Glycerolipid Synthesis and Lipid Droplet Formation in the Endoplasmic Reticulum

Cold Spring Harbor Perspectives in Biology, Journal Year: 2022, Volume and Issue: 15(5), P. a041246 - a041246

Published: Sept. 12, 2022

Robert V. Farese Jr.1,2,3,4 and Tobias C. Walther1,2,3,4,5 1Department of Molecular Metabolism, Harvard T. H. Chan School Public Health, Boston, Massachusetts 02115, USA 2Department Cell Biology, Medical School, 3Broad Institute MIT, Cambridge, 02142, 4Center for Causes Prevention Cardiovascular Disease (CAP-CVD), 5Howard Hughes Correspondence: robert{at}hsph.harvard.edu, twalther{at}hsph.harvard.edu

Language: Английский

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CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Sept. 23, 2022

Myelin is required for rapid nerve signaling and emerging as a key driver of CNS plasticity disease. How myelin built remodeled remains fundamental question neurobiology. Central to myelination the ability oligodendrocytes add vast amounts new cell membrane, expanding their surface areas by many thousand-fold. However, how membrane build or remodel not fully understood. Here, we show that addition requires exocytosis mediated vesicular SNARE proteins VAMP2/3. Genetic inactivation VAMP2/3 in myelinating caused severe hypomyelination premature death without overt loss oligodendrocytes. Through live imaging, discovered VAMP2/3-mediated drives expansion within sheaths initiate wrapping power sheath elongation. In conjunction with expansion, mass spectrometry oligodendrocyte revealed incorporates axon-myelin adhesion are collectively form nodes Ranvier. Together, our results demonstrate indispensable formation, uncovering cellular pathway could sculpt patterns response activity-dependent signals be therapeutically targeted promote regeneration

Language: Английский

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Nutrient-regulated control of lysosome function by signaling lipid conversion

Cell, Journal Year: 2023, Volume and Issue: 186(24), P. 5328 - 5346.e26

Published: Oct. 25, 2023

Lysosomes serve dual antagonistic functions in cells by mediating anabolic growth signaling and the catabolic turnover of macromolecules. How these janus-faced activities are regulated response to cellular nutrient status is poorly understood. We show here that lysosome morphology function reversibly controlled a nutrient-regulated lipid switch triggers conversion between peripheral motile mTOR complex 1 (mTORC1) signaling-active static mTORC1-inactive degradative lysosomes clustered at cell center. Starvation-triggered relocalization phosphatidylinositol 4-phosphate (PI(4)P)-metabolizing enzymes reshapes lysosomal surface proteome facilitate proteolysis repress mTORC1 signaling. Concomitantly, 3-phosphate (PI(3)P), which marks periphery, erased. Interference with this PI(3)P/PI(4)P module impairs adaptive altering supply. Our data unravel key for phosphoinositide metabolism rewiring organellar membrane dynamics status.

Language: Английский

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Integrative metabolomics science in Alzheimer’s disease: Relevance and future perspectives

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 89, P. 101987 - 101987

Published: June 19, 2023

Language: Английский

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Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 8, 2023

Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross outer membrane to support mitochondrial function, but how they do this is unclear. We identify Voltage Dependent Anion Channel (VDAC), an abundant protein, as a scramblase-type lipid transporter catalyzes entry. On reconstitution into vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation mechanism unrelated their channel activity. Coarse-grained molecular dynamics simulations reveal scrambling occurs at specific dimer interface where polar residues induce large water defects bilayer thinning. The rate phospholipid import yeast mitochondria order magnitude lower in absence VDAC homologs, indicating VDACs provide main pathway for Thus, isoforms, members superfamily beta barrel proteins, moonlight class scramblases - distinct from alpha-helical scramblase proteins act mitochondria.

Language: Английский

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Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C

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

Published: June 8, 2024

Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, bridge-like lipid transport protein and PD gene, sensor of stress/damage. Upon membrane perturbation, VPS13C rapidly relocates from the cytosol surface lysosomes where it tethers their membranes ER. This recruitment depends Rab7 requires signal at damaged releases an inhibited state which hinders access its VAB domain lysosome-bound Rab7. While another protein, LRRK2, also recruited stressed/damaged lysosomes, occurs much later stages by different mechanisms. Given VPS13 proteins bulk transport, these findings suggest delivery part early protective response damage.

