Pan-cellular organelles and suborganelles—from common functions to cellular diversity?

Genes & Development, Journal Year: 2024, Volume and Issue: 38(3-4), P. 98 - 114

Published: Feb. 1, 2024

Cell diversification is at the base of increasing multicellular organism complexity in phylogeny achieved during ontogeny. However, there are also functions common to all cells, such as cell division, migration, translation, endocytosis, exocytosis, etc. Here we revisit organelles involved functions, reviewing recent evidence unexpected differences proteins these organelles. For instance, centrosomes or mitochondria differ significantly their protein composition different, sometimes closely related, types. This has relevance for development and disease. Particularly striking high amount diversity RNA-binding other organelles, which brings us review RNA different suborganelles. We include a discussion about (sub)organelles nucleolus ribosomes, type-specific been reported. propose here that heterogeneity compartments represents novel mechanism regulating diversity. One reason can be multiplied by contributions distinct exemplified with moonlighting function. The specialized still perform pan-cellular but mode, discussed centrosomes, mitochondria, vesicles, These serve regulatory hubs storage transport specific functionally important regulators. In this way, they control differentiation, plasticity, survival. further examples highlighting disease examine many more types possible functional relevance.

Language: Английский

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Golgi-associated retrograde protein (GARP) complex-dependent endosomes to trans Golgi network retrograde trafficking is controlled by Rab4b

Cellular & Molecular Biology Letters, Journal Year: 2024, Volume and Issue: 29(1)

Published: April 16, 2024

Abstract Background The trafficking of cargoes from endosomes to the trans -Golgi network requires numerous sequential and coordinated steps. Cargoes are sorted into endosomal-derived carriers that transported, tethered, fused network. tethering step several complexes, including Golgi-associated retrograde protein complex, whose localization at is determined by activity small GTPases Arl Rab family. However, how complex recognizes endosome-derived will fuse with still unknown. Methods We studied using fluorescent in cells overexpressing Rab4b or after knocked-down interfering RNA combination downregulation subunits complex. used immunofluorescence image processing (Super Resolution Radial Fluctuation 3D reconstruction) as well biochemical approaches characterize consequences these interventions on cargo trafficking. Results reported VPS52 subunit an effector Rab4b. found overexpression wild type active increased early endosomal cation-independent mannose-6-phosphate receptor a complex-dependent manner. Conversely, inactive knockdown attenuated this In absence Rab4b, internalized mannose 6 phosphate did not have access VPS52-labeled structures look like subdomains and/or carriers, subcellular distribution Rab4b-independent. Consequently, was blocked no longer had Conclusion Our results support controlling sorting towards microdomains, confers directional specificity for en route Given importance endocytic recycling cell homeostasis, disruption Rab4b/Golgi-associated could serious pathologies.

Language: Английский

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ER-associated biogenesis of PINK1 preprotein for neuronal mitophagy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 24, 2024

Abstract A central role in mitochondrial quality control is played by the Parkinson-related kinase PINK1, whose mRNA transported neurons hitch- hiking. Using a live-cell imaging assay for translation of PINK1 precursor, we show that local requires concerted interplay between mitochondria and ER neurons. For efficient translation, Pink1 needs to relocate ribosomes located near endolysosomes ER. The membrane-tethered chaperone DNAJB6 then shields precursor on transit following ER-SURF pathway. Loss hence leads persistence ER/endolysosome-associated stores failure mitophagy upon damage.

Language: Английский

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Mitochondrial Dynamics and mRNA Translation: A Local Synaptic Tale

Biology, Journal Year: 2024, Volume and Issue: 13(9), P. 746 - 746

Published: Sept. 23, 2024

Mitochondria are dynamic organelles that can adjust and respond to different stimuli within a cell. This plastic ability allows them effectively coordinate several cellular functions in cells becomes particularly relevant highly complex such as neurons. An imbalance mitochondrial dynamics disrupt function, leading abnormal function ultimately range of diseases, including neurodegenerative disorders. Regulation mRNA transport local translation inside neurons is crucial for maintaining the proteome distal mitochondria, which vital energy production synaptic function. A significant portion axonal transcriptome dedicated mRNAs proteins, emphasizing importance sustaining areas far from cell body. In neurons, regulation encoding mitochondrial-shaping proteins could be essential plasticity neuronal health. The these mRNAs, their translation, may influence morphology thereby affecting overall status responsiveness synapses. Comprehending mitochondria-related well its on near synapses will help better understand physiology neurological diseases where dysfunction impaired play central role.

Language: Английский

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A Novel Human TBCK- Neuronal Cell Model Results in Severe Neurodegeneration and Partial Rescue with Mitochondrial Fission Inhibition

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Abstract Background and Objectives TBCK syndrome is a rare fatal pediatric neurodegenerative disease caused by biallelic loss-of-function mutations in the gene. Previous studies our lab others have implicated mTOR, autophagy, lysosomes, intracellular mRNA transport, however exact primary pathologic mechanism unknown. This gap has prevented development of targeted therapies. Methods We employed human neural progenitor cell line (NPC), ReNcell VM, which can differentiate into neurons astrocytes, to understand role mTORC1 activity neuronal autophagy cellular mechanisms pathology. used shRNA technology knockdown ReNcells. Results These data showed that loss did not inhibit neither NPC nor neurons. Additionally, analysis eight patient-derived cells knock down HeLa inhibition inconsistent across different patients types. ReNcells affected differentiation astrocytes. Specifically, defects are coupled cycle increased death during differentiation. RNAseq indicated downregulation several neurodevelopmental pathways. observed higher number LC3-positive vesicles soma neurites cells. Further, altered mitochondrial dynamics membrane potential NPC, found partial rescue with fission inhibitor mdivi- 1. Discussion work outlines new Human Cell Model for TBCK-related neurodegeneration essential health inhibitor. data, along illuminate provide possible novel therapeutic avenue patients.

Language: Английский

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