bims-auttor 2026-07-05 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–07–05
38 papers selected by
Viktor Korolchuk, Newcastle University

Disentangling the response to lysosomal damage.
BNIP3/NIX-dependent mitophagy: molecular mechanisms and physiological roles.
Mechanistic studies of autophagic cargo recruitment and membrane shaping through in vitro reconstitution.
Beyond autophagic flux: selective autophagy adaptors and cargo prioritization in cardiac disease.
Two parallel neuronal circuits involving electrical synapse and DAF-7/TGF-β signaling regulate muscle autophagy in C. elegans.
A human lysosomal storage disorder toolkit for decoding proteome landscapes in cortical-like and dopaminergic-like induced neurons.
Translation control of autophagy genes modulates cellular response to hydroxyurea-induced genotoxic stress.
RAPSN/rapsyn aggregation-induced HSPA/HSP70-BAG3 aggrephagy maintains CHRN integrity in myasthenia gravis.
AARS2-mediated lactylation of ULK1 promotes autophagy-dependent progression of clear cell renal cell carcinoma.
COPII meets autophagy at the ER membrane.
Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.
Autophagic therapeutic targeting for Doxorubicin-induced cardiomyopathy.
The SQSTM1 L341V Variant Associated With Sporadic ALS Promotes the Accumulation of Enlarged Ubiquitin-Positive SQSTM1 Bodies.
Receptor-cargo coupling during ER-autophagy depends on coat proteins and ER membrane properties.
Mitophagy interacts with mitochondrial dynamics and biogenesis, acting as a double-edged sword in digestive cancer.
Mechanisms Associated with PINK1 Variants in Parkinson's Disease.
A PARK9 iPSC-Derived Dopaminergic Neuron Model Enables Drug Screening Targeting Autophagy-Lysosome Pathway Dysfunction in Parkinson's Disease.
Biomolecular condensates for proteostasis and potential therapeutic applications.
A genome-wide screen identifies that PLCG2 restrains lysosomal GCase activity.
Protein arginine methyltransferases coordinate mitochondrial stress adaptation and neuromuscular function.
Dysregulation of the TFEB-ATP6V0C axis in microglia exacerbates α-synuclein pathology through impaired lysosomal acidification in Parkinson's disease.
ENPP1-dependent USP2 ubiquitination governs SQSTM1-mediated autophagy-dependent ferroptosis in trophoblast cells and exacerbates placental dysfunction in gestational diabetes mellitus.
Krüppel-like Factor 2 (KLF2) Regulates Autophagy, Mitophagy, Mitochondrial Health, and Function During Foam Cell Formation.
Lipid droplets promote aberrant liquid-liquid phase separation of alpha-synuclein impairing energy homeostasis.
Exercise and dietary interventions in the regulation of hepatic mitophagy and liver recovery (Review).
The dual role of mTOR in multiple sclerosis pathophysiology: a systematic review.
VPS13C/PARK23 initiates lipid transfer and membrane remodeling for efficient lysosomal repair.
Mitochondrial quality control in human ageing and longevity.
Tegument protein UL16 of herpes simplex virus 1 suppresses the innate immune response by downregulating MAVS abundance via mitophagy.
Advancing the monitoring of organelle contact sites in vitro and in vivo.
Rapamycin and nicotinamide treatment attenuates senescence-associated features in mesenchymal stromal cells isolated from elderly donors by modulating autophagy.
Silibinin promotes hepatocyte proliferation through PINK1/Parkin-mediated mitophagy to alleviate acetaminophen-induced liver injury.
De novo VPS16 missense variant causes infantile-onset dystonia with defective autophagic flux.
GDAP1 orchestrates redox signaling at membrane contact sites to preserve axonal integrity in Charcot-Marie-Tooth disease.
Scaling of Neuronal Growth and Excitability Through Separable mTORC1 and mTORC2 Pathways.
GBA mutation exacerbates α-synuclein pathology with involvement of ROS and p38 MAPK signaling in Parkinson's disease.
Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses during inflammation.
TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.

J Cell Sci. 2026 Jul 01. pii: jcs264806. [Epub ahead of print]139(13):

Disentangling the response to lysosomal damage.

Hemmo Meyer, Akiko Kuma, Shuhei Nakamura.

  The limiting membrane of lysosomes is prone to damage that can have deleterious consequences for cellular homeostasis. Cells respond to this damage with an array of molecular countermeasures, ranging from membrane repair mechanisms to elimination of terminally damaged lysosomes by selective macroautophagy. The various elements of this response therefore need to be carefully assessed in the context of the specific pathological or experimental conditions being studied. Emerging evidence has revealed further complexity within the lysosomal damage response, such as processes that contribute to initial membrane resealing as well as lysosome regeneration required to restore the lysosomal system. These mechanisms involve unusual ubiquitylation, non-canonical ATG8 lipidation, or modifications that govern lysosome tubulation or microlysophagy pathways. Therefore, caution is advised when using previously established lysosome damage reporters that might confound interpretation of the underlying events and outcomes. This Opinion article seeks to shed light on the emerging regulatory mechanisms of lysosomal regeneration and evaluate the appropriateness of various reporters and assays for studying the lysosomal damage response.

Keywords:  ATG8; ESCRT; Lysosomes; Membrane permeabilization; Microautophagy; Ubiquitin

DOI:  https://doi.org/10.1242/jcs.264806
J Biochem. 2026 Jun 30. pii: mvag048. [Epub ahead of print]

BNIP3/NIX-dependent mitophagy: molecular mechanisms and physiological roles.

Tamara Ginevskaia, Takayuki Mito, Keiichi Inoue, Tomotake Kanki.

Mitochondria are essential for cellular metabolism and homeostasis, and their quality and quantity must therefore be tightly controlled. Mitophagy, a selective form of autophagy targeting mitochondria, contributes to this control by eliminating damaged or superfluous mitochondria. Among the known mitophagy pathways, BNIP3/NIX-dependent mitophagy has emerged as a key mechanism, particularly under hypoxic and metabolic stress. Recent studies have provided important insights into how BNIP3 and NIX are transcriptionally induced, post-translationally regulated, and functionally coupled to the core autophagy machinery. These studies have also clarified their roles in isolation membrane tethering, membrane elongation, and mitophagosome formation. Beyond its molecular basis, accumulating evidence indicates that BNIP3/NIX-dependent mitophagy contributes to mitochondrial homeostasis, redox balance, and cellular stress adaptation. This review summarizes recent progress in understanding the molecular mechanisms and physiological significance of BNIP3/NIX-dependent mitophagy.

DOI: https://doi.org/10.1093/jb/mvag048
Autophagy. 2026 Jun 30.

Mechanistic studies of autophagic cargo recruitment and membrane shaping through in vitro reconstitution.

Wenxin Zhang, Thomas Litschel, Anne Schreiber, Rocco D'Antuono, Sharon A Tooze.

  Macroautophagy/autophagy, a conserved intracellular catabolic pathway, removes deleterious cytosolic material to maintain homeostasis and survival. Upon autophagy induction, a unique double-membraned structure, the phagophore, forms and engulfs cytosolic material, the cargo, as it closes to become an autophagosome. Mammalian Atg8-family proteins (ATG8s) are ubiquitin-like proteins which are essential for engulfment of the cargo and membrane closure. ATG8s are recruited to the phagophore by ATG12-ATG5-ATG16L1, an E3-like ligase which is recruited by PtdIns3P-binding WIPI proteins. Covalent lipidation of the ATG8s to phosphatidylethanolamine by the E3 ligase occurs specifically on the phagophore membrane allowing recruitment of cytosolic cargo and cargo receptors, such as SQSTM1/p62. While ATG8-cargo receptor interactions are well established, how the ATG8s bind cargo and cargo receptors on the inner membrane of the phagophore has not been studied. To recapitulate these events, we use giant unilamellar vesicles (GUVs) and encapsulate protein machinery and cargo, generating a membrane platform to which ATG8 proteins can be recruited. Inside the GUVs we reconstituted WIPI2B-directed and cargo-directed ATG8 lipidation revealing distinct roles of WIPI2B and SQSTM1 in initiating ATG8 conjugation. We show that SQSTM1 and SQSTM1 droplets are recruited to the GUV inner membrane through interaction with membrane bound ATG8s. Through the development of a bead-based membrane deformation assay, we show redistribution and local enrichment of membrane-bound ATG8s occurs upon binding to SQSTM1 droplets. Our work demonstrates fundamental molecular mechanisms into phagophore-ATG8-cargo interactions providing novel model systems to investigate ATG8-cargo interactions on the inner phagophore membrane.Abbreviations:ATG: autophagy related; cDICE: continuous droplet interface crossing encapsulation; DOPE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; GABARAP: GABA type A receptor-associated protein; GUV: giant unilamellar vesicle; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LIR: LC3-interacting region; LUV: large unilamellar vesicle; NBD: 7-nitrobenz-2-oxa-1,3-diazol-4-yl; PE: phosphatidylethanolamine; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; PolyUb: K63-linked polyubiquitin; POPC: 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine; POPE: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine; Rh-PE: 18:1 Liss Rhod PE; SQSTM1/p62: sequestosome 1; WIPI2B: WD repeat domain, phosphoinositide interacting 2B.

