bims-auttor 2026-09-06 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–09–06
27 papers selected by
Viktor Korolchuk, Newcastle University

RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.
Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
Reconstitution of multistep recruitment of ULK1 to membranes in autophagy.
Chaperone-assisted selective autophagy (CASA) in polyglutamine-related diseases: From mechanisms to therapeutic perspectives.
Mitochondrial Microautophagy: An Emerging Pathway in Maintaining Mitochondrial Homeostasis.
Phase Separation, Material State, and Condensate Fate in Mammalian Autophagy.
A GABARAP-PtdIns3K-C1 positive feedback loop at the heart of the phagophore nucleation.
AKAP11 links autophagy to cognitive impairment in psychiatric diseases.
Autophagic degradation of RAB8A promotes ferroptosis through dysregulation of TFRC-mediated iron uptake.
Aβ-induced CaMKII hyperactivation is associated with impaired lysosomal maturation and mitophagy.
Myofibrillar myopathy-associated KY protein promotes muscle fibre size rescue independent of its predicted catalytic triad.
Jer1-Ga2-LpR1 axis mediates upstream input of alpha-mannosidosis.
Restoring lysosomal proteostasis reverses steatohepatitis and fibrosis in experimental MASH.
Autophagy Deficits in Lower Motor Neuron and Striated Muscle Diseases: From Genetics to Therapeutic Advances.
Clinical and biochemical footprints of inherited disorders of autophagy.
MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
A novel dual-pathway AhR mechanism underpins cardiac senescence induced by 6PPDQ.
UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis.
"Trojan" Methionine Probe Reveals PKM2 as a Methionine-Sensing Protein in the mTORC1 Pathway.
A Hox-dependent anchoring mechanism mediates transcriptional repression of autophagy-related genes at the nuclear periphery.
DNA nanodevice-mediated perinuclear accumulation of lysosomes for functional regulation.
Rebalancing α-Synuclein Clearance: Novel Therapeutic Frontiers in Parkinson's Disease.
Spatial autophagy failure as a pharmacodynamic endpoint for autophagy-targeted dermatological interventions.
Glycoprotein-induced phase separation drives unconventional secretion of galectin-3.
APOE4 astrocytes call the shots on neuronal α-synuclein pathology.
TLDc proteins: Stress-responsive nexus regulators of redox signaling, V-ATPase dynamics, and organellar crosstalk in neurodegeneration.
Age-related disruptions in ubiquitination and mitochondrial proteostasis are associated with neuronal compartment-specific mitochondrial changes.

Autophagy. 2026 Sep 01.

RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.

Waka Kojima, Ryu Endo, Kei Okatsu, Hiroki Kinefuchi, Tomoko Tokita, Reika Kikuchi, Noriyuki Matsuda, Shuya Fukai, Koji Yamano.

  Damaged mitochondria are selectively eliminated through mitophagy, a critical quality control process. A kinase PINK1 and an E3 ubiquitin ligase PRKN/Parkin, both of which are mutated in familial Parkinson disease, amplify ubiquitin signals on the damaged mitochondria. The autophagy receptor OPTN plays a pivotal role in mitophagy by bridging ubiquitinated mitochondria with autophagy components. Although OPTN is known to recruit ATG9A-positive vesicles to facilitate mitophagy progression, the precise molecular mechanisms governing this recruitment remain poorly understood. In this study, we identify the small RAB GTPases RAB1A and RAB1B as direct binding partners of the OPTN leucine zipper (LZ) domain. We demonstrate that RAB1A/1B is required for the recruitment of ATG9A vesicles to mitochondria during the initial stages of mitophagy. Knockdown of RAB1A and RAB1B significantly impaired the assembly of OPTN at phagophore formation sites, leading to a profound inhibition of mitophagy progression. Mechanistically, we found that RAB1A/1B associate with ATG9A-positive vesicles via their C-terminal prenylation, thereby tethering these vesicles to the OPTN-bound mitochondria. Our findings establish a novel OPTN-RAB1-ATG9A axis that drives the de novo synthesis of phagophore membranes in close proximity to damaged mitochondria. This work clarifies how selective autophagy receptors spatially coordinate membrane trafficking to ensure the efficient clearance of dysfunctional organelles.

Keywords:  Autophagy; Optineurin; PINK1; Parkin; RAB GTPase; mitochondria; ubiquitin

DOI:  https://doi.org/10.1080/15548627.2026.2728346
J Clin Invest. 2026 Sep 01. pii: e199847. [Epub ahead of print]136(17):

Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.

Bishal Basak, Julia F Riley, Neha M Nataraj, Erika Lf Holzbaur.

Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson's disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin-dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin-dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.

DOI: https://doi.org/10.1172/JCI199847
Sci Adv. 2026 Sep 04. 12(36): eaeg3201

Reconstitution of multistep recruitment of ULK1 to membranes in autophagy.

Yongjia Duan, Ye Lu, Sanjoy Paul, Johannes Betz, Léa P Wilhelm, Annan S I Cook, Xuefeng Ren, Elias Adriaenssens, Sascha Martens, Ian G Ganley, Gerhard Hummer, James H Hurley.

The human Unc51-like kinase 1 (ULK1) autophagy-initiating complex consists of ULK1, FIP200, and the Hop/Rev7/Mad2 (HORMA) domain heterodimer ATG13:ATG101. Phosphatidylinositol 3-phosphate (PI3P) is essential to recruit ULK1 complex (ULK1C) to membranes for ULK1, but ULK1C subunits do not contain PI3P-binding domains. Here, we show that the ATG13:ATG101 dimer forms a complex with the PI3P-binding protein WD40 interacting with phosphoinositide protein 3 (WIPI3), as well as WIPI2. Bound to WIPI2 and WIPI3, ATG13:ATG101 inserts its Trp-Phe (WF) finger into the membrane. Molecular dynamics simulations show that WIPIs and the WF finger cooperatively stabilize the complex on membranes. Biochemical reconstitution and cell-based assays show that WIPI3:ATG13 engagement promotes ATG16L1 phosphorylation, autophagy, and mitophagy. A kinase domain (KD)-proximal Pro-Val-Pro (PVP) motif in the ULK1 intrinsically disordered region docks onto the ATG13:ATG101 HORMA dimer brings the ULK1 KD close to the membrane. The PVP motif is essential for in vitro ULK1 phosphorylation of ATG16L1 and important for autophagy and mitophagy. These data establish a stepwise pathway for recruitment of the ULK1 KD to the vicinity of the membrane surface.

