scholarly journals Molecular mechanism of mitochondrial phosphatidate transfer by Ups1/Mdm35

2019 ◽  
Author(s):  
Jiuwei Lu ◽  
Kevin Chan ◽  
Leiye Yu ◽  
Jun Fan ◽  
Yujia Zhai ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Conformational Changes ◽  
Transfer Rate ◽  
Mitochondrial Membrane ◽  
Physiological Function ◽  
Bound State ◽  
Outer Mitochondrial Membrane ◽  
Structural Elements ◽  
Inner Mitochondrial Membrane ◽  
Dynamics Simulations

ABSTRACTCardiolipin plays many important roles for mitochondrial physiological function and is synthesized from phosphatidic acid (PA) at inner mitochondrial membrane (IMM). PA synthesized from endoplasmic reticulum needs to transfer to IMM via outer mitochondrial membrane (OMM). The transfer of PA between IMM and OMM is mediated by Ups1/Mdm35 protein family. Although there are many structures of this family available, the detailed molecular mechanism of how PA is transferred between membranes is yet unknown. Here, we report another crystal structures of Ups1/Mdm35 in the authentic monomeric apo state and the DHPA bound state. By combining subsequent all-atom molecular dynamics simulations, extensive structural comparisons and biophysical assays, we discovered the conformational changes of Ups1/Mdm35, identified key structural elements and residues during membrane binding and PA entry. We found the monomeric Ups1 on membrane is an important transit for the success of PA transfer, and the equilibrium between monomeric Ups1 and Ups1/Mdm35 complex on membrane affects the PA transfer rate and can be regulated by many factors including environmental pH.

scholarly journals Molecular mechanism of mitochondrial phosphatidate transfer by Ups1

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Jiuwei Lu ◽  
Chun Chan ◽  
Leiye Yu ◽  
Jun Fan ◽  
Fei Sun ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Mitochondrial Membrane ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Membranes ◽  
Inner Mitochondrial Membrane ◽  
Membrane Interaction ◽  
Detailed Mechanism ◽  
Physiological Regulator ◽  
Membrane Bound ◽  
Dynamics Simulations

AbstractCardiolipin, an essential mitochondrial physiological regulator, is synthesized from phosphatidic acid (PA) in the inner mitochondrial membrane (IMM). PA is synthesized in the endoplasmic reticulum and transferred to the IMM via the outer mitochondrial membrane (OMM) under mediation by the Ups1/Mdm35 protein family. Despite the availability of numerous crystal structures, the detailed mechanism underlying PA transfer between mitochondrial membranes remains unclear. Here, a model of Ups1/Mdm35-membrane interaction is established using combined crystallographic data, all-atom molecular dynamics simulations, extensive structural comparisons, and biophysical assays. The α2-loop, L2-loop, and α3 helix of Ups1 mediate membrane interactions. Moreover, non-complexed Ups1 on membranes is found to be a key transition state for PA transfer. The membrane-bound non-complexed Ups1/ membrane-bound Ups1 ratio, which can be regulated by environmental pH, is inversely correlated with the PA transfer activity of Ups1/Mdm35. These results demonstrate a new model of the fine conformational changes of Ups1/Mdm35 during PA transfer.

Relationships between mitochondrial outer membranes and agranular reticulum in nervous tissue: ultrastructural observations and a new interpretation

1980 ◽  
Vol 46 (1) ◽  
pp. 129-147
Author(s):  
J. Spacek ◽  
A.R. Lieberman
Keyword(s):  
Nervous Tissue ◽  
Mitochondrial Membrane ◽  
Nerve Cells ◽  
Outer Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Thin Sections ◽  
3 Dimensional ◽  
Outer Membranes ◽  
New Interpretation ◽  
In Cells

This study is concerned with extensions of the outer membranes of mitochondria in cells of nervous tissue, and with possible relationships between the extensions and the agranular reticulum. A variety of preparative techniques was applied to a large number of different central nervous tissues (CNS) and peripheral nervous tissues (PNS), using conventional thin sections, thicker sections (100 nm or more) and 3-dimensional reconstructions of serial thin sections. Extensions were commonly observed, particularly from the ends of longitudinally oriented mitochondria in axons and dendrites. Often these had the appearance of, and could be traced into apparent continuity with, adjacent elements of the agranular membrane. In addition to these apical tubular extensions, we also observed and reconstructed short lateral tubular or sac-like extensions and vesicular protrusions of the outer mitochondrial membrane. We discuss and discount the possibility that the extensions are artefacts, consider the structural and biochemical similarities between the outer mitochondrial membrane and agranular reticulum and propose that the outer mitochondrial is part of the agranular reticulum (or a specialized portion of the agranular reticulum). We suggest that the translocation of mitochondria in nerve cells, and probably in other cells as well, involves movement of the inner mitochondrial membrane and the enclosed matrix (mitoplast) within channels of agranular reticulum in continuity, or in transient continuity, with the outer mitochondrial membrane.