Keywords:  ATG8 lipidation; giant unilamellar vesicles; in vitro reconstitution; liquid-liquid phase separation; membrane expansion

DOI:  https://doi.org/10.1080/15548627.2026.2697432
Cardiol Plus. 2026 Apr-Jun;11(2):11(2): 134-150

Beyond autophagic flux: selective autophagy adaptors and cargo prioritization in cardiac disease.

Jenaro A Espitia-Corredor, Francisco Olivares-Silva, Constanza Alanis-Cubillos, Yingfeng Deng, Zhao V Wang.

  Cardiovascular disease is the leading cause of death worldwide. Disrupted protein homeostasis contributes significantly to cardiomyocyte dysfunction and loss. While autophagy is recognized as a critical cardioprotective mechanism, most therapeutic strategies have targeted overall autophagic flux, assuming that increasing degradative capacity is inherently beneficial. This approach overlooks a fundamental question: when multiple substrates compete for limited autophagic capacity, what determines which cargo is prioritized? This review focuses on the selective autophagy adaptors (sequestosome 1 [p62/SQSTM1], neighbor of BRCA1 gene 1 [NBR1], Tax1-binding protein 1 [TAX1BP1], optineurin [OPTN], nuclear dot protein 52 kDa [NDP52], and Fab1, YOTB, Vac1, EEA1 domain, and coiled-coil domain containing 1 [FYCO1]) as the molecular machinery governing cargo selectivity. We synthesize evidence demonstrating that adult cardiomyocytes face a unique "triage problem": as post-mitotic cells with a massive proteome and high metabolic demands, they must continuously prioritize which damaged mitochondria, protein aggregates, or sarcomeric components to eliminate. We integrate findings from cardiac studies with mechanistic insights from other cell types to map adaptor function in the heart. We propose that targeting selective autophagy adaptors may offer therapeutic precision beyond global flux modulation, directing autophagic machinery toward the cargo most relevant to individual pathological contexts. Currently, FYCO1 overexpression remains the only adaptor-level intervention validated to rescue cardiac function in vivo, highlighting both proof-of-concept and substantial opportunity for further investigation. Understanding not just how much the heart degrades, but also what it chooses to degrade may open new avenues for treating heart failure and cardiomyopathies.

Keywords:  Autophagy; Cardiovascular disease; Cargo selection; Proteostasis

DOI:  https://doi.org/10.1097/CP9.0000000000000161
Dev Cell. 2026 Jun 29. pii: S1534-5807(26)00218-2. [Epub ahead of print]

Two parallel neuronal circuits involving electrical synapse and DAF-7/TGF-β signaling regulate muscle autophagy in C. elegans.

Hui Zheng, Hongyu Zhao, Hong Zhang.

  The systemic coordination of autophagy during development remains poorly understood. Here, we identify two parallel neuronal circuits that regulate the autophagy-lysosome pathway in the body wall muscle of C. elegans. One circuit, utilizing UNC-7/UNC-9 electrical synapses between AVA interneurons and A-type motor neurons (A-MNs), promotes autophagy by inhibiting neuropeptide release from A-MNs. The other employs the TGF-β-like molecule DAF-7, secreted from ASI sensory neurons, which activates autophagy via the canonical TGF-β pathway. These pathways converge to regulate cytosolic Ca²⁺ levels in the muscle, thereby maintaining lysosomal integrity. Disruption of either circuit elevates Ca²⁺, overactivating calpain. This leads to the accumulation of non-degradative autolysosomes and accelerates muscle degeneration. Our findings elucidate a neuronal mechanism for controlling muscle autophagy and provide insights into the pathogenesis of neurogenic myopathy.

Keywords:  C. elegans; TGF-β; autophagy; calpain; electrical synapse; lysosome; muscle degeneration; neurogenic myopathy; neuropeptide

DOI:  https://doi.org/10.1016/j.devcel.2026.06.001
Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2609132123

A human lysosomal storage disorder toolkit for decoding proteome landscapes in cortical-like and dopaminergic-like induced neurons.

Felix Kraus, Yuchen He, Yizhi Jiang, Delong Li, Yohannes A Ambaw, Federico M Gasparoli, Joao A Paulo, Tobias C Walther, Robert V Farese, Steven P Gygi, Florian Wilfling, J Wade Harper.

  Lysosomes maintain cellular homeostasis by degrading proteins delivered via endocytosis and autophagy and by recycling building blocks for organelle biogenesis. Lysosomal storage disorders (LSDs) comprise a group of diseases affecting diverse lysosomal functions. To facilitate molecular phenotyping across diverse LSD gene classes, we are developing a library of human embryonic stem cells engineered to lack individual LSD genes as a resource for the field. Here, we report our initial stem cell toolkit lacking one of 23 LSD genes, including the majority of genes associated with sphingolipidoses and neuronal ceroid lipofuscinoses, and its use in the generation of a proteomic resource for induced cortical-like and midbrain dopaminergic-like neurons. In-depth abundance and correlation profiling across organelles and suborganelle components revealed potential vulnerabilities that reflect distinct patterns of proteome alterations across both genotypes and neuronal cell types. We characterize alterations in the mitochondrial proteome associated with GBA1 and ASAH1 deficiency and identify synaptic and mitochondrial defects in ASAH1-/- induced neurons that correlate with defects in neuronal firing rates. Moreover, we developed an informatic pipeline for proteome-wide identification of individual protein-protein interactions and protein complexes that may be disrupted as a result of LSD gene deficiency. Finally, we visualized structural alterations of ASAH1-deficient endolysosomes in situ using cryoelectron tomography, revealing swollen organelles that were largely devoid of dense internal membranes characteristic of wild-type cells, but containing numerous intralumenal vesicle compartments. This toolkit and associated proteomic landscapes provide a resource for defining molecular signatures associated with LSD gene dysfunction and organelle vulnerability.

Keywords:  iNeurons; lysosome; organelle; protein interactions; proteomics

DOI:  https://doi.org/10.1073/pnas.2609132123
Autophagy. 2026 Jun 29.

Translation control of autophagy genes modulates cellular response to hydroxyurea-induced genotoxic stress.

Gayatri Mohanan, Kumkum Nag, Harsh Singh Senger, Parvathy J, Purusharth I Rajyaguru.

  The fine balance between cellular homeostasis and stress response is crucial for cell survival under conditions of genotoxic stress. Here, we identify a regulatory role for the translation repressor Sbp1 in modulating autophagy during hydroxyurea (HU)-induced replication stress. We observe that Sbp1 localizes to reversible, mRNA-containing cytoplasmic granules specifically upon HU treatment in an RGG motif-dependent manner. Loss of Sbp1 leads to selective translational upregulation of key autophagy genes ATG1, ATG2, and ATG9. Consistent with these translational changes, sbp1∆ cells exhibit increased selective macroautophagy/autophagy and enhanced bulk autophagy, whereas Sbp1 overexpression suppresses both processes. Interestingly, overexpression of Sbp1 shifts DNA repair toward non-homologous end joining (NHEJ) repair, linking altered autophagy to genome maintenance. Together, these findings identify Sbp1 as a negative regulator of autophagy during replication stress and suggest a regulatory axis linking granule-mediated mRNA sequestration, translational control of autophagy factors, and the cellular response to genotoxic stress.Abbreviations: CHX: cycloheximide; CPT: camptothecin; DDR: DNA damage response; GTA: genotoxin-associated targeted autophagy; HR: homologous recombination; HU: hydroxyurea; MMS: methyl methanesulfonate; mRNPs: mRNA-protein complexes; NHEJ: non-homologous end joining; P-bodies: processing bodies; RBPs: RNA binding proteins.

Keywords:  Autophagy; DNA repair; Sbp1; hydroxyurea; mrnps; translation regulation; yeast

DOI:  https://doi.org/10.1080/15548627.2026.2694657
Autophagy. 2026 Jun 28. 1-17

RAPSN/rapsyn aggregation-induced HSPA/HSP70-BAG3 aggrephagy maintains CHRN integrity in myasthenia gravis.

Yujia Liu, Guofang Xia, Huaiying Shi, Simeng Zhu, Hailong Li, Yifan Shi, Wanling Ouyang, Congfeng Xu, Ailian Du.

  Accelerated CHRN/AChR/nicotinic acetylcholine receptor internalization induced by auto-antibodies impairs neuromuscular junction transmission and contributes to myasthenia gravis (MG), a typical autoimmune disease. Although CHRN internalization is well established in MG pathogenesis, the downstream cellular events, especially those related to autophagy, remain poorly described. Here, we report that RAPSN/rapsyn, an intracellular CHRN-binding protein essential for its clustering, accumulates as aggregates in experimental autoimmune myasthenia gravis (EAMG) mice. In CHRN antibody-treated myotubes, RAPSN dissociates from internalized CHRN and forms aggregates due to exposure of its hydrophobic domains. These aggregates in turn impair the trafficking and membrane incorporation of newly synthesized CHRN, thereby exacerbating CHRN loss. Notably, the accumulation of RAPSN aggregates facilitates formation of HSPA/HSP70-BAG3 complex, which recognizes and transports the aggregates along microtubules to form perinuclear aggresomes for subsequent lysosomal degradation. Accordingly, pharmacological inhibition or knockdown of HSPA-BAG3 complex increases RAPSN aggregation, which participates in enhanced CHRN loss and worsened muscle weakness in EAMG mice. This study identifies HSPA-BAG3 aggrephagy as a protective mechanism that clears RAPSN aggregates to maintain CHRN integrity and suggests a potential therapeutic strategy for MG.Abbreviation: 3-MA: 3-methyladenine; AAV: adeno-associated virus; CASA: chaperone-assisted selective autophagy; CHRN/nicotinic acetylcholine receptor: cholinergic receptor nicotinic; CHRN-ab: CHRN antibodies; CHX: cycloheximide; CMAP: compound muscle action potential; CQ: chloroquine; EAMG: experimental autoimmune myasthenia gravis; ER: endoplasmic reticulum; GAS: gastrocnemius; MAP1LC3A/B: microtubule associated protein 1 light chain 3 alpha/beta; MG: myasthenia gravis; NMJ: neuromuscular junction; Rapa: rapamycin; RAPSN/rapsyn: receptor associated protein of the synapse; SQSTM1: sequestosome 1; TA: tibialis anterior; αBTX-A594: α-bungarotoxin-Alexa-594.