Language: Английский

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Lipid scrambling is a general feature of protein insertases

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(17)

Published: April 15, 2024

Glycerophospholipids are synthesized primarily in the cytosolic leaflet of endoplasmic reticulum (ER) membrane and must be equilibrated between bilayer leaflets to allow ER membranes derived from it grow. Lipid equilibration is facilitated by integral proteins called “scramblases.” These feature a hydrophilic groove allowing polar heads lipids traverse hydrophobic interior, similar credit card moving through reader. Nevertheless, despite their fundamental role expansion dynamics, identity most scramblases has remained elusive. Here, combining biochemical reconstitution molecular dynamics simulations, we show that lipid scrambling general protein insertases, which insert polypeptide chains into organelles disconnected vesicle trafficking. Our data indicate occurs same channel insertion takes place abolished presence nascent chains. We propose insertases could have so-far-overlooked as scramblases.

Language: Английский

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Biological Polymers: Evolution, Function, and Significance

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

ConspectusA holistic description of biopolymers and their evolutionary origins will contribute to our understanding biochemistry, biology, the life, signatures life outside planet. While biopolymer sequences evolve through known Darwinian processes, backbones polypeptides, polynucleotides, polyglycans are less certain. We frame this topic two questions: (i) Do characteristics indicate origins? (ii) Are there reasonable mechanistic models such pre-Darwinian processes? To address these questions, we have established criteria distinguish chemical species produced by mechanisms from those formed nonevolutionary physical, chemical, or geological processes. compile evaluate properties shared all rather than isolating a single type. Polypeptide, polynucleotide, polyglycan kinetically trapped thermodynamically unstable in aqueous media. Each forms variety elaborate assemblies with diverse functions, phenomenon call polyfunction. backbone changes structure function upon subtle as reduction ribose change linkage site stereochemistry polymerized glucose, function-switching. Biopolymers display homo- heterocomplementarity, enabling atomic-level control function. Biopolymer access recalcitrant states, where assembly modulates kinetics thermodynamics hydrolysis. emergent; biological building blocks significantly polymerization. In cells, compose mutualistic networks; cell is an Amazon Jungle molecules. conclude that exhibit hallmarks evolution. Neither nor processes can produce molecules consistent observations. faced paradox evolution relies on evolved but cannot alter backbones. This constraint underlined observation across tree ribosomes everywhere always been composed RNA protein. Our data suggest Hadean Earth underwent non-Darwinian coevolution driven part hydrolytic stress, ultimately leading argue highly facilitated seamless transition model challenges convention, products direct prebiotic synthesis. conventional models, retain vestiges chemistry. findings, however, align iterative recursive sculpting, selection, exaptation. supports Orgel's "gloomy" prediction modern biochemistry has discarded But hope. believe progress during challenging exciting integration sciences theory. These efforts provide new perspectives deepen sciences. working definition continuous exploration spaces avoidance equilibrium. alignment model, observe complex mixtures undergoing wet-dry cycling, which does appear undergo while avoiding

Language: Английский

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Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 19, 2025

Abstract Mitochondrial dynamics are orchestrated by protein assemblies that directly remodel membrane structure, however the influence of specific lipids on these processes remains poorly understood. Here, using an inducible heterodimerization system to selectively modulate lipid composition outer mitochondrial (OMM), we show local production diacylglycerol (DAG) leads transient tubulation and rapid fragmentation network, which mediated isoforms endophilin B (EndoB) dynamin-related 1 (Drp1), respectively. Reconstitution experiments cardiolipin-containing templates mimicking planar constricted OMM topologies reveal DAG facilitates binding remodeling activities both EndoB Drp1, thereby independently potentiating fission events. Drp1 do not interact with each other, suggesting activates multiple pathways for in parallel. Together, our data emphasizes importance regulating dynamics.

Language: Английский

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Lipid scrambling is a general feature of protein insertases

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 1, 2023

Glycerophospholipids are synthesized primarily in the cytosolic leaflet of endoplasmic reticulum (ER) membrane and must be equilibrated between bilayer leaflets to allow ER membranes derived from it grow. Lipid equilibration is facilitated by integral proteins called "scramblases". These feature a hydrophilic groove allowing polar heads lipids traverse hydrophobic interior, similar credit-card moving through reader. Nevertheless, despite their fundamental role expansion dynamics, identity most scramblases has remained elusive. Here, combining biochemical reconstitution molecular dynamics simulations, we show that lipid scrambling general protein insertases, which insert polypeptide chains into organelles disconnected vesicle trafficking. Our data indicate occurs same channel insertion takes place, abolished presence nascent chains. We propose insertases could have so-far overlooked as scramblases.

Language: Английский

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