Lysosomal storage disease proteo/lipidomic profiling using nMOST links ferritinophagy with mitochondrial iron deficiencies in cells lacking NPC2 DOI Creative Commons
Felix Kraus, Yuchen He, Sharan Swarup

et al.

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

Published: March 27, 2024

SUMMARY Lysosomal storage diseases (LSDs) comprised ∼50 monogenic characterized by the accumulation of cellular material in lysosomes and associated defects lysosomal function, but systematic molecular phenotyping is lacking. Here, we develop a nanoflow-based multi-omic single-shot technology (nMOST) workflow allowing simultaneously quantify HeLa cell proteomes lipidomes from more than two dozen LSD mutants, revealing diverse phenotypes. Defects delivery ferritin its autophagic receptor NCOA4 to (ferritinophagy) were pronounced NPC2 -/- cells, which correlated with increased lyso-phosphatidylcholine species multi-lamellar membrane structures visualized cryo-electron-tomography. Ferritinophagy loss mitochondrial cristae, MICOS-complex components, electron transport chain complexes rich iron-sulfur cluster proteins. Strikingly, alleviated when iron was provided through transferrin system. This resource reveals how function can impact homeostasis trans highlights nMOST as discovery tool for illuminating phenotypes across LSDs.

Language: Английский

Autophagy, aging, and age-related neurodegeneration DOI Creative Commons
Jennifer E. Palmer,

Niall Wilson,

Sung Min Son

et al.

Neuron, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance toxic proteins, proinflammatory molecules, dysfunctional organelles. inhibition also induces neuronal glial senescence, phenomenon occurs with increasing age non-diseased brains as well response to stresses. However, aging mutations impair autophagy. This creates potentially detrimental feedback loop whereby accumulation these disease-associated impairs their autophagic clearance, facilitating further aggregation. Thus, understanding how interacts aging, neurodegenerative diseases temporal, cellular, genetic context important for future clinical application autophagy-modulating therapies neurodegeneration.

Language: Английский

Citations

21
Two FAM134B isoforms differentially regulate ER dynamics during myogenesis DOI Creative Commons

Viviana Buonomo,

Kateryna Lohachova, Alessio Reggio

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: 44(4), P. 1039 - 1073

Published: Jan. 6, 2025

Language: Английский

Citations

3
Endoplasmic reticulum (ER) protein degradation by ER-associated degradation and ER-phagy DOI
Shuangcheng Alivia Wu,

Zexin Jason Li,

Ling Qi

et al.

Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

1
Lysosomal degradation of ER client proteins by ER-phagy and related pathways DOI Creative Commons
Carla Salomo-Coll, Natalia Jiménez-Moreno, Simon Wilkinson

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169035 - 169035

Published: Feb. 1, 2025

The endoplasmic reticulum (ER) is a major site of cellular protein synthesis. Degradation overabundant, misfolded, aggregating or unwanted proteins required to maintain proteostasis and avoid the deleterious consequences aberrant accumulation, at organismal level. While extensive research has shown an important role for proteasomally-mediated, ER-associated degradation (ERAD) in maintaining proteostasis, it becoming clear that there substantial lysosomal "client" from ER lumen membrane (ER-to-lysosome degradation, ERLAD). Here we provide brief overview broad categories ERLAD - predominantly ER-phagy (ER autophagy) pathways related processes. We collate client known date, either individual species proteins. Where known, summarise molecular mechanisms by which they are selected setting client(s) correct cell tissue function. Finally, highlight questions remain open this area.

Language: Английский

Citations

1
Fam134c and Fam134b shape axonal endoplasmic reticulum architecture in vivo DOI Creative Commons
Francescopaolo Iavarone, Marta Zaninello, Michela Perrone

et al.

EMBO Reports, Journal Year: 2024, Volume and Issue: 25(8), P. 3651 - 3677

Published: July 22, 2024

Abstract Endoplasmic reticulum (ER) remodeling is vital for cellular organization. ER-phagy, a selective autophagy targeting ER, plays an important role in maintaining ER morphology and function. The FAM134 protein family, including FAM134A, FAM134B, FAM134C, mediates ER-phagy. While FAM134B mutations are linked to hereditary sensory autonomic neuropathy humans, the physiological of other proteins remains unknown. To address this, we investigate roles using single combined knockouts (KOs) mice. Single KOs young mice show no major phenotypes; however, Fam134b Fam134c deletion ( Fam134b/c dKO ) , but not combination Fam134a deletion, leads rapid neuromuscular somatosensory degeneration, resulting premature death. loss motor axons peripheral nervous system. Long from exhibit expanded tubular with transverse ladder-like appearance, whereas obvious abnormalities present cortical ER. Our study unveils critical FAM134C formation network both neurons.