DOI: https://doi.org/10.1126/sciadv.aeg3201
J Huntingtons Dis. 2026 Sep 03. 18796397261478173

Chaperone-assisted selective autophagy (CASA) in polyglutamine-related diseases: From mechanisms to therapeutic perspectives.

Barbara Tedesco, Marta Chierichetti, Riccardo Cristofani, Angelo Poletti.

  Chaperone-assisted selective autophagy (CASA) is a crucial process aimed at maintaining proteostasis in several neurodegenerative diseases associated with protein misfolding, including polyglutamine (polyQ) diseases. Autophagy is a critical lysosome-mediated degradation pathway, particularly essential in neurons, which are highly susceptible to proteotoxic stress due to their post-mitotic nature. Selective autophagy pathways, including CASA, ensure the targeted removal of misfolded proteins and damaged organelles, thereby preserving cellular homeostasis. CASA is based on the intersection of chaperones and autophagy, where HSPB8 and BAG3 interact with HSPA and STUB1 forming a complex that identifies, ubiquitinates, and directs aberrant proteins toward autophagosomes for subsequent lysosomal degradation. In polyQ diseases, such as spinal and bul muscular atrophy (SBMA) and Huntington's disease (HD), mutant proteins accumulate, overwhelming the protein quality control systems. The CASA components are upregulated as a compensatory response, promoting toxic aggregates clearance and cellular damage mitigation. However, chronic proteotoxic stress and progressive impairment of autophagic and lysosomal pathways eventually limit CASA efficiency, contributing to disease progression. The review highlights how CASA exerts its protective activities in polyQ diseases and reports therapeutic strategies aimed at enhancing CASA activity, including pharmacological inducers and combinatorial approaches targeting autophagy and the ubiquitin-proteasome system. Overall, CASA emerges as a crucial adaptive mechanism and a promising therapeutic target in polyQ-related neurodegeneration.

Keywords:  CAG repeat expansions; Huntington disease; chaperone-assisted selective autophagy; polyglutamine diseases; protein misfolding; spinal and bul muscular atrophy

DOI:  https://doi.org/10.1177/18796397261478173
Antioxid Redox Signal. 2026 Sep 02. 15230864261481794

Mitochondrial Microautophagy: An Emerging Pathway in Maintaining Mitochondrial Homeostasis.

Huijia Zhang, Ying Chen, Junjie Jiang, Yarong Ding, Si Hu, Zhongzhi Zhou, Li Chen.

  Background:Mitochondrial quality control has traditionally been attributed to mitophagy. However, emerging evidence indicates that mitochondrial microautophagy represents a distinct quality control pathway. This pathway enables selective removal of damaged mitochondrial subdomains while preserving overall organelle integrity. Therefore, mitochondrial microautophagy can be viewed as a redox-adaptive, sub-organelle quality control system that responds to localized mitochondrial stress.Scope of Review: In this review, we integrate recent mechanistic, imaging, and molecular studies to establish an updated framework of mitochondrial microautophagy. We describe this process as a sequential pathway involving damage sensing, mitochondria-lysosome contact formation, lysosomal membrane remodeling, selective degradation, and metabolic recycling. Localized reactive oxygen species (ROS) serve as important signals during this process. ROS define specific damage microdomains and facilitate selective mitochondrial component recognition. Subsequent cargo delivery and degradation are regulated by multiple molecular modules. These modules include the ubiquitin-autophagy-related protein 8 system, vacuolar-type H+-ATPase-dependent membrane remodeling, Ras-related in brain-endosomal sorting complexes required for transport signaling, the spermatogenesis-associated 18/mitochondria-eating protein pathway, and the mechanistic target of rapamycin complex 1-transcription factor EB and nuclear factor erythroid 2-related factor 2 stress-response networks.Outstanding Questions: Despite substantial progress, several fundamental questions remain unresolved. The mechanisms underlying cargo recognition require further clarification. The existence of specific redox-sensitive receptors remains to be determined. In addition, future technological advances will provide deeper insights into this pathway.Conclusions: Understanding mitochondrial microautophagy may reveal new therapeutic opportunities for mitochondrial dysfunction-associated disorders, including neurodegeneration, ischemic injury, metabolic disorders, and aging. Antioxid. Redox Signal. 00, 000-000.

Keywords:  ESCRT complex; Rab GTPase; SPATA18/Mieap; TFEB; V-ATPase; autophagy; lysosomal membrane remodeling; mitochondrial microautophagy; mitochondrial quality control

DOI:  https://doi.org/10.1177/15230864261481794
Adv Sci (Weinh). 2026 Sep 01. e77360

Phase Separation, Material State, and Condensate Fate in Mammalian Autophagy.

Yuanqiang Lin, Mingran Dai, Enyong Dai, Rui Kang, Daniel J Klionsky, Daolin Tang, Yu Sun, Ningning Lv, Junnan Jiang.

  Biomolecular phase separation has emerged as a key organizing principle in macroautophagy (hereafter autophagy). In mammalian cells, phase-separated condensates not only serve as substrates for selective degradation, but also act as dynamic platforms for cargo recognition, signaling integration, and autophagosome assembly. The material state of these condensates is an important determinant of autophagic fate. Condensates exist along a continuum ranging from liquid-like droplets to gel-like and solid assemblies, and their progressive maturation can alter accessibility to autophagic machinery. Scaffold proteins and selective autophagy receptors further organize these assemblies into degradation-competent mesoscale reaction fields that couple cargo recognition with phagophore formation. Dysregulation of this phase separation-autophagy axis is increasingly implicated in neurodegeneration, cancer, aging, and stress-associated degenerative disease. Here, we propose a multiscale framework in which molecular accessibility, mesoscale organization, and condensate state transitions collectively shape autophagic outcome, providing a conceptual basis for predictive models and therapeutic strategies aimed at restoring condensate degradability.

