High-energy demand and nutrient exhaustion in MTCH2 knockout cells DOI Creative Commons

Sabita Chourasia,

Christopher Petucci,

Hu Wang

et al.

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

Published: Dec. 16, 2023

Abstract Mitochondrial carrier homolog 2 (MTCH2) is a regulator of apoptosis, mitochondrial dynamics, and metabolism. Loss MTCH2 results in fragmentation, an increase whole-body energy utilization, protection from diet-induced obesity. We now show using temporal metabolomics that deletion high ATP demand, oxidized environment, lipid/amino acid/carbohydrate metabolism, the decrease many metabolites. Lipidomics analyses strategic adaptive membrane lipids storage knockout cells. Importantly, all metabolic changes cells were rescued by re-expression. Interestingly, this imbalance metabolism reductive potential triggered MTCH2-deletion inhibits adipocyte differentiation, consuming biosynthetic process. In summary, loss demand triggers catabolic oxidizing which fails to fuel anabolic processes during differentiation.

Language: Английский

Pragmatic Coarse-Graining of Proteins: Models and Applications DOI
Luís Borges-Araújo, Ilias Patmanidis, Akhil Pratap Singh

et al.

Journal of Chemical Theory and Computation, Journal Year: 2023, Volume and Issue: 19(20), P. 7112 - 7135

Published: Oct. 3, 2023

The molecular details involved in the folding, dynamics, organization, and interaction of proteins with other molecules are often difficult to assess by experimental techniques. Consequently, computational models play an ever-increasing role field. However, biological processes involving large-scale protein assemblies or long time scale dynamics still computationally expensive study atomistic detail. For these applications, employing coarse-grained (CG) modeling approaches has become a key strategy. In this Review, we provide overview what call pragmatic CG models, which strategies combining, at least part, physics-based implementation top-down approach their parametrization. particular, focus on most residues represented two beads, allowing retain some degree chemical specificity. A description main modern is provided, including review recent applications outlook future perspectives

Language: Английский

Citations

48
Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase DOI Creative Commons
Helene Jahn,

Ladislav Bartoš,

Grace I. Dearden

et al.

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

Citations

32
Insertases scramble lipids: Molecular simulations of MTCH2 DOI Creative Commons

Ladislav Bartoš,

Anant K. Menon, Robert Vácha

et al.

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

Citations

14
Lipid scrambling is a general feature of protein insertases DOI Creative Commons
Dazhi Li, Cristian Rocha‐Roa,

Matthew A. Schilling

et al.

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

Citations

13
A spatiotemporal proteomic map of human adipogenesis DOI Creative Commons
Felix Klingelhuber, Scott Frendo‐Cumbo, Muhmmad Omar‐Hmeadi

et al.

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(5), P. 861 - 879

Published: April 2, 2024

White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic disorders; however, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, we generate a spatiotemporal proteomic atlas human adipogenesis, which elucidates remodelling well spatial reorganization pathways to optimize cells for lipid accumulation highlights coordinated regulation protein localization abundance adipocyte formation. We identify compartment-specific levels changes enzymes reprogramme branched-chain amino acids one-carbon metabolism provide building blocks reduction equivalents. Additionally, C19orf12 differentiation-induced droplet that interacts translocase outer membrane complex droplet-associated mitochondria regulates storage determining capacity metabolize fatty acids. Overall, our study provides comprehensive resource understanding future discoveries field.

Language: Английский

Citations

12
MTCH2 in Metabolic Diseases, Neurodegenerative Diseases, Cancers, Embryonic Development and Reproduction DOI Creative Commons
Xiaoqing Peng, Yuanyuan Yang,

Ruirui Hou

et al.

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

Citations

5
Endoplasmic Reticulum Membrane Homeostasis and the Unfolded Protein Response DOI
Robert Ernst, Mike F. Renne, Aamna Jain

et al.

