Sequestration of SerRS through LLPS Impairs Localized Translation and Contributes to Antibiotic Persistence

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Abstract Antibiotic-tolerant persisters contribute to the emergence of resistance, posing a significant challenge efficacy antibiotic therapies. Despite extensive research, mechanisms underlying persistence remain inadequately understood. By tracking evolution exponential-phase bacterial populations subjected intermittent high-dose ertapenem exposure, we characterized evolved strains in terms tolerance. Mutant strains, harboring mutations seryl-tRNA synthetase gene ( serS) , exhibited abrupt growth arrest upon serine depletion during exponential growth, resembling phenotype induced by hydroxamate (SHX). Under starvation, mutated SerRS protein was sequestrated into liquid-liquid phase separation (LLPS)-driven condensates, disrupting their composition and impairing localized translation. This event precipitated dormancy SerS T strain, triggering persistence. Our findings reveal an unrecognized role for aminoacyl-tRNA synthetases (aaRSs) modulating condensates provide insights molecular Graphic abstract Recruitment Disrupts Localized Translation DeaD-marked Condensates. Upon partitions LLPS-driven translation activity suggesting arising phase. These evolutionarily conserved orchestrate robust program enable stress responses instruct cell fate decisions populations.

Language: Английский

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Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases

Frontiers in Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: Jan. 14, 2025

Mitochondria and lysosomes are critical for neuronal homeostasis, as highlighted by their dysfunction in various neurological diseases. Recent studies have identified dynamic membrane contact sites between mitochondria lysosomes, independent of mitophagy the lysosomal degradation mitochondrial-derived vesicles (MDVs), allowing bidirectional crosstalk these cell compartments, regulation organelle networks, substance exchanges. Emerging evidence suggests that abnormalities mitochondria-lysosome (MLCSs) contribute to diseases, including Parkinson’s disease, Charcot–Marie-Tooth (CMT) storage epilepsy. This article reviews recent research advances regarding tethering processes, regulation, function MLCSs role

Language: Английский

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Multi-organelle-mediated mRNA localization in neurons and links to disease

Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 92, P. 102332 - 102332

Published: March 7, 2025

Brain function requires precise spatiotemporal regulation of the neuronal proteome. To allow adaptation proteome in distal outposts neurons, mRNAs are transported into neurites for localized translation. This mRNA localization and local translation is crucial neuron maintenance, dysregulation these processes can contribute to neurological disease. Recently, organelles have emerged as key players regulating dendrites axons. In this review, we discuss current evidence open questions organelle-mediated localization. We highlight an emerging model which multiple create orchestrate a subcellular microenvironment that support selective seems essential maintaining organellar health, mutations many involved proteins lead various disorders.

Language: Английский

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TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

ABSTRACT Monogenic pediatric neurodegenerative disorders can reveal fundamental cellular mechanisms that underlie selective neuronal vulnerability. TBCK-Encephaloneuronopathy (TBCKE) is a rare autosomal recessive disorder caused by stop-gain variants in the TBCK gene. Clinically, patients show evidence of profound neurodevelopmental delays, but also symptoms progressive encephalopathy and motor neuron disease. Yet, physiological role protein remains unclear. We report human TBCKE model, derived from iPSCs homozygous for Boricua variant (p.R126X). Using unbiased proteomic analyses neurons, we find interacts with PPP1R21, C12orf4, Cryzl1, consistent being part FERRY mRNA transport complex. Loss leads to depletion C12ORF4 levels across multiple cell types, suggesting may play regulating at least some members preferentially, not exclusively, localizes surface endolysosomal vesicles colocalize lysosomes. Furthermore, TBCK-deficient neurons have reduced content axonal compartment relative soma. lysosomal dynein/dynactin adapter JIP4, which functionally exhibiting striking retrograde trafficking defects. Hence, our work reveals mediate mRNA, particularly along lysosomes compartments. TBCK-deficiency compartment-specific defects likely contribute preferential susceptibility neurodegeneration.

Language: Английский

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Intranasally Delivered Echinacoside Micelles Modulate Mitochondrial Fusion Against Postoperative Cognitive Dysfunction

Advanced Functional Materials, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

Abstract The disruption of mitochondrial homeostasis in neurons accounts for the onset and progression postoperative cognitive dysfunction (POCD). Echinacoside (ECH) can facilitate fusion to mediate neuroprotection, but its therapeutic efficacy is greatly limited by inefficient brain accumulation neuronal delivery. Herein, ECH‐encapsulated micelles are constructed from copolymer containing poly(carboxybetaine methacrylate) (PCBMA) block phenylboronic acid (PBA)‐modified poly(dimethylamino)ethyl methacrylate block, which mediates effective, brain‐targeted delivery via intranasal administration. In POCD mice, efficiently penetrate nasal mucosa betaine structure PCBMA that be recognized betaine‐GABA transporter 1 (BGT‐1) on epithelial cells, followed into hippocampus through submucosal olfactory trigeminal nerve pathways. Subsequently, internalized BGT‐1‐mediated endocytosis. over‐produced reactive oxygen species inside trigger dissociation ECH release, thereby inducing enhance neuron survival, ameliorate cerebral microenvironment, restore memory functions. This study reports a non‐invasive strategy overcome physiological barriers against drug renders profound implications treatment.

Language: Английский

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FMRP gains mitochondrial fission control

Nature Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 15, 2024

Language: Английский

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