Keywords:  autophagy; condensate; disease; phase separation; receptor

DOI:  https://doi.org/10.1002/advs.77360
Nat Commun. 2026 Jul 30. pii: 9473. [Epub ahead of print]17(1):

A GABARAP-PtdIns3K-C1 positive feedback loop at the heart of the phagophore nucleation.

Antoine N Dessus, Yohei Ohashi, Maxime Bourguet, Tomos E Morgan, Anastasia Nunez, Maria Manifava, Nicholas T Ktistakis, Roger L Williams.

In mammalian cells, autophagosomes can reach diameters of over 1000 nm within 30 min after triggering starvation, but how such substantial amounts of membranes can be synthesized remains elusive. The phagophore initiation needs the lipid kinase PIK3C3-Complex 1 (PtdIns3K-C1), which produces phosphatidylinositol-3-phosphate (PtdIns3P). PtdIns3P recruits WIPI2 that facilitates lipidation of mammalian ATG8 (mATG8) family proteins on phagophores. Here we show that recombinant membrane-coupled GABARAP binds to and potently activates PtdIns3K-C1. By a combination of cryo-electron microscopy, structural mass spectrometry, activity assays and mutagenesis, we show that GABARAP activates PtdIns3K-C1 through two binding sites. We propose that once GABARAP is indirectly recruited by PtdIns3P generated by basal activity of PtdIns3K-C1, a positive feedback loop is formed where PtdIns3K-C1 interacts with GABARAP and becomes activated to produce more PtdIns3P, thereby further stimulating GABARAP lipidation. This mechanism would be central for autophagosome biogenesis, where enlarged membranes need to be rapidly synthesized.

DOI: https://doi.org/10.1038/s41467-026-76135-w
Autophagy. 2026 Sep 01. 1-3

AKAP11 links autophagy to cognitive impairment in psychiatric diseases.

Yuxuan Kan, Zhenyu Yue, Min Li, Zhiqiang Deng.

  Schizophrenia (SCZ) and bipolar disorder (BD) share genetic risk factors and cognitive impairments, yet the underlying mechanisms remain incompletely understood. Loss-of-function variants in AKAP11 (A-kinase anchoring protein 11) have recently emerged as major risk factors for both disorders. Our recent study demonstrates that AKAP11 deficiency in the mouse hippocampus causes cognitive deficits and synaptic dysfunction, accompanied by autophagy dysregulation. Mechanistically, AKAP11 interacts with PPP3CB (protein phosphatase 3 catalytic subunit beta) to promote TFEB (transcription factor EB) dephosphorylation and nuclear translocation, thereby sustaining autophagy-lysosomal gene expression. AKAP11 knockout cells display impaired autophagy initiation, reduced lysosomal activity, and compromised autophagic flux. Therapeutically, pharmacological activation of TFEB rescues cognitive deficits in Akap11-deficient mice. These findings position AKAP11 as a critical regulator of TFEB-mediated autophagy and suggest that enhancing autophagy-lysosomal function may represent a therapeutic strategy for SCZ and BD.

Keywords:  AKAP11; TFEB; autophagy; cognition; psychiatric diseases

DOI:  https://doi.org/10.1080/15548627.2026.2709295
Autophagy. 2026 Aug 30.

Autophagic degradation of RAB8A promotes ferroptosis through dysregulation of TFRC-mediated iron uptake.

Jingbo Li, Qile Zhou, Jiao Liu, Xin Chen, Chunhua Yu, Rui Kang, Daolin Tang.

  Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation; however, how selective autophagy regulates ferroptotic sensitivity remains incompletely understood. Here, we identify RAB8A as a selective autophagic substrate and negative regulator of ferroptosis. Quantitative proteomic analyses reveal that ferroptotic stress induces ATG5- and ATG7-dependent degradation of RAB8A. Mechanistically, ferroptotic stimuli induce RNF126-dependent polyubiquitination of RAB8A and subsequent SQSTM1-mediated autophagic degradation. Functionally, loss of RAB8A sensitizes cancer cells to ferroptosis, whereas expression of the degradation-resistant active mutant RAB8AQ67L suppresses ferroptotic cell death. RAB8A interacts with TFRC and facilitates stress-induced redistribution of TFRC from the plasma membrane toward endolysosomal compartments. RAB8A deficiency impairs TFRC clearance, enhances transferrin-dependent iron uptake, and increases intracellular Fe2+ accumulation and lipid peroxidation. In fibrosarcoma and pancreatic cancer xenograft models, RAB8A depletion enhances the antitumor efficacy of ferroptosis-inducing therapy. Clinically, RAB8A is upregulated and associated with poor prognosis and ferroptosis resistance in pancreatic cancer. Collectively, these findings establish an autophagy-RAB8A-TFRC axis that regulates ferroptotic sensitivity.

Keywords:  Iron metabolism; SQSTM1; lysosomal degradation; membrane trafficking; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2026.2726089
Neurochem Int. 2026 Sep 01. pii: S0197-0186(26)00143-9. [Epub ahead of print]200 106252

Aβ-induced CaMKII hyperactivation is associated with impaired lysosomal maturation and mitophagy.

Eun Cheng Suh, Yul A Kim, Kyung Eun Lee, Eun-Mi Park.

  Alzheimer's disease (AD) is characterized by amyloid-β (Aβ)-associated synaptic failure, intracellular Ca2+ dysregulation, and progressive impairment of lysosome-dependent clearance pathways. Aβ induces sustained Ca2+ overload, resulting in pathological hyperactivation of CaMKII, which normally participates in the regulation of autophagy. However, whether CaMKII hyperactivation contributes to Aβ-induced late-stage autophagy-lysosomal dysfunction and mitophagy failure remains unclear. This study aimed to examine the effects of the CaMKII inhibitor KN93 in Aβ25-35-exposed rat organotypic hippocampal slice cultures (OHSCs, ex vivo model) and the mouse brain in vivo. The results showed that Aβ25-35 induced intracellular Ca2+ elevation, CaMKII hyperactivation, and marked accumulation of LC3-II and p62. Ultrastructural and biochemical analyses revealed impaired lysosomal maturation, defective autophagosome-lysosome coupling, and accumulation of autophagic vacuoles, consistent with a blockade of late-stage autophagic flux. Increased levels of immature cathepsin D and reduced colocalization of LC3 with lysosomal markers further supported compromised lysosomal competence. Damaged mitochondria were recruited to lysosomal compartments but failed to undergo effective degradation, indicating abortive mitophagy under Aβ25-35 exposure. KN93 attenuated Aβ25-35-induced defects in lysosomal protease maturation, autophagosome-lysosome fusion, and mitochondrial clearance in both the ex vivo OHSCs model and the in vivo mouse brain. KN93 also ameliorated cognitive impairment in Aβ25-35-exposed mice. Taken together, these findings indicate that CaMKII hyperactivation contributes to Aβ25-35-induced autophagy-lysosomal dysfunction and neuronal damage, and that pharmacological inhibition of CaMKII with KN93 restores intracellular degradative capacity and ameliorates cognitive impairment under Aβ stress.