Keywords:  Aggregate; CHRN; HSPA; RAPSN; autophagy; myasthenia gravis

DOI:  https://doi.org/10.1080/15548627.2026.2693778
Autophagy. 2026 Jul 01.

AARS2-mediated lactylation of ULK1 promotes autophagy-dependent progression of clear cell renal cell carcinoma.

Xiangbo Zeng, Yuanchao Zhu, Yongyuan Xiao, Zhiyong Zhang, Xiaoliang Chen, Daqiang Wei, Can Huang, Kaizheng Liu, Xianghua Shi, Fei Luo, Qiong Wang, Zhe Lin, Wenfeng Xu, Wanlong Tan, Zaosong Zheng.

  Macroautophagy/autophagy is an evolutionarily conserved degradation pathway wherein cytoplasmic components are sequestered within double-membrane autophagosomes for lysosomal delivery. The initiation of autophagy is governed by autophagy-related (ATG) proteins, with the ULK1 kinase complex serving as the most upstream regulator. However, how ULK1 senses and integrates metabolic signals via post-translational modifications remains poorly understood. Here, we discover that ULK1 undergoes lactylation at lysine 46, catalyzed by the mitochondrial aminoacyl-tRNA synthetase AARS2, in response to autophagic stimuli. This modification promotes ULK1 kinase activity, leading to enhanced and selective phosphorylation of its downstream substrate ATG14 at Ser29, thereby activating the class III PtdIns3K complex and facilitating autophagosome biogenesis. Furthermore, we demonstrate that AARS2-mediated ULK1 lactylation drives autophagic flux and promotes tumor metastasis in clear cell renal cell carcinoma (ccRCC), and that a cell-penetrating peptide targeting K46 lactylation suppresses ccRCC progression in vitro and in vivo. Our study identifies lactylation as a novel regulatory mechanism controlling autophagy initiation and suggests that targeting AARS2-mediated ULK1 lactylation could be a potential strategy for treating ccRCC.

Keywords:  AARS2; ULK1; autophagy; clear cell renal cell carcinoma; lactylation; post-translational modification

DOI:  https://doi.org/10.1080/15548627.2026.2694660
Nat Rev Mol Cell Biol. 2026 Jun 30.

COPII meets autophagy at the ER membrane.

Lisa Heinke.

DOI: https://doi.org/10.1038/s41580-026-00997-7
Transl Neurodegener. 2026 Jun 28. pii: 29. [Epub ahead of print]15(1):

Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.

Honglin Zheng, Haiyang Luo, Yongting Lu, Yapei Yuan, Na Zhang, Suying Duan, Zongping Xia, Yuming Xu.

   BACKGROUND: Accumulation of Annexin A11 (ANXA11) aggregates is a distinct pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While genetic studies have linked ANXA11 mutations (e.g., D40G) to disease, the precise molecular events converting aggregation into neurotoxicity and intercellular propagation remain elusive. We hypothesize that lysosomal integrity serves as a critical checkpoint in ANXA11 proteinopathy and that its failure drives disease progression.
METHODS: To model the human pathology of ANXA11, we generated pre-formed fibrils (PFFs) of wild-type and FTLD/ALS-linked D40G mutant ANXA11. Human iPSC-derived neurons, 3D cerebral organoids, and bulk RNA-sequencing were employed to investigate neurotoxicity. High-resolution imaging, lentiviral knockdown, and biochemical assays were performed to delineate the lysosomal damage response and the subsequent "prion-like" spreading of aggregates.
RESULTS: The internalized ANXA11 fibrils accumulated in lysosomes, triggering lysosomal membrane permeabilization (LMP). The D40G mutation exacerbated this toxicity, leading to severe LMP, mitochondrial depolarization, and specific transcriptional downregulation of the dynactin subunit ACTR10. Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy. Notably, in human cerebral organoids, failure of this lysophagic clearance facilitated the cytoplasmic escape of ANXA11, thereby accelerating its seeding activity and propagation to neighboring cells. Pharmacological or genetic modulation of this pathway significantly altered neuronal survival.
CONCLUSIONS: Our study established lysosomal rupture as a primary driver of ANXA11-associated neurodegeneration and validated the p38/MK2/HSP27 axis as a crucial defense mechanism in human neural tissue. These findings provide a novel mechanistic link between lysosomal quality control and ANXA11 propagation, highlighting that enhancing lysophagic flux represents a promising translational strategy to halt the progression of FTLD and ALS.

Keywords:  Annexin A11; Cerebral organoids; Frontotemporal lobar degeneration; Lysophagy; Lysosomal membrane permeabilization; Prion-like propagation

DOI:  https://doi.org/10.1186/s40035-026-00561-5
Mol Biol Rep. 2026 Jun 30. pii: 1068. [Epub ahead of print]53(1):

Autophagic therapeutic targeting for Doxorubicin-induced cardiomyopathy.

Noha H Badr, Eman G Khedr.

  Autophagy has been extensively studied in a variety of pathologies, including neurological disorders, cancers, muscle diseases, aging, and cardiovascular diseases. Doxorubicin (Dox) is a potent anticancer drug widely used to treat various cancers. Despite its therapeutic benefits, it has cardiotoxic side effects, interfering with its clinical application. Dox-induced cardiomyopathy (DIC) is one of the most prominent and lethal side effects associated with the use of Dox. Numerous investigations have revealed that Dox administration impacts autophagy; however, the precise mechanism by which Dox modifies this process remains unclear, as the role of autophagy in heart tissue is controversial, ranging from being cytoprotective to cytotoxic. Various therapeutic interventions, including pharmacological drugs and natural products, have been reported to influence the autophagic flux in DIC. In this review, we explore the therapeutic potential of autophagy modulation in DIC, focusing on how various pharmacological drugs and natural products influence autophagy to mitigate cardiac damage. This review uniquely emphasizes the mechanistic role of autophagy in DIC and provides a comprehensive analysis of therapeutic interventions targeting autophagy as a strategy for cardioprotection.

Keywords:  Autophagy; Cardiomyopathy; Cardiovascular diseases; Doxorubicin

DOI:  https://doi.org/10.1007/s11033-026-12165-3
Genes Cells. 2026 Jul;31(4): e70134

The SQSTM1 L341V Variant Associated With Sporadic ALS Promotes the Accumulation of Enlarged Ubiquitin-Positive SQSTM1 Bodies.

Kento Shimakura, Akira Oka, Haruka Yudahira, Yutaro Hama, Asako Otomo, Shinji Hadano.

  SQSTM1 is one of the causative genes of neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The SQSTM1 protein regulates the degradation of polyubiquitinated proteins and autophagosome formation through its interaction with microtubule-associated protein light chain 3 (MAP1LC3/LC3). However, the molecular mechanisms by which SQSTM1-LC3 binding regulates the autophagy-endolysosomal system (APELS) remain unclear. To elucidate the spatiotemporal role of SQSTM1, we transiently expressed wild-type SQSTM1 or missense mutants carrying mutations in the LC3-interacting region (LIR), fused with the photoconvertible fluorescent protein Dendra2. Live-cell fluorescence imaging and co-localization analyses with markers of the APELS were then performed. Particle analysis of photoconverted or non-photoconverted SQSTM1-positive structures in live cells revealed that the pathogenic L341V variant formed larger structures than the wild-type. Co-localization analyses further showed that both the L341V and artificial LIR3A mutants accumulated in large ubiquitin-positive structures, likely due to impaired localization to autophagosomes. These results suggest that mutations within the LIR differentially affect autophagosome formation and cargo degradation within APELS-related compartments, highlighting the importance of SQSTM1 structural integrity in ALS/FTD pathogenesis.

Keywords:  ALS; Dendra2; FTD; LC3; SQSTM1; autophagy‐endolysosomal system (APELS)

DOI:  https://doi.org/10.1111/gtc.70134
Autophagy. 2026 Jul 03. 1-3

Receptor-cargo coupling during ER-autophagy depends on coat proteins and ER membrane properties.

Shuliang Chen, Subhrajit Banerjee, Peter Novick, William A Prinz, Susan Ferro-Novick.