Cold Spring Harbor Perspectives in Biology, Journal Year: 2024, Volume and Issue: 16(8), P. a041400 - a041400

Published: Jan. 22, 2024

Robert Ernst1,2, Mike F. Renne1,2, Aamna Jain1,2 and Alexander von der Malsburg1,2 1Medical Biochemistry Molecular Biology, Medical Faculty, Saarland University, 66421 Homburg, Germany 2Preclinical Center for Signaling (PZMS), Correspondence: robert.ernst{at}uks.eu

Language: Английский

Citations

4
Emerging functions of the mitochondria–ER–lipid droplet three‐way junction in coordinating lipid transfer, metabolism, and storage in cells DOI Creative Commons
Vera F. Monteiro-Cardoso, Francesca Giordano

FEBS Letters, Journal Year: 2024, Volume and Issue: 598(10), P. 1252 - 1273

Published: May 1, 2024

Over the past two decades, we have witnessed a growing appreciation for importance of membrane contact sites (CS) in facilitating direct communication between organelles. CS are tiny regions where membranes organelles meet but do not fuse and allow transfer metabolites organelles, playing crucial roles coordination cellular metabolic activities. The significant advancements imaging techniques molecular cell biology research revealed that more complex than what originally thought, as they extremely dynamic, can remodel their shape, composition, functions accordance with environmental changes occur Here, describe how recent studies led to identification three-way mitochondria-ER-lipid droplet discuss emerging these contacts maintaining lipid storage, homeostasis, balance. We also summarize properties key protein components localized at interface, special focus on proteins. Understanding tripartite is essential unraveling complexities inter-organelle cooperation within cells.

Language: Английский

Citations

4
Simulation-based survey of TMEM16 family reveals that robust lipid scrambling requires an open groove DOI Open Access
C. Stephens, Niek van Hilten,

Lisa Zheng

et al.

Published: Jan. 31, 2025

Biological membranes are complex and dynamic structures with different populations of lipids in their inner outer leaflets. The Ca 2+ -activated TMEM16 family membrane proteins plays an important role collapsing this asymmetric lipid distribution by spontaneously, bidirectionally, scrambling phospholipids between the two leaflets, which can initiate signaling alter physical properties membrane. While evidence shows that occur via open hydrophilic pathway (“groove”) spans membrane, it remains unclear if all members facilitate movement manner. Here we present a comprehensive computational study experimentally solved structures. We performed coarse-grained molecular dynamics (MD) simulations 27 from five under activating non-activating conditions, captured over 700 events aggregate. This enabled us to directly compare rates, mechanisms, protein-lipid interactions for fungal mammalian TMEM16s, both (Ca -bound) closed -free) conformations statistical rigor. show thin majority (>90%) occurs at groove only when TM4 TM6 have sufficiently separated. Surprisingly, also observed 60 occurred outside canonical groove, 90% took place dimer-dimer interface TMEM16s. new site suggests alternative mechanism absence groove.

Language: Английский

Citations

0
Simulation-based survey of TMEM16 family reveals that robust lipid scrambling requires an open groove DOI Open Access
C. Stephens, Niek van Hilten,

Lisa Zheng

et al.

Published: Jan. 31, 2025

Biological membranes are complex and dynamic structures with different populations of lipids in their inner outer leaflets. The Ca 2+ -activated TMEM16 family membrane proteins plays an important role collapsing this asymmetric lipid distribution by spontaneously, bidirectionally, scrambling phospholipids between the two leaflets, which can initiate signaling alter physical properties membrane. While evidence shows that occur via open hydrophilic pathway (“groove”) spans membrane, it remains unclear if all members facilitate movement manner. Here we present a comprehensive computational study experimentally solved structures. We performed coarse-grained molecular dynamics (MD) simulations 27 from five under activating non-activating conditions, captured over 700 events aggregate. This enabled us to directly compare rates, mechanisms, protein-lipid interactions for fungal mammalian TMEM16s, both (Ca -bound) closed -free) conformations statistical rigor. show thin majority (>90%) occurs at groove only when TM4 TM6 have sufficiently separated. Surprisingly, also observed 60 occurred outside canonical groove, 90% took place dimer-dimer interface TMEM16s. new site suggests alternative mechanism absence groove.

Language: Английский

Citations

0