Keywords:  Amyloid beta; Autophagic flux; CaMKII; Calcium dysregulation; Lysosomal dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.neuint.2026.106252
Hum Mol Genet. 2026 Aug 25. pii: ddag086. [Epub ahead of print]35(18):

Myofibrillar myopathy-associated KY protein promotes muscle fibre size rescue independent of its predicted catalytic triad.

Ahmed Nouh, Oscar Harrad, Andrzej M Brzozowski, William Grey, Gonzalo Blanco.

  Mutations in the Ky gene are the underlying cause of Myofibrillar Myopathy-7 (MFM-7), a rare progressive muscle weakness disease of childhood onset. A defining characteristic of the KY protein is the presence of a conserved transglutaminase-like domain, but unequivocal evidence of its enzymatic function remains to be established. To investigate the functional relevance of the predicted KY catalytic triad we use here in vitro enzymatic assays, structural modeling and in vivo rescue experiments in ky/ky mice. While structural modelling shows a striking conservation of the catalytic pocket architecture, our results show that recombinant KY proteins showed no detectable enzymatic activity under the assay conditions used. Moreover, while deletion of transglutaminase-like domain prevents phenotype rescue, replacements of the predicted catalytic residues do not impair the protein's ability to rescue fibre size in ky/ky muscle, indicating that the predicted catalytic residues are dispensable for fibre size rescue in these assays. Proteomic analyses identified KY-associated protein complexes involved in protein quality control, including core components of the Chaperone-Assisted Selective Autophagy machinery. In agreement, basal autophagic flux is significantly reduced in both KY-deficient C2C12 cells and ky/ky muscle fibres. Collectively, our data suggests that the TGN/PROT domain facilitates critical molecular associations at the sarcomeric Z-disc through a mechanism independent of catalysis and that impaired autophagic flux may contribute to the muscle phenotype.

Keywords:  Mendelian disorder; autophagy; monogenic disorders; muscular dystrophy; pproteostasis; rare disease

DOI:  https://doi.org/10.1093/hmg/ddag086
J Mol Cell Biol. 2026 Aug 29. pii: mjag035. [Epub ahead of print]

Jer1-Ga2-LpR1 axis mediates upstream input of alpha-mannosidosis.

Wenting Li, Shengnan Li, Qi Wang, Xiuxiu Ti, Zhaoliang Shan, Yuxue Gao, Qing Zhang.

  Alpha-mannosidosis (AMD) is a well-known lysosomal storage disorder caused by the loss of α-mannosidase activity due to the mutation of the MAN2B1 gene. Defective α-mannosidase cannot completely degrade the sugar chains of upstream input glycoproteins, leading to the accumulation of oligosaccharides with α-mannosidic linkages in lysosomes, finally causing AMD. However, till now, the upstream input mediating AMD remains elusive, which hinders the development of alternative therapeutic treatments. To address this question, we establish the first Drosophila model of AMD and, through genetic screen, identify three novel upstream factors named Jer1, Ga2, and LpR1. We demonstrate that knocking down either of them can rescue the lethal phenotype of AMD flies and they mediate upstream input of AMD through a Jer1-Ga2-LpR1 axis. Mechanistically, Jer1 recruits the E3 ligase Ga2, which mediates the ubiquitination of the glycoprotein LpR1 for subsequent lysosomal degradation. Therefore, knockdown of Jer1 or Ga2 downregulates LpR1 ubiquitination and prevents it from degradation in lysosomes, reducing the burden on lysosomes and alleviating the symptoms of AMD. Importantly, our study further demonstrates that IPP, UBE3C, and VLDLR, the mammalian counterparts of Jer1, Ga2, and LpR1, respectively, are functionally conserved during evolution, suggesting that they can be used as potential therapeutic targets for the treatment of AMD.

Keywords:  Ga2; Jer1; LpR1; MAN2B1; alpha-mannosidosis (AMD); lysosome; ubiquitination

DOI:  https://doi.org/10.1093/jmcb/mjag035
Pharmacol Res. 2026 Sep 01. pii: S1043-6618(26)00342-7. [Epub ahead of print]232 108427

Restoring lysosomal proteostasis reverses steatohepatitis and fibrosis in experimental MASH.

Dylan Mastrippolito, Lauriane Gur, Malia Lasalo, Lara El Kaakour, Cindy Verdot, Franck Coste, Sébastien Blaise, Sylviane Muller.

  Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by progressive inflammation and fibrosis. Left untreated, MASH can progress to cirrhosis, hepatocellular carcinoma, and liver failure. MASH has become the leading indication for liver transplantation worldwide. While global prevalence is increasing, effective and mechanism-oriented therapies remain limited. Based on earlier independent studies showing that lysosomes are impaired and autophagy is dysregulated in MASH, our aim was to finely map autophagy dysfunction in an experimental mouse model of MASH and explore the capacity of a modulator of chaperone-mediated autophagy to mitigate the course of the disease. We effectively identified a number of markers whose expression was pathologically increased or decreased in various autophagy pathways. In vivo, pharmacological modulation with the phosphopeptide P140 -currently evaluated in phase III-clinical trials for lupus- corrected the expression of some of these markers and restored lysosomal and mitochondrial autophagy programs. It reduced steatohepatitis and fibrosis, and improved systemic inflammatory features without, however, broadly correcting metabolic parameters. Mechanistically, consistent with its established HSPA8 interaction, P140 restored lysosomal/autophagy markers, supporting modulation of this proteostasis network. Our data indicate that this pharmacological restoration of lysosomal proteostasis engages key transcriptional regulators (Mediator complex), leading to the selective remodeling of pro-fibrotic and inflammatory pathways. Collectively, we identified a coordinated disruption of lysosomal quality control networks across multiple autophagy pathways in a validated mouse model of advanced MASH. We established lysosomal autophagy as a druggable vulnerability in MASH and support therapeutic repositioning of P140 as a safe strategy to counter progressive liver diseases.