  Selective autophagy of the endoplasmic reticulum (reticulophagy) is driven by receptor-mediated ER remodeling. Reticulophagy receptors are essential for ER turnover. Productive cargo recognition during autophagosome-mediated reticulophagy depends on the interaction of the receptor with the COPII subunit Sfb3/Lst1 (SEC24C in mammals) as well as the phospholipid composition of the ER. We unexpectedly found that the conserved reticulophagy receptor Atg40 traffics to the vacuole/lysosome without cargo (ER membrane proteins) or Sfb3/Lst1 in neutral lipid-deficient mutant cells. Comprehensive lipidomic profiling of this lipid mutant revealed a shift in the phosphatidylethanolamine (PE)-to-phosphatidylcholine (PC) ratio, a compositional change predicted to alter biophysical properties of the ER, including membrane bendability. The discovery that membrane properties regulate receptor - cargo coupling efficiency at autophagic sites, as they do at secretory exit sites, extends current mechanistic models of reticulophagy and suggests membrane properties may also affect cargo selection on other types of selective autophagy pathways.

Keywords:  Coat proteins; membrane curvature; neutral lipid; receptor–cargo coupling; reticulophagy

DOI:  https://doi.org/10.1080/15548627.2026.2695313
iScience. 2026 Jul 17. 29(7): 116449

Mitophagy interacts with mitochondrial dynamics and biogenesis, acting as a double-edged sword in digestive cancer.

Enming Qiu, Guoqing Lv, Jianing Hou, Zhou Li, Gang Wang.

  Mitophagy is a selective autophagy that degrades dysfunctional mitochondria to maintain cellular homeostasis. Mitophagy is functionally coordinated with and regulated by mitochondrial biogenesis and mitochondrial dynamics, which include mitochondrial fusion, mitochondrial fission, and mitochondrial trafficking. Furthermore, researches have demonstrated that mitophagy plays a critical role in the occurrence and development of digestive cancer. Nonetheless, the mechanism of how mitophagy modulates digestive cancer and the mechanism of how mitochondrial biogenesis and dynamics influence mitophagy warrant more investigations. This review summarizes the current understanding of the regulatory mechanism of mitophagy and outlines recent advances from investigations that explore how mitochondrial biogenesis and dynamics coordinate with mitophagy. Additionally, this review provides a comprehensive view about how mitophagy could regulate the occurrence and development of digestive cancer. A deeper understanding about the role of mitophagy in regulation of digestive cancer benefits the development of more efficient therapeutic strategies for patients.

Keywords:  Biological sciences

DOI:  https://doi.org/10.1016/j.isci.2026.116449
F1000Res. 2025 ;14 1138

Mechanisms Associated with PINK1 Variants in Parkinson's Disease.

Hanliang Dan, Xiaohui Huang, Zheng Liu, Bing Wei, Maslinda Musa.

  Parkinson's disease (PD) is a widespread and progressively debilitating neurodegenerative disorder with a growing global prevalence. While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD. This review critically explores the molecular mechanisms linking PINK1 dysfunction to PD, with a specific focus on the kinase's role in phosphorylating Ubiquitin and Parkin at the conserved Serine 65 (Ser65) residue. We discuss how this phosphorylation event acts as a molecular switch to recruit the novel autophagy receptors Optineurin (OPTN) and NDP52, thereby initiating mitophagy-a process often disrupted by pathogenic variants. Furthermore, we examine the emerging role of PINK1 in suppressing neuroinflammation via the STING pathway and evaluate the translational potential of targeting these molecular checkpoints for therapeutic intervention. These insights lay the groundwork for developing precision medicine strategies to address the urgent need for effective PD treatments.

Keywords:  PINK1; Parkinson's disease; autophagy pathways; genetic mutation; mitochondrial phosphorylation; oxidative stress

DOI:  https://doi.org/10.12688/f1000research.170090.2
J Neurochem. 2026 Jul;170(7): e70515

A PARK9 iPSC-Derived Dopaminergic Neuron Model Enables Drug Screening Targeting Autophagy-Lysosome Pathway Dysfunction in Parkinson's Disease.

Kei-Ichi Tsukiboshi, Kei-Ichi Ishikawa, Akihiro Yamaguchi, Kimihito Arai, Kazuaki Kanai, Taiji Tsunemi, Hideyuki Okano, Nobutaka Hattori, Wado Akamatsu.

Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuronal degeneration in the substantia nigra, in which lysosomal dysfunction and impaired autophagy-lysosome pathway activity are increasingly recognized as important pathogenic mechanisms. However, disease-modifying therapies targeting this pathway remain unavailable. Here, we generated induced pluripotent stem cells (iPSCs) from a PARK9 patient carrying an ATP13A2 mutation and established mutation-corrected isogenic control iPSCs. PARK9 iPSC-derived neurons recapitulated lysosomal dysfunction-associated cellular phenotypes, including impaired lysosomal acidification, reduced mature cathepsin D levels, CD63-positive vesicle accumulation, LC3B-positive autophagosome accumulation, cytoplasmic pSer129 α-synuclein accumulation, and increased cleaved caspase-3 signals. These phenotypes were ameliorated in mutation-corrected neurons, supporting the contribution of ATP13A2 dysfunction to these abnormalities. We then performed high-content imaging-based compound screening targeting LC3B-positive autophagosome accumulation in PARK9 neurons. A three-step workflow identified 19 candidate compounds that reduced autophagosome accumulation consistent with partial improvement of lysosome-dependent downstream autophagosome processing rather than simple suppression of autophagosome formation. Among these, paroxetine, Ro 25-6981, amisulpride, and PK11195 showed additional, compound-dependent effects on PARK9-associated phenotypes, including lysosomal acidification, CD63-positive vesicle accumulation, cytoplasmic pSer129 α-synuclein signals, and cleaved caspase-3 signals. These findings establish PARK9 iPSC-derived neurons as a useful model of lysosomal dysfunction-associated PD pathology and provide a practical screening platform for identifying candidate compounds that modulate autophagy-lysosome pathway-related cellular phenotypes.

DOI: https://doi.org/10.1111/jnc.70515
Mol Cell. 2026 Jun 30. pii: S1097-2765(26)00387-4. [Epub ahead of print]

Biomolecular condensates for proteostasis and potential therapeutic applications.

Wen Jia, Pilong Li.

  Proteostasis is essential for cellular function, and its dysregulation underlies a wide spectrum of diseases. Growing evidence underscores liquid-liquid phase separation (LLPS) as a central mechanism governing protein degradation through the formation of condensates for proteostasis. These membraneless biomolecular condensates concentrate or sequester key degradation factors, substrates, and enzymes, enabling spatiotemporally regulated protein clearance. Condensates for proteostasis represent a mechanism for degrading pathogenic proteins that remain refractory to conventional therapeutics. In this perspective, we explore how LLPS drives the assembly of condensates for proteostasis, outline their physiological functions, and highlight their emerging utility as a versatile platform for targeted protein degradation. Harnessing these condensates offers a promising route to eliminate "undruggable" targets and reestablish proteostasis, opening new avenues for precision medicine across a range of major diseases.

Keywords:  E3 ligase; autophagy; biomolecular condensate; degradation condensate; liquid-liquid phase separation; proteasome; proteostasis; targeted protein degradation

DOI:  https://doi.org/10.1016/j.molcel.2026.06.016
Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2514112123

A genome-wide screen identifies that PLCG2 restrains lysosomal GCase activity.

Jessica Lawrence, Vineet Vinay Kulkarni, Chan Lek Tan, Marinella Callow, Yves Juste, Dewakar Sangaraju, Mike Costa, Baris Bingol.

  Mutations in the GBA1 gene, which encodes the lysosomal glucocerebrosidase enzyme GCase, cause the lysosomal storage disorder Gaucher disease and represent the most common genetic risk factor for Parkinson's disease (PD). These mutations deplete lysosomal GCase activity and cause accumulation of GCase substrate, glucosylceramide, and its pathological metabolite, glucosylsphingosine. Impaired GCase activity then drives immune and neuronal dysfunction in Gaucher disease and promotes pathogenic aggregation of α-Synuclein in PD. As such, boosting the lysosomal activity of GCase is a therapeutic strategy to ameliorate substrate accumulation and prevent associated neurotoxicity. To identify the regulators of GCase activity in lysosomes, we conducted a genome-wide screen in primary mouse macrophages using a fluorescent enzyme activity reporter. By validating the screen hits in cellular biochemical and profiling assays, we identified pathways that promote or inhibit lysosomal GCase activity. Our screen identified PLCG2 as a regulator of lysosomal GCase activity. Mechanistically, PLCG2 depletion accumulates Golgi-associated phosphatidylinositols, promoting the transport of mutant GCase into lysosomes while reducing its Golgi-associated pool. Functionally, PLCG2 depletion boosts the activity of lysosomal mutant GCase, the cellular flux of glucosylceramide, and the clearance of pathogenic GCase substrates. In summary, our screen has uncovered the regulators of GCase abundance and trafficking at a whole-genome scale and identified potential pathways for future therapeutic interventions in Gaucher and Parkinson's to boost the activity of this enzyme in lysosomes.

Keywords:  Gaucher disease; Parkinson’s disease; functional genomics; lipid homeostasis; lysosomes

DOI:  https://doi.org/10.1073/pnas.2514112123
Exp Mol Med. 2026 Jul 03.

Protein arginine methyltransferases coordinate mitochondrial stress adaptation and neuromuscular function.

