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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Insertases scramble lipids: Molecular simulations of MTCH2

Structure, Journal Year: 2024, Volume and Issue: 32(4), P. 505 - 510.e4

Published: Feb. 19, 2024

Scramblases play a pivotal role in facilitating bidirectional lipid transport across cell membranes, thereby influencing metabolism, membrane homeostasis, and cellular signaling. MTCH2, mitochondrial outer protein insertase, has membrane-spanning hydrophilic groove resembling those that form the transit pathway known scramblases. Employing both coarse-grained atomistic molecular dynamics simulations, we show MTCH2 significantly reduces free energy barrier for movement along therefore can indeed function as scramblase. Notably, scrambling rate of silico is similar to voltage-dependent anion channel (VDAC), recently discovered scramblase membrane, suggesting potential complementary physiological these proteins. Finally, our findings suggest other insertases which possess path like also

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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MTCH2 controls energy demand and expenditure to fuel anabolism during adipogenesis

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

Published: Jan. 3, 2025

Language: Английский

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Any1 is a phospholipid scramblase involved in endosome biogenesis

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(4)

Published: March 6, 2025

Endosomes are central organelles in the recycling and degradation of receptors membrane proteins. Once endocytosed, such proteins sorted at endosomes into intraluminal vesicles (ILVs). The resulting multivesicular bodies (MVBs) then fuse with lysosomes, leading to ILVs monomers. However, biogenesis MVBs requires a constant lipid supply for efficient ILV formation. An ER-endosome contact site has been suggested play critical role MVB biogenesis. Here, we identify Any1 as novel phospholipid scramblase, which functions transfer protein Vps13 We uncover that cycles between early Golgi colocalizes Vps13, possibly here-discovered potential droplets (LDs) endosomes. Strikingly, both required formation, presumably couple flux homeostasis during formation endosome maturation.

Language: Английский

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MTCH2 in Metabolic Diseases, Neurodegenerative Diseases, Cancers, Embryonic Development and Reproduction

Drug Design Development and Therapy, Journal Year: 2024, Volume and Issue: Volume 18, P. 2203 - 2213

Published: June 1, 2024

Mitochondrial carrier homolog 2 (MTCH2) is a member of the solute 25 family, located on outer mitochondrial membrane. MTCH2 was first identified in 2000. The development research rapidly increasing. most well-known role linking to pro-apoptosis BID facilitate apoptosis. Genetic variants have been investigated for their association with metabolic and neurodegenerative diseases, however, no intervention or therapeutic suggestions were provided. Recent studies revealed physiological pathological function cancers, embryonic reproduction via regulating apoptosis, shift between glycolysis oxidative phosphorylation, fusion/fission, epithelial-mesenchymal transition, etc. This review endeavors assess total 131 published articles summarise structure physiological/pathological MTCH2, which has not previously conducted. concludes that plays crucial reproduction, predominant molecular mechanism regulation function. gives comprehensive state current knowledgement will promote MTCH2.

Language: Английский

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MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion

EMBO Reports, Journal Year: 2023, Volume and Issue: 25(1), P. 45 - 67

Published: Dec. 14, 2023

Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet differential contribution each these proteins less understood. Mitochondrial carrier homolog (MTCH2) also plays a role in fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent proposedly modulating phospholipid lysophosphatidic acid (LPA), which synthesized glycerol-phosphate acyl transferases (GPATs) endoplasmic reticulum (ER) OMM. Here we report that requires MFN1 to enforce fusion fragmentation caused loss can be specifically counterbalanced MFN2 not MFN1, partially independent GTPase activity localization. Pharmacological inhibition GPATs (GPATi) or silencing ER-resident suppresses MFN2's ability compensate for MTCH2. Loss either MTCH2, MFN2, GPATi does impair stress-induced whereas combined does. Taken together, unmask two cooperative mechanisms sustain fusion.

Language: Английский

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Its own architect: Flipping cardiolipin synthase

Science Advances, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 3, 2025

Current dogma assumes that lipid asymmetry in biological membranes is actively maintained and dispensable for cell viability. The inner (cytoplasmic) membrane (IM) of Escherichia coli asymmetric. However, the molecular mechanism maintains this uneven distribution unknown. We engineered a conditionally lethal phosphatidylethanolamine (PE)–deficient mutant which presence cardiolipin (CL) on periplasmic leaflet IM essential viability, revealing provides CL desired IM. synthase (ClsA) flips its catalytic cytoplasmic domain upon depletion PE to supply nonbilayer-prone In physiological amount PE, osmotic down-shock induces topological inversion ClsA, establishing relevance protein reorientations wild-type cells. These findings support flippase-less maintaining biogenic by self-organization lipid-synthesizing enzyme.

Language: Английский

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Mitochondrial Sorting and Assembly Machinery: Chaperoning a Moonlighting Role?

Biochemistry, Journal Year: 2025, Volume and Issue: 64(2), P. 312 - 328

Published: Jan. 4, 2025

The mitochondrial outer membrane (OMM) β-barrel proteins link the mitochondrion with cytosol, endoplasmic reticulum, and other cellular membranes, establishing homeostasis. Their active insertion assembly in is achieved an energy-independent yet highly effective manner by Sorting Assembly Machinery (SAM) of OMM. core SAM constituent 16-stranded transmembrane Sam50. For over two decades, primary role Sam50 has been linked to its function as a chaperone OMM, wherein it assembles all β-barrels through lateral gating switching mechanism. Interestingly, recent studies have demonstrated that despite low copy number, performs various diverse functions beyond assembling β-barrels. This includes maintaining cristae morphology, bidirectional lipid shuttling between ER inner membrane, import select proteins, regulation PINK1-Parkin function, timed trigger cell death. Given these multifaceted critical regulatory across eukaryotes, we now reason merely moonlights hub for biogenesis indeed evolved array roles

Language: Английский

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Lipid Scrambling Pathways in the Sec61 Translocon Complex

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: May 5, 2025

Cellular homeostasis depends on the rapid, ATP-independent translocation of newly synthesized lipids across endoplasmic reticulum (ER) membrane. Lipid is facilitated by membrane proteins known as scramblases, a few which have recently been identified in ER. Our previous structure translocon-associated protein (TRAP) bound to Sec61 channel revealed local thinning, suggesting that Sec61/TRAP complex might be involved lipid scrambling. Using complementary fluorescence spectroscopy assays, we detected nonselective scrambling reconstituted translocon complexes. This activity was unaffected inhibitors block its lateral gate, second pathway within complex. Molecular dynamics simulations indicate trimeric TRAP subunit forms this alternative route, facilitating via "credit card" mechanism, using crevice lined with polar residues shield head groups from hydrophobic interior. Kinetic and thermodynamic analyses confirmed thinning enhances efficiency both scramble phosphatidylcholine faster than phosphatidylethanolamine phosphatidylserine, reflecting intrinsic flip-flop tendencies these species. As site lies gate region, it likely inaccessible during translocation, line our experiments Sec61-inhibited samples. Hence, findings suggest metazoan-specific bundle viable candidate for insensitive functional state translocon.

Language: Английский

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