Keywords:  Autophagy; Lysosomes; MASLD; Protein homeostasis; Therapeutic peptide

DOI:  https://doi.org/10.1016/j.phrs.2026.108427
Annu Rev Pathol. 2026 Sep 03.

Autophagy Deficits in Lower Motor Neuron and Striated Muscle Diseases: From Genetics to Therapeutic Advances.

Angela Sisto, Freke Mertens, Mélissa Lallier, Rani Robeyns, Alexander L N van Nuijs, Pieter Van der Veken, Wim Martinet, Vincent Timmerman.

The degradation and recycling of damaged proteins and organelles through autophagy is a vital process to maintain terminally differentiated cells under energy-demanding physiological conditions and mechanical stress. Clinical and molecular studies of numerous congenital disorders of striated muscle and inherited neuropathies have reported severe autophagy defects as an underlying pathological mechanism. In this review, we investigate the genetic mutations underlying lower motor neuron diseases, skeletal muscle dystrophies, and (cardio)myopathies and how these mutations disrupt autophagy pathways. Through an in-depth analysis of the defective step of the autophagy pathway, we propose pharmacological targets that are able to correct the autophagy defects, thereby improving disease pathology. Finally, we discuss the current limitations in the development of autophagy-modulating drugs and propose novel technologies to support this growing field. By outlining key mechanisms and targets, this review supports the development of more effective autophagy modulators for rare diseases.

DOI: https://doi.org/10.1146/annurev-pathmechdis-032125-020448
Mol Genet Metab. 2026 Aug 26. pii: S1096-7192(26)00531-7. [Epub ahead of print]149(1-2): 110248

Clinical and biochemical footprints of inherited disorders of autophagy.

Heinz Jungbluth, Hormos S Dafsari, Carlos R Ferreira, Nenad Blau.

  Autophagy is an evolutionarily conserved lysosomal recycling system that integrates nutrient sensing, organelle quality control, proteostasis, cellular stress responses and metabolic adaptation. Autophagy is particularly relevant for post-mitotic tissue such as neurons, skin, and immune cells. Monogenic disorders disrupting autophagy or closely coupled endolysosomal trafficking pathways have recently emerged as a recognizable group of inherited metabolic diseases. These conditions are individually rare inborn errors of metabolism and collectively important because they bridge neurodevelopmental, neuromuscular and neurodegenerative disorders, including hereditary forms of Parkinson's disease, spastic paraplegias and neurodegeneration with brain iron accumulation. Multisystem involvement is common but variable. The prototypic disorder is EPG5-related Vici syndrome, in which defective autophagosome-lysosome fusion causes severe neurodevelopmental and multisystem disease. Other disorders may affect any step of the pathway, from phosphatidylinositol 3-phosphate effector biology and ATG conjugation/lipidation to autophagosome maturation, ATG9 trafficking, HOPS/CORVET-related vesicle trafficking (including VPS16 and VPS33A), autophagosome-lysosome fusion, autolysosome reformation and lysosome-mTOR signaling. Clinically, affected individuals commonly present with global developmental delay and/or intellectual disability, epilepsy, movement disorders including dystonia, parkinsonism, ataxia and spasticity, and both neuropathic and myopathic neuromuscular manifestations. A biphasic course with progressive neurodegeneration and variable multisystem (including ocular, cardiac, immunological, cutaneous and growth) involvement are important clinical clues. Diagnosis relies on careful phenotyping, brain MRI, targeted metabolic exclusion of mimics, genomic sequencing and functional assays in patient-derived cells as required. Supportive multidisciplinary management is essential. No disease-modifying therapy is currently established in humans, but pathway-based cellular assays, model systems and small-molecule or gene-replacement strategies are creating a rational therapeutic pipeline. Importantly, IEMbase dyadic nomenclature with system-level clinical annotations provides a standardized framework for quantifying shared phenotypic signatures across these ultra-rare conditions. This review summarizes pathobiochemistry, genetics, clinical presentation, diagnosis and treatment prospects for inherited disorders of autophagy.

Keywords:  Autophagosome; Autophagy; Genomics; Inherited metabolism; Lysosome; Neurodegeneration; Neurodevelopment

DOI:  https://doi.org/10.1016/j.ymgme.2026.110248
Cell Rep. 2026 Sep 01. pii: S2211-1247(26)01008-9. [Epub ahead of print]45(9): 117930

MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.

Nuo Chen, Zhirong Li, Xiyuan Wang, Hong Xu, Wei Wang, Weina Shang, Liquan Wang, Chao Tong.

  Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.

Keywords:  CP: cell biology; CP: metabolism; antioxidant defenses; mitochondrial integrated stress response; mitochondrial repair; mitophagy; transient mitochondrial damage

DOI:  https://doi.org/10.1016/j.celrep.2026.117930
Environ Int. 2026 Aug 26. pii: S0160-4120(26)00441-1. [Epub ahead of print]215 110483

A novel dual-pathway AhR mechanism underpins cardiac senescence induced by 6PPDQ.

Baoqiang Fu, Jinhao Li, Mingxuan Zhang, Changyi Shang, Yaru Wu, Qian Zhang, Xiaoyu Wu, Bin Jiang, Tao Chen, Yan Jiang.

