase complex serve as a scaffold for recruiting other Atg proteins. The lipid transfer protein Atg2 forms a complex with the phosphatidylinositol 3-phosphate (PI3P)-binding protein Atg18 and mediates lipid influx from the endoplasmic reticulum to the PAS for membrane expansion. In this study, we discover that the Atg2-Atg18 complex interacts with the Atg1 complex. This interaction involves the C-terminal regions of Atg2 and the Atg1 complex subunit Atg29, and is enhanced by Atg1-dependent phosphorylation of Atg29. This interaction, together with Atg18 binding to PI3P, promotes PAS localization of the Atg2-Atg18 complex. These findings provide new insight into PAS organization and highlight the Atg1 complex as a central hub coordinating Atg protein assembly during autophagosome formation.

DOI: https://doi.org/10.1091/mbc.E25-06-0273
Curr Med Chem. 2026 Jan 13.

Geniposide Attenuates Post-Myocardial Infarction Cardiac Remodeling via Parkin-Dependent Suppression of Hyperactivated Mitophagy.

Yang Wei, Qian Zhou, Dan Li, Honghong He, Yao Su, Guanglei Chang, Youqin Jiang.

   BACKGROUND: Cardiac remodeling Post-Myocardial Infarction (MI) drives heart failure. Geniposide (GP), a traditional Chinese medicine-derived compound, exhibits cardioprotective potential, yet its mechanisms remain unclear. This study explored the GP's role in post-MI remodeling via Parkin-dependent mitophagy.
METHODS: Murine MI and cardiomyocyte Chronic Hypoxia (CH) models were established. MI mice received GP; cardiac function, histopathology, apoptosis, fibrosis/autophagy markers, and mitochondrial clearance were assessed. in vitro, Parkin-silenced hypoxic cardiomyocytes were used to evaluate GP's effects on viability, oxidative stress, mitochondrial function, autophagy proteins, and autophagosome formation.
RESULTS: in vivo, GP improved cardiac function, reduced fibrosis/apoptosis, and suppressed fibrosis-related genes (Col1a1, Col3a1, Tgfb1, Mmp9). GP enhanced clearance of damaged mitochondria via autophagy, mitigating oxidative stress. in vitro, GP's protection against hypoxia required Parkin: it preserved mitochondrial homeostasis, inhibited ROS-mediated apoptosis, and reduced autophagosome accumulation. Mechanistically, GP attenuated excessive mitophagy by modulating Parkin, thereby maintaining mitochondrial quality and reducing oxidative injury.
CONCLUSION: GP alleviates post-MI remodeling by suppressing Parkin-dependent hyperactivated mitophagy, reducing cardiomyocyte loss and fibrosis. Parkin is central to GP's therapeutic effects, highlighting its potential as a target for MI-related heart failure. This study elucidates GP's cardioprotective mechanism and proposes Parkin pathway modulation as a novel strategy to counteract pathological cardiac remodeling.

Keywords:  Geniposide; Parkin; cardiac fibrosis.; cardiac remodeling; mitophagy; myocardial infarction

DOI:  https://doi.org/10.2174/0109298673402330251125051751
Front Cell Infect Microbiol. 2025 ;15 1764139

Editorial: The role of autophagy in infectious diseases, volume II.

Hua Niu, Marc Herb, Joaquin Miguel Pellegrini.



Keywords:  autophagic regulation; autophagy; host defense; infectious diseases; pathogens

DOI:  https://doi.org/10.3389/fcimb.2025.1764139
EMBO J. 2026 Jan 22.

The lysosomal LAMTOR-Rag complex functions as a checkpoint for antiviral interferon production.

Zeming Feng, Lulu Wang, Shujun Chen, Sihan Cao, Miao Lei, Xiuzhen Yang, Kaixiong Ma, Shi Yu, Huina Hu, Kaixuan Zheng, Xin Xu, Qi Zheng, Shaobo Wang, Wenxiang Hu, Chun-Yan Lim.