Ju-Hyeon Bae, Chang-Lim You, Jeongmin Park, Jong-Sun Kang.

Sarcopenia and neuromuscular degeneration are key drivers of functional decline during ageing and arise not solely from muscle loss but also from failure of mitochondrial and metabolic stress adaptation across the neuromuscular system. Mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, defective quality control and redox imbalance, contributes directly to muscle weakness, neuromuscular junction instability and motor unit degeneration. However, the upstream mechanisms governing the transition from adaptive remodelling to degenerative collapse remain incompletely defined. Protein arginine methyltransferases (PRMTs) have emerged as critical modulators of mitochondrial and metabolic stress signalling. Beyond epigenetic regulation, PRMTs influence signalling pathways that intersect with AMP-activated protein kinase (AMPK)-Forkhead box O (FOXO) and mechanistic target of rapamycin (mTOR), thereby regulating mitochondrial biogenesis, selective autophagy and mitophagy, proteostatic balance, and anabolic restraint. Distinct PRMT family members exert non-redundant functions across muscle fibres, satellite cells and motor neurons, collectively shaping neuromuscular stress resilience. We propose that PRMTs act as molecular rheostats that bias cellular responses to mitochondrial stress towards adaptive resolution or progression to neuromuscular degeneration, thereby positioning PRMT-regulated metabolic signalling as a unifying mechanism underlying sarcopenia and compromised healthspan.

DOI: https://doi.org/10.1038/s12276-026-01762-8
Cell Death Differ. 2026 Jun 30.

Dysregulation of the TFEB-ATP6V0C axis in microglia exacerbates α-synuclein pathology through impaired lysosomal acidification in Parkinson's disease.

Yiming Wang, Zhuoran Ma, Zongjie Jin, Liang Kou, Nian Xiong, Tao Wang, Yun Xia.

Emerging evidence suggests that microglia exhibit dual regulatory roles in the pathogenesis of Parkinson's disease (PD); however, their precise function in α-synuclein clearance remains incompletely understood. Here, we provide compelling evidence that α-synuclein preformed fibrils (α-syn PFF) impair lysosomal acidification in microglia, leading to defective autophagic flux and disrupted α-syn degradation. This dysfunction further promotes the secretion of microglial extracellular vesicles (EVs), exacerbating disease pathology. Mechanistic investigations uncover that α-syn PFF directly interacts with ATP6V0C, a pivotal V0 subunit of V-ATPase. This interaction sterically hinders V0-V1 domain assembly, disrupting proton pump complex formation and reducing ATP6V0C expression. Functionally, ATP6V0C overexpression rescues lysosomal acidification deficits and facilitates α-syn degradation in vitro, while in vivo, ATP6V0C overexpression alleviates neurotoxicity and reduces phosphorylated α-syn aggregation in α-syn PFF mouse models. Further investigation identifies the PI3K-AKT-mTOR-TFEB pathway as a key regulatory axis of ATP6V0C-mediated lysosomal acidification in microglia. Notably, both TFEB activation and mTOR inhibition restore lysosomal acidity and upregulate ATP6V0C expression, thereby enhancing α-syn clearance. These findings establish the TFEB-ATP6V0C axis as a key determinant of microglial proteostasis, proposing targeted activation of this pathway as a promising strategy to mitigate PD progression.

DOI: https://doi.org/10.1038/s41418-026-01800-y
J Immunol. 2026 Jun 07. pii: vkag127. [Epub ahead of print]215(6):

ENPP1-dependent USP2 ubiquitination governs SQSTM1-mediated autophagy-dependent ferroptosis in trophoblast cells and exacerbates placental dysfunction in gestational diabetes mellitus.

Yahui Xu, Guanglei Zhong, Xianghong Cheng, Jun Yan, Yan Zhou, Yan Feng, Rujia Fan.

  Downregulation of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been implicated in autophagic cell death. However, how ENPP1 regulates the interplay between autophagy and ferroptosis to maintain trophoblast homeostasis in the context of gestational diabetes mellitus (GDM) remains unclear. To determine ENPP1's role in autophagy-dependent ferroptosis and its contribution to GDM-related placental injury, clinical placental tissues, hyperglycemia-treated HTR8/SVneo trophoblasts, and streptozotocin-induced GDM mice were analyzed. Ubiquitination assays, co-immunoprecipitation, functional studies, and therapeutic interventions were conducted. ENPP1 was significantly reduced in GDM placentas and correlated with increased ferroptosis and lipid peroxidation. Mechanistically, ENPP1 recruited USP2 (ubiquitin-specific peptidase 2) to inhibit the ubiquitination and autophagic degradation of SQSTM1 (sequestosome 1), thereby enhancing its stability. ENPP1 loss promoted NCOA4-mediated ferritinophagy, leading to iron overload and ferroptosis. Restoring ENPP1 or inhibiting autophagy alleviated placental thinning and fetal growth restriction in GDM mice. ENPP1 regulates autophagy-dependent ferroptosis via the USP2-SQSTM1 axis, and its deficiency contributes to placental dysfunction.

Keywords:  ENPP1; autophagy; ferroptosis; gestational diabetes mellitus; ubiquitination

DOI:  https://doi.org/10.1093/jimmun/vkag127
Dis Res. 2026 Jun;6(2): 53-64

Krüppel-like Factor 2 (KLF2) Regulates Autophagy, Mitophagy, Mitochondrial Health, and Function During Foam Cell Formation.

Md Sariful Islam Howlader, Manjusri Das, Surajit Hansda, Prathyusha Naidu, Hiranmoy Das.

   Backgrounds: Foam cell (FC) formation is a hallmark of early atherosclerosis, driven by dysregulated lipid uptake, impaired mitochondrial clearance, and metabolic reprogramming in myeloid cells. However, the precise role of KLF2 in modulating autophagy, mitophagy, and glycolysis during FC formation remains inadequately explored.
Methods: This study uncovers the critical regulatory role of Krüppel-like factor 2 (KLF2) during foam cell formation of myeloid cells (RAW264.7) using quantitative real-time PCR, immunocytochemistry, confocal microscopy, and glycolysis stress test methods.
Results: Exposure to oxidized low-density lipoprotein (ox-LDL) suppressed autophagy and mitophagy markers in myeloid cells. It also increased glycolytic activity in myeloid cells during FC formation. A well-known chemical suppressor of KLF2, GGPP, further amplified these changes, highlighting the importance of endogenous KLF2 in maintaining mitochondrial health and metabolic functions during formation. To confirm the role of KLF2 in this process, when a chemical inducer of KLF2, GGTI298, was added during FC formation, it restored autophagic and mitophagic machinery, including the expression of Beclin1, LC3B, Parkin, and Pink1, and reversed the abnormal increase in glycolysis during FC formation.
Conclusion: These findings demonstrate that KLF2 is a key transcriptional regulator that limits FC formation by preserving mitochondrial health and reducing excessive glycolysis. Furthermore, these results suggest KLF2 could be a target for future development of therapeutics for preventing FC formation, which is an early event in atherosclerosis development.

Keywords:  Autophagy; Foam cell; Glycolysis; Kruppel-like factor 2; Mitophagy

DOI:  https://doi.org/10.54457/dr.202601003
EMBO Rep. 2026 Jul 02.

Lipid droplets promote aberrant liquid-liquid phase separation of alpha-synuclein impairing energy homeostasis.

Jose Cevallos, Elena Eubanks, Sunghoo Jung, Yiming Huang, Elyse Guadagno, Nora Jaber, Yuzhou Xia, Jinying Wang, Huan Wang, Neeharika Rao Suvvari, Aryan Doshi, Nitya Ravinutala, Alejandro Mosera, Timothy Hsu, Jiya Mody, Benjamin Sacks, Anvi Narayan, Breanna Smith, Maia Wang, Meghana Gottapu, Heba Alnakhala, Nagendran Ramalingam, Arati Tripathi, Tim Bartels, Ulf Dettmer, Zheng Shi, Wei Dai, Eleanna Kara.

Alpha-synuclein (αSyn) inclusions are a defining neuropathological feature of Parkinson's disease, but the cellular events that initiate their formation and promote neurotoxicity remain incompletely understood. Aberrant liquid-liquid phase separation has emerged as a potential early step in αSyn dysregulation, yet the physiological triggers and functional consequences of this process are unclear. Here, we show that lipid droplets promote the spontaneous phase separation of wild-type and E46K mutant αSyn into condensates. These condensates sequester lipid droplets and impair their turnover, indicating disruption of cellular lipid homeostasis. Mitochondria in close proximity to αSyn condensates exhibit reduced membrane potential and increased mitophagy. Correlative light and electron microscopy further reveals αSyn oligomers associated with mitochondrial membranes displaying structural abnormalities. Together, these findings identify lipid droplets as drivers of aberrant αSyn phase separation and suggest that lipid droplet-rich condensates contribute to mitochondrial dysfunction and impaired energy homeostasis. Given the enrichment of lipid droplets within neuromelanin-containing dopaminergic neurons of the substantia nigra, this mechanism may be relevant to the selective neuronal vulnerability observed in Parkinson's disease.

DOI: https://doi.org/10.1038/s44319-026-00856-8
Biomed Rep. 2026 Aug;25(2): 96

Exercise and dietary interventions in the regulation of hepatic mitophagy and liver recovery (Review).