  N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPDQ), an emerging tire-wear-derived environmental pollutant, has been associated with cardiac senescence, though its pathogenic mechanism remains unclear. Using in vitro (differentiated H9c2 cardiomyocytes, mechanistically optimized dose, 500 μg/L) and in vivo (zebrafish, environmentally relevant concentrations, 2 μg/L) models, we demonstrate that 6PPDQ induces cardiac senescence through indoleamine 2,3-dioxygenase 1 (IDO1)/kynurenine-mediated activation of the aryl hydrocarbon receptor (AhR). This process engages two parallel and functionally independent AhR signaling branches. In the canonical genomic pathway, AhR transcriptionally upregulates Cyp1a1, leading to reactive oxygen species overproduction, DNA damage, and ultimately cellular senescence evidenced by an increased proportion of SA-β-galactosidase positive cells, elevated p21 and p16 expression, compromised Lamin B1 integrity, and diminished cardiac function. Concurrently, non-genomic AhR pathway is initiated via Src kinase, which propagates signals through PI3K/AKT. This signaling cascade functionally correlates with transcription factor EB (TFEB) cytoplasmic retention, impairing its nuclear translocation and the subsequent transcription of key autophagy-lysosomal genes such as Lamp1 and Lamp2. Consequently, 6PPDQ disrupts lysosomal biogenesis and autophagic flux, marked by lysosomal depletion, p62 accumulation and defective autophagosome clearance, thereby accelerating cardiac senescence. Importantly, pharmacological inhibition of AhR attenuates DNA damages, facilitates TFEB nuclear translocation, recovers the autophagic flux, thereby mitigating the senescent phenotype induced by 6PPDQ. Reciprocal cross-pathway inhibition further confirmed that these branches do not functionally interact. Collectively, our findings delineate a kynurenine-driven, dual-pathway mechanism: genomic (Cyp1a1/ROS/DNA damage) and non-genomic (autophagy-lysosomal disruption) AhR signaling underlying 6PPDQ induced cardiac aging. These results establish AhR as pivotal node in pollutant related cardiovascular aging, offering novel mechanistic insights and potential therapeutic targets.

Keywords:  6PPDQ; AhR; Autophagy; Cardiac senescence; DNA damage

DOI:  https://doi.org/10.1016/j.envint.2026.110483
Nat Metab. 2026 Sep 04.

UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis.

Feng Wang, Jin Lee, Jeong-Su Park, Meizhou Huang, Hwan Ma, Guoyan Sui, Zixiong Zhou, Michitaka Matsuda, So Yeon Kim, Takashi Tsuchiya, Xuefeng Wu, Haram Lee, Soohwan Oh, Hanseul Park, Key-Hwan Lim, Chun-Woong Park, Sang-Bae Han, Jin Tae Hong, Michael Karin, Yoon Seok Roh, Ekihiro Seki.

K63-linked ubiquitination (K63) is closely associated with the interaction, intracellular trafficking or activity of tagged proteins. However, its role during metabolic dysfunction-associated steatohepatitis (MASH) is largely unknown. Here we show that UBE2N, a ubiquitin-conjugating enzyme that specializes in creating K63, is downregulated by THAP11 in human and mouse hepatocytes with MASH. While hepatocyte-specific Ube2n deficiency exacerbates western diet-induced MASH and fibrosis via PANoptosis and impaired mitophagy, its overexpression reverses these pathological phenotypes and restores hepatic homeostasis. Mechanistically, UBE2N increases PARKIN-mediated K63-p62 at lysine 420, promoting K63-p62 translocation into damaged mitochondria for mitophagic clearance. Ube2n deficiency, conversely, induces cytoplasmic p62 accumulation and NRF2 hyperactivation, driving PANoptosis. Additional Sqstm1 deletion mitigates Ube2n deletion-induced pathologies, highlighting the importance of p62 accumulation for MASH progression. Thus, our results demonstrate that hepatocyte UBE2N is essential for regulation of metabolic stress-mediated mitophagy and PANoptosis, and that p62 is a proof-of-concept target for treating MASH and fibrosis.

DOI: https://doi.org/10.1038/s42255-026-01590-0
J Am Chem Soc. 2026 08 26. 148(33): 35538-35550

"Trojan" Methionine Probe Reveals PKM2 as a Methionine-Sensing Protein in the mTORC1 Pathway.

Zixin Sang, Yiqiang Zheng, Xia Wang, Cang Wu, Jiaqi Zhao, Jun Joelle Wang, Senfang Sui, Jie Wang.

Methionine (Met) plays a pivotal role in numerous cellular functions. Methionine restriction has been demonstrated to provide metabolic benefits in aging, obesity, diabetes and as an adjunct to cancer therapy. However, the methionine-sensing proteins and how cells directly sense the methionine level have remained elusive. In this study, we developed a photoaffinity analogue of methionine to capture proteins that specifically recognize and sense methionine in living cells. Using chemoproteomic profiling and biochemical validation, we found that PKM2 is a specific methionine sensor that transduces methionine availability signals through the interaction with the GATOR2 complex, which, in turn, modulates the downstream response of the mTORC1 pathway through a novel methionine-recognition pocket on PKM2. As our findings indicate that the sensing of methionine by PKM2 is independent of its enzymatic activity, we envision that disrupting the binding of methionine to PKM2 or stabilizing the PKM2-GATOR2 interaction would create a methionine pseudostarvation state in living cells, which holds promise as a novel therapeutic avenue that could emulate the physiological benefits of a methionine-restricted diet and circumvent the drawbacks of dietary methionine restriction.

DOI: https://doi.org/10.1021/jacs.6c06772
Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2616645123

A Hox-dependent anchoring mechanism mediates transcriptional repression of autophagy-related genes at the nuclear periphery.

Solène Vanderperre, Leiore Ajuria, Marilyne Duffraisse, Tristan Da Silva, Samantha Vonau, Jacques Brocard, Christelle Forcet, Samir Merabet.

  The spatial organization of the genome within the nucleus is critical for gene regulation, yet the mechanisms by which transcription factors (TFs) orchestrate this process remain poorly understood. Here, we demonstrate that the Drosophila Hox protein Ultrabithorax (Ubx) represses autophagy-related (atg) genes by tethering their loci to the nuclear periphery. This repressive activity relies on the interaction with the nuclear lamina component Lamin-C (LamC). Furthermore, we identify that DNA-binding of Ubx is determinant for both the physical interaction with nucleoplasmic LamC and the repression of atg genes in vivo. Together, our findings reveal a mechanism whereby a Hox TF functions as a spatial anchor, positioning target genes within a LamC-rich nuclear compartment to ensure efficient transcriptional repression.