  Lysosomes are emerging as important signaling hubs for antiviral defense, yet how they enable type I interferon (IFN-β) production is unclear. Here, we identify an evolutionarily repurposed lysosomal pathway, centered on the LAMTOR-Rag GTPase complex, that governs IFN-β production through dual transcriptional and post-transcriptional regulation. Genetic ablation of LAMTOR or Rag GTPases in macrophages abolishes IFN-β responses despite intact pattern recognition receptor (PRR) signaling, uncovering a lysosome-specific checkpoint essential for antiviral immunity. Mechanistically, Rag GTPase activity controls IRF expression to prime IFN transcription, while upon PRR stimulation, the tumor suppressor FLCN recruits p38 MAPK to lysosomes, where Rag-dependent p38 phosphorylation stabilizes Ifnb1 mRNA. Nutrient availability dynamically modulates Rag nucleotide states and thereby its activation, linking IFN production to metabolic capacity. Notably, this checkpoint operates independently of mTORC1, illustrating how an ancient nutrient-sensing module has been co-opted for immune regulation. Disruption of the LAMTOR-Rag-FLCN-p38 axis impairs IFN induction in vitro and antiviral responses in vivo, underscoring its physiological significance. Our findings support the role of the lysosome as a central signaling hub integrating metabolic and immune cues, suggesting future directions for potential therapeutic strategies against viral infections.

Keywords:  Innate Immunity; LAMTOR/Ragulator; Lysosomes; Type I Interferon; p38 MAPK

DOI:  https://doi.org/10.1038/s44318-026-00695-2
bioRxiv. 2025 Dec 07. pii: 2025.12.03.692150. [Epub ahead of print]

Neddylation Regulates Mitochondrial Dynamics and Turnover in the Adult Heart.

Jianqiu Zou, Wenjuan Wang, Chen Qu, Lingxian Zhang, Josue Zambrano-Carrasco, Yilang Li, Yi Lu, Hongyi Zhou, Kunzhe Dong, Tohru Fukai, Masuko Ushio-Fukai, Dawn Bowles, Michelle Mendiola Pla, Ryan Gross, Weiqin Chen, Jiliang Zhou, Jie Li, Huabo Su.

BACKGROUND: Disruption of mitochondrial homeostasis drives cardiomyopathy and heart failure, yet upstream regulatory mechanisms remain poorly defined. Neddylation, a reversible post-translational conjugation of the ubiquitin-like protein NEDD8 by E1/E2/E3 enzymes, is essential for cardiac morphogenesis, but its role in the adult heart is unknown.
METHODS: We assessed the relevance of neddylation to human cardiac disease by gene set enrichment analysis of ischemic (ICM) and non-ischemic cardiomyopathy (NICM) datasets and by immunoblotting and qPCR of ventricular tissue from patients with ICM or dilated cardiomyopathy (DCM). In adult mice, we induced cardiomyocyte-restricted deletion of the NEDD8-activating enzyme 1 (NAE1) by tamoxifen injection and monitored cardiac function at baseline and after transverse aortic constriction (TAC). Bulk RNA-seq 4 weeks post-tamoxifen was combined with bioenergetic, biochemical, and ultrastructural analyses. To assess mitochondrial dynamics, we generated NAE1/MFN2 and NAE1/DRP1 double-knockout mice. Cullin activity, mitochondrial ubiquitination, and mitophagy were measured in hearts and cultured cardiomyocytes.
RESULTS: Neddylation pathways were dysregulated in human ICM and NICM datasets and in failing ICM/DCM myocardium. Cardiomyocyte-specific NAE1 deletion caused systolic dysfunction and heart failure by 10 weeks post-tamoxifen, culminating in premature death and exacerbating TAC-induced pressure-overload heart failure. At 4 weeks, NAE1 loss repressed metabolic and mitochondrial bioenergetic programs, reduced ATP production, and impaired respiration. Electron microscopy revealed elongated mitochondria and accumulated mitophagic vesicles, with dysregulation of DRP1, MFN2, PINK1, LC3-II, and p62. DRP1/NAE1 co-deletion accelerated systolic failure relative to either single knockout, whereas MFN2/NAE1 co-deletion did not alter early disease progression, implicating pathogenic mitochondrial hyperfusion. Genetic NAE1 depletion in vivo and pharmacologic NAE1 inhibition in vitro impaired mitophagic vesicle formation and flux, inactivated cullin scaffold proteins, reduced mitochondrial ubiquitination, and blunted mitophagic clearance.
CONCLUSIONS: Cardiac neddylation preserves adult heart function by coordinating mitochondrial fusion-fission dynamics and sustaining cullin-dependent ubiquitination and turnover of damaged mitochondria. These findings identify neddylation as a key regulator of mitochondrial quality control and link its disruption to human cardiomyopathy. Therapeutically, targeting the neddylation-cullin axis may limit mitochondrial dysfunction, enhance mitophagy, and improve energetic reserve in failing hearts, while neddylation signatures in patient myocardium may help guide stratification and precision therapy for cardiomyopathy.
Clinical Perspective: What Is New?: • Demonstrates for the first time that the NEDD8-activating enzyme (NAE1)driven neddylation pathway is indispensable for maintaining mitochondrial quality control in the adult heart.• Links loss of neddylation to mitochondrial hyperfusion, impaired mitophagy, and rapid progression to heart failure.• Reveals that neddylation promotes cullin-RING ligase-mediated ubiquitination of damaged mitochondria, coupling mitochondrial dynamics with turnover.What Are the Clinical Implications?: • Restoring or enhancing cardiac neddylation may represent a novel therapeutic avenue for cardiomyopathies characterized by mitochondrial dysfunction.• Pharmacologic agents that bolster DRP1-dependent fission or activate cullin neddylation could potentially normalize mitochondrial dynamics and improve myocardial energetics.• Conversely, systemic neddylation inhibitors now in oncology trials warrant careful cardiac monitoring, as they may precipitate mitochondrial injury and heart failure.• Circulating or tissue markers of neddylation might help stratify patients at heightened risk for mitochondrial-driven cardiac disease and guide precision therapy.