Language: Английский

Citations

4
Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST DOI Creative Commons
Felix Kraus, Yuchen He, Sharan Swarup

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(4)

Published: Jan. 22, 2025

Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping proteins and lipids is lacking. We present a nanoflow-based multiomic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between identified autophagy defects, notably accumulation ferritinophagy substrates receptors, especially NPC1 −/− NPC2 mutants, where lysosomes accumulate cholesterol. Autophagic endocytic cargo delivery failures correlated with elevated lysophosphatidylcholine species multilamellar structures visualized cryo–electron tomography. Loss mitochondrial cristae, MICOS complex components, OXPHOS components rich iron-sulfur cluster cells was largely alleviated when iron provided through transferrin system. This study reveals how lysosomal dysfunction affects homeostasis underscores nMOST as valuable discovery tool for identifying phenotypes across LSDs.

Language: Английский

Citations

0
EndoMAPV1, a Structural Protein Complex Landscape of Human Endosomes DOI Creative Commons
Miguel A. Gonzalez‐Lozano, E. Schmid, Enya Miguel Whelan

et al.

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

Published: Feb. 9, 2025

ABSTRACT Early/sorting endosomes are dynamic organelles that play key roles in proteome control by triaging plasma membrane proteins for either recycling or degradation the lysosome 1,2,3 . These events coordinated numerous transiently-associated regulatory complexes and integral components contribute to organelle identity during endosome maturation 4 While a subset of several hundred protein cargoes known associate with have been studied at biochemical and/or structural level, interaction partners higher order molecular assemblies many endosomal remain unknown. Here, we combine cross-linking native gel mass spectrometry 5-8 purified early AlphaFold 9,10 computational analysis create systematic human interactome. We present dozens models pairs supported experimental cross-links from their subcellular context, suggesting mechanisms previously reported processes. Using induced neurons, validate two candidate whose interactions crosslinks predictions: TMEM230 as subunit ATP8/11 lipid flippases 11 TMEM9/9B subunits CLCN3/4/5 chloride-proton antiporters 12 This resource its accompanying network viewer provide an framework understanding organellar interactomes large-scale validation predictions.

Language: Английский

Citations

0
How does autophagy impact neurological function? DOI Creative Commons
Angeleen Fleming, Ana López,

Matea Rob

et al.

The Neuroscientist, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Autophagies describe a set of processes in which cells degrade their cytoplasmic contents via various routes that terminate with the lysosome. In macroautophagy (the focus this review, henceforth autophagy), contents, including misfolded proteins, protein complexes, dysfunctional organelles, and pathogens, are captured within double membranes called autophagosomes, ultimately fuse lysosomes, after degraded. Autophagy is important maintaining neuronal glial function; consequently, disrupted autophagy associated neurologic diseases. This review provides broad perspective on roles CNS, highlighting recent literature furthers our understanding multifaceted role healthy nervous system.

Language: Английский

Citations

0
The life and times of brain autophagic vesicles DOI
Lisa Gambarotto, Erin Wosnitzka, Vassiliki Nikoletopoulou

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169105 - 169105

Published: March 1, 2025

Language: Английский

Citations

0
Autophagy, ER-phagy and ER dynamics during cell differentiation DOI Creative Commons
Michele Cillo,

Viviana Buonomo,

Anna Vainshtein

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169151 - 169151

Published: April 1, 2025

The endoplasmic reticulum (ER) is a multifunctional organelle essential for protein and lipid synthesis, ion transport inter-organelle communication. It comprises highly dynamic network of membranes that continuously reshape to support wide range cellular processes. During differentiation, extensive remodelling both ER architecture its proteome required accommodate alterations in cell morphology function. Autophagy, ER-phagy particular, plays pivotal role reshaping the ER, enabling cells meet their evolving needs adapt developmental cues. Despite ER's critical mechanisms responsible regulating dynamics are not fully understood. Emerging evidence suggests transcriptional post-translational regulation play fine-tuning unfolded response (UPR). This review explores molecular basis autophagy ER-phagy, highlighting during differentiation. A deeper understanding these processes could open new avenues targeted therapeutic approaches conditions where impaired.

Language: Английский

Citations

0