Keywords:  Drosophila; Lamin-C; Ultrabithorax; autophagy; fat body

DOI:  https://doi.org/10.1073/pnas.2616645123
Talanta. 2026 Aug 27. pii: S0039-9140(26)01178-1. [Epub ahead of print]312(Pt B): 130522

DNA nanodevice-mediated perinuclear accumulation of lysosomes for functional regulation.

Weihong Yang, Zhaoyang Wang, Xiangli Li, Dunji Shu, Yao He, Xinran Lian, Shuxin Sun, Xiaowei Feng, Xiaoyan Wu, Cheng Cui, Zhimin Wang, Hui Wu, Liping Qiu, Weihong Tan.

  The cellular positioning of lysosomes, especially their perinuclear accumulation, plays an essential role in regulating many biological processes. In this work, we developed a non-genetic approach to drive lysosomes to the perinuclear region by displaying a nucleus-targeting DNA nanodevice on their outer surface. Our experimental results demonstrated that this nanodevice efficiently anchored onto the outer leaflet of lysosomal membrane, and then effectively promoted perinuclear clustering of lysosomes. Further analysis revealed that this repositioning significantly enhanced autophagic flux and altered the expression of autophagy-associated genes. Our study provides a versatile platform for elucidating the functional consequences of lysosomal positioning and its regulatory mechanisms in cellular physiology.

Keywords:  Autophagy; DNA nanodevice; Lysosomal distribution; Lysosome; Perinuclear accumulation

DOI:  https://doi.org/10.1016/j.talanta.2026.130522
Neuromolecular Med. 2026 Aug 31. pii: 51. [Epub ahead of print]28(1):

Rebalancing α-Synuclein Clearance: Novel Therapeutic Frontiers in Parkinson's Disease.

Maryam Jabeen, Huma Hameed, Syed Muhammad Ahmad, Tehreem Mushtaq, Mahtab Ahmad Khan, Anam Hameed.

  Parkinson's disease (PD), the second most common neurodegenerative condition, develops because of abnormal protein misfolding and aggregation of α-synuclein with its subsequent intercellular spread. Such pathological changes lead to disruption of neuronal homeostasis and contribute to neuronal degeneration. During normal conditions, α-synuclein clearance is controlled by different types of lysosomal degradation, namely, macro autophagy, chaperone-mediated autophagy (CMA), micro autophagy, and the ubiquitin-proteasome system. Malfunction of these systems results in increased α-synuclein secretion due to exosome-dependent, direct, and damage-induced mechanisms, which, in turn, promotes enhanced intercellular propagation, inflammation, mitochondrial dysfunction, blood-brain barrier leakage, and neuronal cell death. Although several approaches targeting α-synuclein clearance have shown biological activity in preclinical or early clinical studies, consistent disease-modifying efficacy has not yet been established, owing to challenges including target specificity, blood brain barrier penetration, biological heterogeneity, and the limited sensitivity of clinical endpoints. Recent research indicates that successful treatment is more related to restoring the balance of these two processes than to manipulating one of them.In this review, it is proposed that a systems-level approach can be taken where PD is understood as a disease characterized by the imbalance in proteostasis. Potential treatment modalities include small molecules targeting lysosome function (ambroxol, rapamycin, TFEB activators), CMA enhancers, gene therapy, and antibodies against extracellular α-synuclein. Furthermore, new modalities like molecular glue degraders, allostery-based stabilization of α-synuclein tetramers, engineered decoy particles, and bispecific antibodies represent some other possible routes towards multimodal disease modification.

Keywords:  Autophagy; Extracellular Propagation; Lysosomal Dysfunction; Nanoparticles; Parkinson’s Disease; α-Synuclein

DOI:  https://doi.org/10.1007/s12017-026-08948-3
Pharmacol Res. 2026 Sep 01. pii: S1043-6618(26)00337-3. [Epub ahead of print]232 108422

Spatial autophagy failure as a pharmacodynamic endpoint for autophagy-targeted dermatological interventions.

Chang Hyung Lee, Ki Won Lee.

  Autophagy-modulating dermatological interventions include topical, intralesional and systemic therapies, defined bioactive molecules and nutraceutical candidates. Their effects are commonly evaluated using tissue-averaged LC3-II, p62/SQSTM1 and canonical pathway markers. Although these measures support assessment of autophagy pathway engagement, they may miss spatially restricted pharmacodynamic non-response and cannot determine whether persistent local dysfunction reflects inadequate exposure or biology-limited non-response. Here we propose spatial autophagy failure (SAF) as a spatial pharmacodynamic endpoint for autophagy-targeted dermatological interventions. SAF denotes contiguous skin domains showing evidence of impaired autophagic processing and lysosomal dysfunction relative to adjacent tissue. We use photoaged skin and melanophagy as the principal test case. In this setting, persistent hyperpigmented hotspots may partly reflect localized defects in melanosome clearance alongside altered melanogenesis and melanosome transfer. Chronic wounds and pathological scars provide additional dermatological settings in which spatially heterogeneous autophagic capacity may influence treatment response. SAF assessment integrates local drug exposure, local target or pathway engagement, autophagy-lysosome readouts and phenotype maps, distinguishing exposure-limited from biology-limited non-response. Treatment effects can be quantified using total SAF burden, largest-zone size (expressed as area in two-dimensional sections or volume in three-dimensional models), zone contiguity and distance to the nearest phenotype-associated region. These SAF-zone metrics may inform lead selection, formulation and route optimization, dose and schedule selection and pharmacodynamic monitoring. Together, these measurements reframe the central questions: Does an intervention merely shift autophagy markers on average? More importantly, does adequate local exposure produce local target or pathway engagement, restore autophagic processing and improve the corresponding local phenotype?

Keywords:  Autophagy; Dermatological pharmacology; Lysosomal dysfunction; Melanophagy; Pharmacodynamics; Spatial drug exposure

DOI:  https://doi.org/10.1016/j.phrs.2026.108422
Nat Commun. 2026 Aug 06. pii: 9484. [Epub ahead of print]17(1):

Glycoprotein-induced phase separation drives unconventional secretion of galectin-3.