DOI: https://doi.org/10.64898/2025.12.03.692150
J Neurochem. 2026 Jan;170(1): e70352

Proteomic Landscape of Sweat Glands in Neuronal Intranuclear Inclusion Disease Reveals a Pathogenic Triad of Abnormal Autophagy, Mitochondrial Dysfunction, and a Failed Oxidative Stress Response.

An Wang, Hong-Fei Tai, Kang Zhang, Yi Zhou, Wei Sun, Zheng-Guang Guo, Hai-Dan Sun, Fan Jian, Xin-Gao Wang, Hua Pan, Zai-Qiang Zhang.

  Neuronal Intranuclear Inclusion Disease (NIID), caused by GGC repeat expansions in the NOTCH2NLC gene, has a poorly understood molecular pathogenesis. This study aimed to systematically delineate the molecular pathology of NIID for the first time by employing an unbiased proteomic approach in sweat gland tissue. We isolated sweat gland tissue from 20 NIID patients and 6 healthy controls via Laser Capture Microdissection and performed in-depth proteomic analysis using data-independent acquisition mass spectrometry, followed by functional annotation and mechanistic prediction through bioinformatics analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis. A total of 265 differentially expressed proteins were identified. Functional enrichment analysis revealed a pathological network composed of three core dysfunctions: (1) widespread mitochondrial dysfunction, evidenced by the general downregulation of proteins associated with energy metabolism and mitochondrial structure; (2) multidimensional autophagy failure, characterized by autophagic flux blockage (macroautophagy failure) and the predicted inhibition of Chaperone-Mediated Autophagy; and (3) a paradoxical and ineffective oxidative stress response, demonstrating a functional uncoupling between the upstream NRF2 activation signal and the execution of the downstream antioxidant pathway. The cellular validation confirmed that the pathogenic uN2CpolyG protein causes the downregulation of core hub proteins, substantiating the molecular pathology observed in patient tissue. Furthermore, a signal decoupling state was identified in the pivotal PI3K-Akt survival pathway. This study provides the first systematic proteomic view of NIID pathology in sweat gland tissue, substantiating that its core pathology is a self-reinforcing vicious cycle of mitochondrial dysfunction, abnormal autophagy, and oxidative stress imbalance. These findings offer a robust molecular framework for understanding GGC repeat expansion pathogenesis and illuminate new therapeutic avenues targeting these interconnected pathways.

Keywords:  autophagy; mitochondrial dysfunction; neuronal intranuclear inclusion disease; oxidative stress; proteomics

DOI:  https://doi.org/10.1111/jnc.70352
Redox Biol. 2026 Jan 17. pii: S2213-2317(26)00027-3. [Epub ahead of print]90 104029

Upregulated GBP2 exacerbates Parkinson's disease pathogenesis by impairing NIX-dependent mitophagy.