Julia Windi Gunadi, Diana Krisanti Jasaputra, Faysal Kastella, Shanti Shanti, Ronny Lesmana.

  The high metabolic demand of the liver renders it dependent on mitophagy for mitochondrial quality control. While exercise and nutritional interventions are known to influence hepatic mitophagy, the precise regulatory mechanisms remain incompletely understood. Mitophagy in the liver is influenced by a combination of exercise-related parameters, dietary factors and sex-specific biological factors. Drawing from 19 animal studies published between 2016 and 2026, the present narrative review examines how different exercise modalities and dietary interventions regulate hepatic mitophagy. Among models of obesity and metabolic dysfunction, structured endurance training and higher-intensity exercise protocols yield better capacity to re-establish coordinated mitochondrial quality control than voluntary or low-intensity physical activity protocols. Notably, a single bout of exercise can produce a transient elevation in mitophagic flux, whereas sustained training over time expands mitophagy capacity without necessarily maintaining heightened flux at rest. Moderate-intensity continuous training more effectively restores canonical PTEN-induced kinase 1/Parkin-dependent flux, whereas high-intensity interval training favors structural mitochondrial recovery and upstream energetic signaling, although the relative efficacy depends on the model, disease severity and readout assessed. In high-fat or Western dietary settings, mitophagy is often compromised, with exercise producing incomplete recovery unless paired with improved diet or weight loss. These responses are also influenced by sex differences: Females tend to maintain higher intrinsic mitochondrial quality with less inducible mitophagy, whereas males exhibit a greater reliance on exercise-induced activation of mitophagy. Paternal and maternal developmental programming has also emerged as an important modulator of mitophagy induction. In conclusion, mitophagy in the liver is modified by different exercise and dietary interventions in a manner that is further conditioned by sex and developmental history.

Keywords:  exercise; metabolic dysfunction-associated steatotic liver disease; mitophagy; paternal programming; sex differences

DOI:  https://doi.org/10.3892/br.2026.2169
J Neurol. 2026 Jul 02. pii: 441. [Epub ahead of print]273(8):

The dual role of mTOR in multiple sclerosis pathophysiology: a systematic review.

Floor Koks, Femke Reubens, Hymke van der Zee, Jacco Jan Briedé.

  Multiple sclerosis (MS) is a chronic autoimmune disease characterized by demyelination, neuroinflammation, and progressive neurodegeneration. The mechanistic target of rapamycin (mTOR) pathway plays a key role in regulating immune responses, cell metabolism, autophagy, and repair processes. Although the role of mTOR in neurodegeneration has been explored in previous reviews, a systematic assessment of its function in MS across different models is still lacking. This systematic review aimed to examine the role of mTOR signaling in the pathophysiology of MS. Following Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, we screened preclinical and clinical studies using two databases and assessed the risk of bias specific to the study types. A total of 189 records were identified, of which 90 met the inclusion criteria for qualitative analysis. Studies using in vitro and in vivo (mainly rodent models, both sexes) models of MS, as well as MS patient tissue or data, consistently demonstrated that mTOR is involved in the MS-related processes neuroinflammation, myelination, autophagy, gliosis, mitochondrial dysfunction, and oxidative stress. mTOR inhibition reduces pro-inflammatory signaling and may enhance autophagy, offering neuroprotection. In contrast, activation of mTOR promotes remyelination by enhancing oligodendrocyte differentiation and maturation. These remyelinating effects may be masked in inflammatory environments, because activation of mTOR supports immune cell expansion and glial reactivity, inducing inflammation and oxidative stress. Overall, our findings underscore a dual role of mTOR in MS pathology, with important implications for disease stage and timing of intervention. Although mTOR is mechanistically important in MS, its therapeutic modulation is unlikely to be readily clinically translatable without a substantial risk of unintended and context-dependent effects.

Keywords:  Myelination; Neurodegeneration; Neuroinflammation; PI3K/AKT signaling; Rapamycin

DOI:  https://doi.org/10.1007/s00415-026-13970-3
Nat Commun. 2026 Jul 02. pii: 5789. [Epub ahead of print]17(1):

VPS13C/PARK23 initiates lipid transfer and membrane remodeling for efficient lysosomal repair.

Oluwatobi Andrew Adeosun, Christian Schröer, Elisabeth Südhoff, Fabio Bergenthal, Katharina Sommer, Emely Döffinger, Britta Fiedler, Angelika Hilderink, Ann-Katrin Lehmann, Lea Sophie Pohle, Sergei M Korneev, Florian Fröhlich, Kenji Maeda, Rainer Kurre, Michael Holtmannspötter, Bianca M Esch, Joost C M Holthuis.

Perturbations in lysosome integrity are tightly linked to neurological disorders and ageing, but the underlying pathogenic mechanisms are incompletely understood. Using an unbiased proteomic approach, we here identified the bridge-like lipid transport protein VPS13C/PARK23 as a key component of a global early response pathway to lysosome damage. VPS13C readily binds lysosomes under mechanical or osmotic tension in anticipation of membrane lesions. The latter trigger a conformational change in the protein's C-terminus, involving its ATG2C domain acting as sensor of damage-induced lipid packing defects. We show that ER-lysosome contacts formed by VPS13C provide critical binding platforms for OSBP/ORPs to enable efficient ER wrapping of damaged lysosomes. A chemical approach to assess directional ER-to-lysosome lipid transport revealed that VPS13C is essential for large-scale lipid delivery to acutely damaged lysosomes to facilitate their repair. Our findings offer new mechanistic insights into how loss-of-function mutations in VPS13C may enhance the risk of Parkinson's disease.

DOI: https://doi.org/10.1038/s41467-026-75145-y
Nat Metab. 2026 Jun 29.

Mitochondrial quality control in human ageing and longevity.

Anna Picca, Luigi Ferrucci.

Mitochondria play central roles in cellular metabolism and in key processes such as inflammation, stress response, cell death and signalling. Mitochondrial quality control (MQC) mechanisms continuously monitor organelle integrity and function, and repair or eliminate damaged mitochondria to replace them with newly formed, healthy organelles. MQC is particularly important under metabolic or environmental stress conditions. Failure of MQC paves the way to chronic diseases, such as diabetes, metabolic syndromes and immunosenescence. This Review summarizes our current understanding of MQC biology in the context of healthy human longevity. We explore the regulation of MQC in physiological conditions and explain how the dysregulation of MQC in ageing negatively impacts systemic metabolism and immune function. We discuss emerging therapeutic strategies-such as NAD+, AMPK activators and caloric restriction-that maintain a robust MQC to improve metabolic resilience and illustrate how preclinical and clinical studies can leverage MQC as a potential gerotherapeutic target.

DOI: https://doi.org/10.1038/s42255-026-01563-3
Autophagy. 2026 Jul 02.

Tegument protein UL16 of herpes simplex virus 1 suppresses the innate immune response by downregulating MAVS abundance via mitophagy.

Jingwen Wang, Rongli Zhu, Ping Yi, Mengyao Gan, Feng Long.

  Herpes simplex virus 1 (HSV-1) is a globally prevalent pathogen that poses a significant health threat due to its lifelong latency. This persistence is driven by intricate immune evasion mechanisms, the deciphering of which remains a challenge. Here, we identified the HSV-1 tegument protein UL16 as a novel viral immunosuppressive factor, which significantly suppresses the RIGI-like receptor (RLR)-mediated antiviral immunity. We found that UL16 can interact with MAVS (mitochondrial antiviral signaling protein) and induce its degradation, thereby inhibiting type I interferon (IFN-I) production. Further investigation revealed that UL16-induced MAVS degradation was facilitated via mitophagy involving the mitochondrial cargo receptor FUNDC1 (FUN14 domain containing 1). Knockout of FUNDC1 expression completely disrupted UL16-induced MAVS degradation and restricted HSV-1 replication. In contrast, overexpression of FUNDC1 augmented the suppressive effect of UL16 on MAVS-triggered IFN-I signaling and consequently benefited viral replication. Notably, the C-terminal domain (CTD) of UL16 primarily accounted for its immunosuppressive function, which was also demonstrated to be essential for UL16 engagement with MAVS, FUNDC1 and MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). A conserved LC3-interacting region (LIR) motif within the UL16 CTD was identified to play a critical role in LC3 recruitment enhancement. Furthermore, the UL16-deficient HSV-1 exhibited markedly attenuated viral infectivity and pathogenicity in vivo. In summary, our findings uncover a previously uncharacterized pathway through which HSV-1 UL16 subverts host immunity by inducing mitophagy. This study provides critical insights into host-pathogen interactions and establishes a rational foundation for developing novel therapeutics against HSV-1 infection.Abbreviations:3-MA: 3-methyladenine; BNIP3L/NIX: BCL2 interacting protein 3 like; BSA: bovine serum albumin; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CARD: caspase recruitment domain; Cas9: CRISPR-associated system 9; CGAS: cyclic GMP-AMP synthase; co-IP: co-immunoprecipitation; COX8: cytochrome c oxidase subunit 8; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; CTD: C-terminal domain; Ctrl: control; CXCL10: C-X-C motif chemokine ligand 10; DAPI: 4,'6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; ds: double-stranded; FBS: fetal bovine serum; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HEK: human embryonic kidney; HSV-1: herpes simplex virus 1; IAV: influenza A virus; IFIH1/MDA5: interferon induced with helicase C domain 1; IFIT1/ISG56: interferon induced protein with tetratricopeptide repeats 1; IFN-I: type I interferon; IgG: Immunoglobulin G; IRF3: interferon regulatory factor 3; ISGs: IFN-stimulated genes; kDa: kilodalton; KO: knockout; KSHV: Kaposi sarcoma-associated herpesvirus; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MG132: cbz-leu-leu-leucinal; MOI: multiplicity of infection; NanoBiT: NanoLuc Binary Technology; NC: negative control; NTD: N-terminal domain; OPTN: optineurin; p-: phosphorylated; PFU: plaque-forming unit; PINK1: PTEN induced kinase 1; poly(I:C): polyinosinic-polycytidylic acid; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; qPCR: quantitative polymerase chain reaction; RIGI/RIG-I: RNA sensor RIG-I; RLR: RIGI-like receptor; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SeV: Sendai virus; sgRNA: single guide RNA; shRNA: short hairpin RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TM: transmembrane; TOMM20: translocase of outer mitochondrial membrane 20; TRAF: TNF receptor associated factor; TUFM: Tu translation elongation factor, mitochondrial; UL16: unique long region 16; VSV: vesicular stomatitis virus; VZV: varicella zoster virus; WCL: whole-cell lysate; WT: wild-type; Z-VAD-FMK: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone.