Zihan Zhao, Zhen He, Hongming Gu, Andong Zhou, Yibing Wang, Zhaoyi Liang, Jie Geng, Xuejiao Xu, Menghui Wang, Chunyao Li, Yuying Fan, Hairong Cheng, Lin Sun, Kevin H Mayo, Avraham Raz, Guihua Tai, Yifa Zhou.

The mechanism of unconventional protein secretion remains an unresolved issue. Here, we describe an unconventional protein secretion pathway for galectin-3 that is mediated by phase separation and condensation. Using four lysosomal damage models, we observed a rapid, pronounced release of galectin-3 in large, non-exosomal particles. This secretion is driven by glycoprotein-induced galectin-3 phase separation and is independent of pyroptosis and secretory autophagy. During phase separation, the S-face of galectin-3 carbohydrate recognition domain binds glycoproteins that triggers galectin-3 N-terminal tail release and condensation. These condensates then recruit ALG-2 via the exposed N-terminal tail. ALG-2 directs the condensates to the endoplasmic reticulum-late endosome interface. After translocation into late endosomes, galectin-3 condensates are secreted into the extracellular milieu by SNARE-dependent vesicular transport. This mechanism of exporting phase-separated protein condensates may serve as a clean-up response to membrane damage.

DOI: https://doi.org/10.1038/s41467-026-76321-w
Cell Stem Cell. 2026 Sep 03. pii: S1934-5909(26)00308-5. [Epub ahead of print]33(9): 1417-1419

APOE4 astrocytes call the shots on neuronal α-synuclein pathology.

Nicole R West, Julia Tcw.

In this issue of Cell Stem Cell, Mesentier-Louro et al. use a multi-cellular integrated brain (miBrain) system to uncover mechanisms underlying the accumulation of neuronal α-synuclein (α-Syn) inclusions in APOE4 carriers.1 Their results suggest that APOE4 increases cholesterol levels and impairs lysosomal function in astrocytes, which release pathogenic α-Syn.

DOI: https://doi.org/10.1016/j.stem.2026.08.007
Redox Biol. 2026 Sep 01. pii: S2213-2317(26)00377-0. [Epub ahead of print]97 104378

TLDc proteins: Stress-responsive nexus regulators of redox signaling, V-ATPase dynamics, and organellar crosstalk in neurodegeneration.

Mohammad Sajid Ghufran, Priyanka Soni, Bobby Thomas.

  Many age-related neurodegenerative disorders are marked by progressive defects in cellular energy metabolism and protein homeostasis that converge on mitochondrial and lysosomal dysfunction. TLDc domain-containing proteins, such as OXR1, NCOA7, and related family members, have emerged as crucial modulators of organellar physiology and cellular stress responses. Growing evidence indicates that TLDc proteins physically interact with vacuolar ATPases (V-ATPases) to modulate their assembly and catalytic activity, linking TLDc function directly to the maintenance of lysosomal and Golgi lumen pH. This organellar pH homeostasis, in turn, is fundamental to intracellular iron handling and metabolic regulation, processes essential for mitochondrial bioenergetics, lysosomal functions, and cellular viability. Lysosomes maintain an acidic lumen via V-ATPase proton pumping, counterbalanced by specific ion channels, including TMEM175. This acidic environment is required for ferric iron reduction and subsequent release into the cytosol; when acidification fails, cells develop cytosolic iron deficiency, mitochondrial defects, pseudohypoxia via HIF-1α activation, and inflammation. Conversely, iron flux from lysosomes to mitochondria depends on acidic conditions and direct organelle contact, as exemplified by BDH2-driven siderophore transport, a V-ATPase-dependent but not TLDc-regulated process, which supports mitochondrial bioenergetics and sustains lysosomal acidity. Iron and pH dysregulation synergize to drive ferroptosis, lipid peroxidation, and neurotoxicity. Emerging studies link lysosomal deacidification and iron dyshomeostasis to the pathogenesis of major neurodegenerative diseases. These mechanisms collectively shape neuronal resilience, survival, and aging trajectories. This review integrates recent insights into how TLDc proteins coordinate organellar pH regulation and iron homeostasis and discusses how disruption of these interconnected pathways contributes to age-related neurodegeneration.

Keywords:  Lysosomal dysfunction; NCOA7; OXR1; Oxidative stress; TBC1D24; TLDc

DOI:  https://doi.org/10.1016/j.redox.2026.104378
Exp Gerontol. 2026 Sep 02. pii: S0531-5565(26)00282-2. [Epub ahead of print]224 113303

Age-related disruptions in ubiquitination and mitochondrial proteostasis are associated with neuronal compartment-specific mitochondrial changes.

Margaret-Jade Searles, Debanjali Dasgupta, Trace A Christensen, Gary C Sieck, Matthew J Fogarty.

  Declining aerodigestive neuromotor function is a major aspect of human aging, with impaired airway defense and swallow manoeuvres implicated in pneumonia and dysphagia. Hypoglossal motor neurons (MNs) innervate tongue muscles, essential for these behaviours. Their degeneration contributes to age-related aerodigestive dysfunctions. In neurodegenerative diseases, the ubiquitin-proteasome system (UPS) is altered, disturbing mitochondrial proteostasis. We have previously shown reduced mitochondrial abundance, dysfunction and mitochondrial fragmentation in aging hypoglossal MN somas and dendrites. However, the relationship between the UPS (pUBS65 and ubiquitinated proteins), mitochondrial fragmentation (pDRP1S616) and fusion promoting proteins (MFN2) in MN aging is unexplored. In other neurons, aging changes mitochondria within axons in an opposite way to somas and dendrites. We used Western blotting to show impairment in mitophagy-related pUBS65, increased fragmentation-promoting pDRP1S616 and unchanged MFN2. Serial Block-Face Scanning Electron Microscopy showed increased mitochondrial volume density and larger, more simplistic mitochondria in old, myelinated hypoglossal axons, while somas and dendrites showed reduced mitochondrial volume density and increased fragmentation. Our results suggest that a more nuanced compartment-specific evaluation of mitochondrial structure and function is required to fully elucidate the pathophysiology underlying age-related neuromotor dysfunction.

Keywords:  Aging; Axon; Brainstem; Dendrite; Hypoglossal; Mitochondria; Motor neuron; Proteostasis

DOI:  https://doi.org/10.1016/j.exger.2026.113303