Wenqi Cui, Tianlu Wang, Juan Feng.

  Parkinson's disease (PD), characterized by dopaminergic neuron loss, still lacks disease-modifying therapies due to incompletely understood mechanisms. Guanylate-binding proteins (GBPs) are well-known immune regulators, but their roles in PD are largely unknown. In this study, we identify GBP2 as a critical driver of PD pathogenesis by impairing mitophagy. We found that GBP2 was significantly upregulated in the substantia nigra of PD patients, and in both MPTP-induced and A53T transgenic mouse models, as well as in MPP+-treated or A53T α-synuclein-overexpressing SH-SY5Y cells. Both in vivo and in vitro, genetic knockdown of GBP2 robustly alleviated the MPTP/MPP+-induced motor deficits, dopaminergic neuron loss, and apoptosis. Mechanistically, PD-related stress promotes GBP2 geranylgeranylation, driving its mitochondrial accumulation. At mitochondria, GBP2 directly binds the mitophagy receptor NIX via its large GTPase domain and targets it for ubiquitin-proteasomal degradation, thereby suppressing NIX-mediated mitophagy. Accordingly, GBP2 knockdown enhanced mitophagy, improved mitochondrial homeostasis, and protected against neuronal apoptosis. The neuroprotective effects of GBP2 knockdown were abolished by either pharmacological inhibition of mitophagy or genetic knockdown of NIX, indicating a linear pathway. Importantly, therapeutically targeting geranylgeranylation with GGTI298 significantly attenuated MPTP-induced neurotoxicity. Our study unveils a novel, druggable axis in PD pathogenesis where GBP2 disrupts mitochondrial quality control. Targeting GBP2 geranylgeranylation with GGTI298 presents a promising therapeutic strategy.

Keywords:  GBP2; Geranylgeranylation; Mitochondrial dysfunction; Mitophagy; NIX; Parkinson's disease

DOI:  https://doi.org/10.1016/j.redox.2026.104029
Autophagy. 2026 Jan 20.

The PI4K2A-OSBPL6/ORP6-PS axis mediates lysosomal membrane repair to restore neuronal lipid homeostasis and promote neuronal survival after spinal cord injury.

Haojie Zhang, Yu Kang, Tianlun Zhao, Daoqiang Huang, Xuantao Hu, Jiawei Di, Yilong Zhang, Yubao Lu, Mudan Huang, Hong Li, Senyu Yao, Bin Liu, Limin Rong.

  Dysfunction of the neuronal macroautophagy/autophagy-lysosome system is a critical contributor to neuronal death following spinal cord injury (SCI), but the underlying mechanisms remain elusive. Our study demonstrated that SCI induced impaired autophagic flux and lysosomal membrane permeabilization (LMP) in neurons. By combining in vivo bulk RNA sequencing with validation experiments, we observed the transient upregulation of the membrane repair factor PI4K2A, which was specifically enriched in lysosomes, after SCI. Crucially, ER-MS and IP-MS analyses revealed an interaction between PI4K2A and the endoplasmic reticulum lipid transfer protein OSBPL6/ORP6. This interaction led to the transport of phosphatidylserine (PS) to damaged lysosomal membranes, promoting LMP repair and subsequently reducing lipid droplet accumulation, which suppressed neuronal death. Furthermore, overexpression of neuronal PI4K2A in vivo, through an OSBPL6- and PS-dependent mechanism, reduced LMP-mediated lipid droplet accumulation and increased neuronal survival, thereby improving functional recovery after SCI. Collectively, our findings establish the PI4K2A-OSBPL6/ORP6-PS axis as a novel and essential mechanism for lysosomal membrane repair in neurons. This pathway is crucial for maintaining neuronal lipid homeostasis and represents a promising therapeutic target for reducing neuronal loss and improving functional recovery after central nervous system trauma.

Keywords:  Lipid homeostasis; lipophagy; lysosomal membrane repair; neuronal apoptosis; phosphatidylinositol 4-kinase type 2 alpha; spinal cord injury

DOI:  https://doi.org/10.1080/15548627.2026.2619576
Neurobiol Dis. 2026 Jan 20. pii: S0969-9961(26)00027-6. [Epub ahead of print] 107283

New perspective on neurodegenerative diseases: Focusing on the interaction between autophagy and oxidative stress and targeted strategies.