Keywords:  FUNDC1; HSV-1; MAVS; UL16; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2698747
Biochem Soc Trans. 2026 Jul 29. 54(7): 887-899

Advancing the monitoring of organelle contact sites in vitro and in vivo.

Lucia Barazzuol, Caterina Peggion, Marisa Brini, Yusuke Nasu, Tito Calì.

  Organelle contact sites are highly dynamic and specialized regions where distinct organelles come into proximity, enabling direct inter-organelle communication. These structures play fundamental roles in cellular homeostasis by coordinating the exchange of lipids, metabolites, and ions, as well as regulating key processes such as organelle dynamics, mitochondrial fission, autophagy, and metabolic integration. Alterations in contact site architecture and function have been increasingly associated with a wide range of human diseases, including neurodegeneration, metabolic disorders, and cancer. Despite their biological relevance, the nanoscale nature and dynamic behaviour of contact sites have historically posed significant challenges for their accurate detection and functional characterization. Here, we provide a comprehensive overview of the methodologies currently available to study organelle contact sites, ranging from classical approaches such as electron microscopy and biochemical fractionation to advanced imaging techniques and genetically encoded reporters. We discuss recent developments in high-resolution and live-cell microscopy that have improved the spatial and temporal resolution of contact site analysis, as well as emerging tools designed to selectively label, quantify, and manipulate these interfaces. Attention is given to the next generation of engineered reporters capable of sensing molecular and ionic exchanges at contact sites, thereby moving beyond structural description toward functional interrogation. By critically evaluating the strengths and limitations of existing approaches, we aim to provide a framework for selecting appropriate tools and to highlight future directions in the field. Ultimately, advancing our ability to monitor and dissect organelle contact sites will be essential for understanding their contribution to cellular physiology and disease.

Keywords:  Organelle contact sites; SPLICS; genetically encoded reporters

DOI:  https://doi.org/10.1042/BST20250371
Sci Rep. 2026 Jun 30.

Rapamycin and nicotinamide treatment attenuates senescence-associated features in mesenchymal stromal cells isolated from elderly donors by modulating autophagy.

Mohammadhossein Khorraminejad-Shirazi, Mahsa Sani, Kimia Falamarzi, Farnaz Sani, Yasamin Dehghan, Mohammad Bagher Nazari, Elham Hassannia, Shiva Aminnia, Seyedarad Mosalamiaghili, Pooneh Mokarram, Behzad Ghaffari, Maral Mokhtari, Negar Azarpira.

  Mesenchymal stromal cells (MSCs) are promising candidates for regenerative medicine due to their multi-lineage differentiation, immunomodulatory properties, and paracrine effects. Old individuals are the prime target population for cell-based therapies. Donor age significantly hinders the efficacy of autologous cell therapy due to the low quantity and senescent profile of isolated stem cells from aged individuals. Dysregulation of the AMPK-mTOR-autophagy pathway challenges the attenuation of senescence-associated features in aged stem cells. Here, we evaluated the effects of short-term treatment with rapamycin and nicotinamide (NAM) on the attenuation of senescence-associated features in aged MSCs. Aged MSCs were isolated from elderly donors and cultured in the medium supplemented with rapamycin (10 nM) and NAM (5 mM) for the duration of a culture passage. Cell proliferation, expression of CKIs, ROS, senescence-associated changes, senescence-associated secretory phenotype (SASP) profile, and osteogenic differentiation were investigated. Furthermore, AMPK, mTORC1, and mTORC2 activity and level of autophagy were evaluated. Aged MSCs treated with rapamycin and NAM exhibited increased replicative capacity and decreased p16 and p21 expression. In contrast to the senescent profile of aged MSCs, rapamycin, and NAM attenuated the senescence-associated changes, including decreased β-galactosidase expression, dysfunctional lysosomes, reduced total cellular ROS, and improved osteogenic differentiation. Treatment with these compounds reduced pro-inflammatory cytokines, IL-1β and IL-6. These partial reversal of senescence-associated features by rapamycin and NAM were associated with altered AMPK, mTORC1 and mTORC2 activity, and autophagy modulation. Short-term in vitro treatment with rapamycin and NAM can potentially yield high-quality autologous MSCs with improved functional characteristics, possibly improving clinical outcomes of cell-based therapies in the elderly population. These short-term in vitro findings require confirmation in further preclinical studies to assess long-term stability and in vivo relevance.

Keywords:  AMPK; Autophagy; Cell therapy; Mesenchymal stromal cell; Nicotinamide; Rapamycin; Regenerative medicine; mTOR

DOI:  https://doi.org/10.1038/s41598-026-58275-7
Clin Exp Med. 2026 Jul 03. pii: 247. [Epub ahead of print]26(1):

Silibinin promotes hepatocyte proliferation through PINK1/Parkin-mediated mitophagy to alleviate acetaminophen-induced liver injury.

Fengming Xu, Mohamed Albadry, Olaf Dirsch, Uta Dahmen.

  Acetaminophen (APAP) intoxication is a common cause of liver injury. Silibinin has demonstrated potent hepatoprotective properties. However, its underlying mechanisms in APAP-induced liver injury (AILI) remain unclear. Autophagy is a critical adaptive response in AILI, contributing to the clearance of damaged mitochondria and the attenuation of oxidative stress. Therefore, we focused primarily on investigating the role of autophagy in mediating the hepatoprotective effects of silibinin. The effects of silibinin were evaluated in both AML12 cells and a C57BL/6J mouse model of AILI. Both the in vitro and in vivo experiments comprised four groups: a control group, an AILI model group, a silibinin treatment group, and a silibinin plus autophagy inhibitor group using PINK1-siRNA in cell culture and 3-Methyladenine in the animal experiment. Following induction of the AILI model in mice with APAP at a dose of 300 mg/kg, the animals received the designated interventions for five consecutive days. Histopathological alterations were assessed using hematoxylin-eosin staining. Hepatocyte proliferation and apoptosis were evaluated using the CCK-8 assay and immunohistochemical staining for Ki-67 and cleaved caspase-3, respectively, as well as ELISA for Cyclin D1. Liver function was assessed by serum biochemical analysis of alanine aminotransferase, aspartate aminotransferase, total bilirubin, and albumin. Mitochondrial oxidative stress-related parameters, including superoxide dismutase and malondialdehyde, were measured using colorimetric assays. The expression of autophagy-related genes and proteins (PINK1, Parkin, AMPK, LC3 and p62) was analyzed by quantitative PCR, immunofluorescence, and Western blotting. Transmission electron microscopy was employed to examine mitochondrial ultrastructure and the formation of autolysosomes in mouse liver tissue. In AML12 cells, silibinin mitigated AILI by activating the PINK1/Parkin pathway, thereby promoting mitophagy and enhancing cell proliferation. Co-treatment with autophagy inhibitor PINK1-siRNA attenuated these protective effects of silibinin. In AILI mice, silibinin treatment markedly improved liver function, attenuated inflammatory responses, restored mitochondrial function, and enhanced hepatocyte proliferation. These improvements were associated with increased LC3-II expression and reduced p62 accumulation, indicating enhanced autophagic activity. Notably, the protective benefits of silibinin were significantly attenuated by the autophagy inhibitor 3-Methyladenine. Our findings suggest that silibinin protects against AILI by activating PINK1/Parkin-dependent mitophagy, which mitigates oxidative stress and inflammation while promoting hepatocyte regeneration.

Keywords:  Acetaminophen-Induced Liver Injury; Autophagy; Hepatocyte Proliferation; Mitophagy; Silibinin

DOI:  https://doi.org/10.1007/s10238-026-02218-z
JCI Insight. 2026 Jun 30. pii: e207998. [Epub ahead of print]

De novo VPS16 missense variant causes infantile-onset dystonia with defective autophagic flux.