Jiaqin Jin, Qiuyu Cen, Huage Wang, Yin Xin, Jing Feng, Yanru Cui, JiaYu Li, Zilong You, Fangyuan Jing, Yang Yu, Yingbo Qiu, Rizhao Pang, Junyu Wang, Anren Zhang.

  Autophagy is a highly conserved lysosome-dependent degradation process that plays a crucial role in maintaining neuronal homeostasis and adaptation during stress by eliminating misfolded proteins, damaged organelles, and pathogens. Oxidative stress, triggered by an imbalance between reactive oxygen speciesreactive oxygen species:ROS (ROS) production and antioxidant defenses, contributes to disease pathogenesis through mechanisms such as lipid peroxidation, protein carbonylation, and mitochondrial DNA damage. Recent studies reveal that autophagy and oxidative stress interact via a dynamic bidirectional regulatory network to modulate neurodegenerative pathology: ROS activate autophagy by regulating signaling pathways and modifying autophagy-associated proteins, while moderate autophagic activity selectively clears ROS-generating components and activates antioxidant pathways. Dysregulation of autophagy or excessive ROS accumulation can disrupt this equilibrium, leading to cell death and disorders such as neurodegenerative diseases, cancer, and aging-related pathologies. They reciprocally serve as "pressure signals" and "clearance targets", synergistically maintaining cellular homeostasis. This review synthesizes insights from current studies to systematically analyze the complex cross-talk between autophagy and oxidative stress in neurodegeneration and evaluates emerging therapeutic strategies targeting this interplay, including autophagy modulators, antioxidants, phytochemicals, and nanomaterials. These advancements offer novel perspectives for developing neuroprotective therapies through therapeutic modulation of the autophagy-oxidative stress axis. Finally, we summarize key challenges in the field and propose potential directions for future research.

Keywords:  Autophagy; Neurodegenerative diseases; Oxidative stress; Targeting strategies

DOI:  https://doi.org/10.1016/j.nbd.2026.107283
Nature. 2026 Jan 21.

Ageing promotes microglial accumulation of slow-degrading synaptic proteins.

Ian H Guldner, Viktoria P Wagner, Patricia Moran-Losada, Sophia M Shi, Sophia W Golub, Johannes F Hevler, Kelly Chen, Barbara T Meese, Ali Ghoochani, Ernst Pulido, Hamilton Se-Hwee Oh, Yann Le Guen, Nannan Lu, Pui Shuen Wong, Ning-Sum To, Dylan Garceau, Zimin Guo, Jian Luo, Carolyn R Bertozzi, Emma Lundberg, Monther Abu-Remaileh, Michael Sasner, Andreas Keller, Andrew C Yang, Tom H Cheung, Tony Wyss-Coray.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing1,2. Here we engineered bioorthogonal tools3 that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age. The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

DOI: https://doi.org/10.1038/s41586-025-09987-9
Autophagy. 2026 Jan 21.

Molecular engineering of lysosome-based degraders unveils a rapidly expanding therapeutic strategy.

Adele Rivault, Jade Dussart-Gautheret, Rachid Benhida, Anthony R Martin, Patrick Auberger, Arnaud Jacquel, Guillaume Robert.

  The targeted degradation of oncogenic or misfolded proteins has emerged as a promising therapeutic strategy. While proteolysistargeting chimeras (PROTACs) and related technologies have successfully hijacked the ubiquitin-proteasome system to eliminate disease-driving proteins, recent advances highlight the lysosome as a powerful alternative degradation route. Lysosome-based degradation strategies offer broader substrate scope, subcellular targeting flexibility, and the ability to degrade proteins beyond the reach of the proteasome. In this review, we provide a comprehensive overview of synthetic molecules and engineered systems designed to traffic target proteins to the lysosome. These include lysosome targeting chimeras (LYTACs), autophagytargeting chimeras (AUTACs), autophagytethering compounds (ATTECs), and other modalities that exploit endogenous trafficking pathways for selective protein clearance. By mapping the current landscape of lysosome-targeting degraders, this article underscores the therapeutic potential of lysosomal proteolysis and outlines future directions for molecular engineering in this rapidly evolving field.

Keywords:  Biodegraders; chimera compounds; drug design; lysosome; targeted degradation

DOI:  https://doi.org/10.1080/15548627.2026.2618626