Enrique Gonzalez Saez-Diez, Xutong Xue, Amy Tam, Hyo-Min Kim, Siofra Carty, Joshua Rong, Monica Ferrer-Socorro, Kathryn Yang, Darius Ebrahimi-Fakhari.



Keywords:  Autophagy; Genetics; Movement disorders; Neurodevelopment; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.207998
Neurobiol Dis. 2026 Jun 28. pii: S0969-9961(26)00257-3. [Epub ahead of print]227 107512

GDAP1 orchestrates redox signaling at membrane contact sites to preserve axonal integrity in Charcot-Marie-Tooth disease.

Lara Cantarero, Mònica Roldán, María Rodríguez-Sanz, Angela J Mathison, Montserrat Olivares-Fuentes, Yaiza Díaz-Osorio, Jordi Pijuan, Marcos Frías, Raul Urrutia, Janet Hoenicka, Francesc Palau.

  Pathogenic variants in GDAP1 cause Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy characterized by progressive axonal degeneration. Although GDAP1 is an atypical glutathione S-transferase localized to the outer mitochondrial membrane, it has been proposed to function as a redox sensor that likely maintains inter-organelle communication in neurons. However, the mechanisms by which GDAP1 performs these functions remain unclear. To address this question, we here used a robust multi-tier approach that combines high-resolution and live-cell imaging with pH-sensitive probes, membrane contact sites (MCSs) analysis, lipid studies, transcriptomics, and nerve ultrastructural studies in both patient-derived fibroblasts and Gdap1-/- mice. We find that deletion of the GDAP1 gene induces localized pH and redox imbalances at mitochondria-lysosomes contact sites, which propagate to defective mitochondria-peroxisome interactions, impaired peroxisome biogenesis and morphology, leading to altered lipid homeostasis. These defects are accompanied by axonal organelle mislocalization, disruption of nodes of Ranvier, and structural abnormalities in peripheral nerves. Investigations on the potential reversibility of these processes, reveal that restoration of redox balance rescues MCS organization, identifying a therapeutically tractable MCS-peroxisome axis downstream of GDAP1. Together, our findings position GDAP1 as a redox-sensing organizer of mitochondrial membrane contact sites whose dysfunction triggers a cascade of organelle and axonal defects underlying CMT pathogenesis. Thus, this new knowledge should be taken into consideration in the future design of therapeutic interventions that can ameliorate the symptoms of this dismal disease.

Keywords:  Charcot-Marie-tooth disease; GDAP1; Lysosome; Membrane contact sites; Mitochondria; Node of Ranvier; Peroxisome

DOI:  https://doi.org/10.1016/j.nbd.2026.107512
bioRxiv. 2026 Jun 26. pii: 2026.06.22.733785. [Epub ahead of print]

Scaling of Neuronal Growth and Excitability Through Separable mTORC1 and mTORC2 Pathways.

Asan F Abdulkareem, Noah H Elste, Rain Younger, Mackenzi L Prina, Evan Dennis, Jessica Urbanczyk, Mohsen Bayat, Hassaan A Malik, Shahriar A Tafti, Hunter S Holoubek, Dylan Marchand, Karen E Beenken, Dennis W Province, Kristopher T Kahle, Matthew C Weston, Jeremy M Barry, Bryan W Luikart.

As neurons grow, they must regulate intrinsic excitability to maintain an appropriate level of spiking based on synaptic inputs. Using gene knockouts, phosphoproteomics, and electrophysiology we show PTEN regulates neuronal growth and intrinsic excitability through separable downstream mechanisms. Pten loss induces cellular hypertrophy, increased excitatory synaptic input, reduced fast afterhyperpolarization, and burst firing. Deleting the mTORC1 scaffold, Raptor, rescues overgrowth and synaptic input but fails to normalize firing, while deleting Akt or the mTORC2 scaffold, Rictor, restores firing without rescuing growth. This dissociation identifies an AKT-mTORC2 mechanism that regulates voltage-gated calcium and BK potassium channels to set spike repolarization and burst firing. In vivo , Pten knockout produces altered network synchrony, lethal seizures, and impaired object and location behavior; Raptor co-deletion display non-lethal hyperexcitability with improved object-location coupling. The biological and pathophysiological significance of these mechanisms is demonstrated by overlap of the PTEN-regulated phosphoproteome with ASD and epilepsy.

DOI: https://doi.org/10.64898/2026.06.22.733785
Int Immunopharmacol. 2026 Jun 30. pii: S1567-5769(26)00935-5. [Epub ahead of print]186 117089

GBA mutation exacerbates α-synuclein pathology with involvement of ROS and p38 MAPK signaling in Parkinson's disease.

Hong Xu, Yu-Ting Tang, Wei-Ling Dong, Man-Hua Liu, Fen Wang, Chun-Feng Liu, Ju-Ping Chen.

  The glucocerebrosidase (GBA) gene is the second most significant genetic risk factor for Parkinson's disease (PD) pathogenesis. Notably, GBA mutations not only enhance PD susceptibility in the general population but also accelerate disease progression. Nevertheless, the precise molecular mechanisms underlying GBA-associated PD pathogenesis remain elusive. In this study, we demonstrated that the L444P mutation in GBA significantly impairs the enzymatic activity of its encoded protein, glucocerebrosidase (GCase). It caused lysosomal dysfunction and increased α-synuclein (α-syn) expression and aggregation induced by α-syn preformed fibril (PFF). Mechanistically, our data revealed that the L444P GBA mutation increased reactive oxygen species (ROS) levels associated with activation of the p38 MAPK signaling pathway. Importantly, pharmacological inhibition of p38 MAPK pathway can change consistent with altered autophagic degradation and reduce PFF-induced α-syn aggregation, which is exacerbated by the L444P GBA mutation. These findings suggest that inhibiting p38 signaling provides a mechanistic rationale for targeting this pathway in GBA-associated PD.

Keywords:  Alpha-synuclein; GBA L444P; Lysosomal dysfunction; Parkinson's disease; p38 MAPK

DOI:  https://doi.org/10.1016/j.intimp.2026.117089
Elife. 2026 Jul 01. pii: e82205. [Epub ahead of print]15

Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses during inflammation.

Priyanka Gajwani, Li Wang, Koushik Debnath, Pierina Danos, Young-Mee Kim, Shubhi Srivastava, Zijing Ye, Sarah Krantz, Dongmei Wang, Chinnaswamy Tiruppathi, Peter T Toth, Sriram Ravindran, Jalees Rehman.

  Eukaryotic mitochondria are characterized by several features that represent vestiges of their prokaryotic ancestry. One such feature is the N-terminal formylation of proteins encoded by mitochondrial DNA that undergo translation by mitochondrial ribosomes. N-formylated proteins are also released by bacteria and trigger activation of immune cells such as neutrophils. Growing evidence indicates that circulating levels of mitochondrial formyl proteins are elevated in the serum of patients with excessive inflammatory responses. However, the mechanisms by which they are released into circulation are not known. In this study, we have identified vascular endothelial cells as a source of Pink1-dependent release of mitochondrial formyl proteins in response to inflammatory mediators. Mechanistically, the mitophagy mediator Pink1 is stabilized by inflammatory activation of endothelial cells, promoting mitophagy and mitochondrial formyl peptide release both in mice and primary human endothelial cells. Using nanoparticle delivery of Pink1-targeting sgRNA in mice expressing endothelial-specific Cas9, we developed a mouse model in which Pink1 is specifically depleted in the endothelium. Deletion of endothelial Pink1 decreased circulating formyl peptide levels, lowered lung neutrophil infiltration and reduced mortality in mice. We thus propose that endothelial cells upregulate pro-inflammatory mitophagy in response to inflammation, leading to the release of mitochondrial formyl peptides and detrimental neutrophil recruitment into the lung.

Keywords:  cell biology; human; immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.82205
Biochem Soc Trans. 2026 Jul 29. 54(7): 901-913

TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.

Eleni Christoforidou, Emily McFagan, Martha McLaughlin, Majid Hafezparast.

  Amyotrophic lateral sclerosis (ALS) is the most common form of adult-onset motor neuron disease, characterised by the degeneration of upper and lower motor neurons. The cytoplasmic aggregation of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein, is considered a hallmark of ALS pathology, found in nearly all postmortem cases of ALS. TDP-43 is normally primarily nuclear, where it has a widespread role in gene regulation. Mutations, extrinsic stressors, and alterations in RNA homeostasis in ALS lead to nuclear depletion of TDP-43 and the formation of cytosolic TDP-43 aggregates. This causes multiple downstream effects on neuronal function and degeneration as well as gene expression. TDP-43 is a promising target as a biomarker, as it is found to be elevated in the biofluids of ALS patients, and its cytoplasmic aggregation can also be observed in peripheral tissues; however, methodological variability and technical limitations currently preclude the establishment of TDP-43 as a standalone biomarker. There are also promising therapeutic strategies in development targeting TDP-43 pathology, but a critical challenge that remains is achieving a balance between eliminating toxic aggregates and preserving the essential functions of TDP-43. In summary, with further research, considering TDP-43 pathology in ALS gives hope for finding future novel diagnostics and therapeutics for ALS.

Keywords:  ALS; Amyotrophic Lateral Sclerosis; MND; Motor Neuron Disease; TARDBP; TDP-43

DOI:  https://doi.org/10.1042/BST20260896