Synthesis of the inner mitochondrial membrane and the intercalation of respiratory enzymes during the cell cycle of Chlorella

1976 ◽  
Vol 21 (2) ◽  
pp. 329-340
Author(s):  
B.G. Forde ◽  
B.E. Gunning ◽  
P.C. John
Keyword(s):  
Cell Cycle ◽  
Succinate Dehydrogenase ◽  
Mitochondrial Membrane ◽  
Extended Period ◽  
Outer Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Chlorella Fusca ◽  
Respiratory Enzymes ◽  
Membrane Area ◽  
Enzyme Molecules

The ratio of inner to outer mitochondrial membrane area remains close to 1–8 throughout the cell cycle in synchronized cells of Chlorella fusca var, vacuolata 211-8p. Using estimates of this ratio, together with our previous estimates of mitochondrial surface area, to calculate the absolute area of inner mitochondrial membrane, it is demonstrated that growth of the inner mitochondrial membrane during the cell cycle occupies an extended period and parallels the growth of the whole cell. In contrast, the synthesis of succinate dehydrogenase and cytochrome oxidase is restricted to the last third of the cell cycle. It is concluded that mitochondrial growth involves the intercalation of periodically synthesized respiratory enzymes into membranes made earlier in the cycle, with consequent 5-fold changes in the density of active enzyme molecules in the membrane. These observations are discussed in relation to the control of mitochondiral membrane synthesis, membrane assembly and respiration rate during the cell cycle.

scholarly journals Molecular mechanism of depolarization-dependent inactivation in W366F mutant of Kv1.2

2018 ◽  
Author(s):  
H. X. Kondo ◽  
N. Yoshida ◽  
M. Shirota ◽  
K. Kinoshita
Keyword(s):  
Membrane Potential ◽  
Potassium Channels ◽  
Molecular Mechanism ◽  
Conformational Changes ◽  
Structural Changes ◽  
Membrane Depolarization ◽  
Potassium Ions ◽  
Selective Filter ◽  
Dependent Inactivation ◽  
Dynamics Simulations

ABSTRACTVoltage-gated potassium channels play crucial roles in regulating membrane potential. They are activated by membrane depolarization, allowing the selective permeation of potassium ions across the plasma membrane, and enter a nonconducting state after lasting depolarization of membrane potential, a process known as inactivation. Inactivation in voltage-activated potassium channels occurs through two distinct mechanisms, N-type inactivation and C-type inactivation. C-type inactivation is caused by conformational changes in the extracellular mouth of the channel, while N-type inactivation is elicited by changes in the cytoplasmic mouth of the protein. The W434F-mutated Shaker channel is known as a nonconducting mutant and is in a C-type inactivation state at a depolarizing membrane potential. To clarify the structural properties of C-type inactivated protein, we performed molecular dynamics simulations of the wild-type and W366F (corresponding to W434F in Shaker) mutant of the Kv1.2-2.1 chimera channel. The W366F mutant was in a nearly nonconducting state with a depolarizing voltage and recovered from inactivation with a reverse voltage. Our simulations and 3D-RISM analysis suggested that structural changes in the selective filter upon membrane depolarization trap potassium ions around the entrance of the selectivity filter and prevent ion permeation. This pore restriction is involved in the molecular mechanism of C-type inactivation.

scholarly journals Molecular Mechanism by Which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial Membrane

Toxins ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 425
Author(s):  
Feng Li ◽  
Indira H. Shrivastava ◽  
Paul Hanlon ◽  
Ruben K. Dagda ◽  
Edward S. Gasanoff
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanism ◽  
Atp Synthase ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Phospholipid Composition ◽  
Phospholipid Bilayer ◽  
Cobra Venom ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Membranes

Cardiotoxin CTII from Naja oxiana cobra venom translocates to the intermembrane space (IMS) of mitochondria to disrupt the structure and function of the inner mitochondrial membrane. At low concentrations, CTII facilitates ATP-synthase activity, presumably via the formation of non-bilayer, immobilized phospholipids that are critical in modulating ATP-synthase activity. In this study, we investigated the effects of another cardiotoxin CTI from Naja oxiana cobra venom on the structure of mitochondrial membranes and on mitochondrial-derived ATP synthesis. By employing robust biophysical methods including 31P-NMR and 1H-NMR spectroscopy, we analyzed the effects of CTI and CTII on phospholipid packing and dynamics in model phosphatidylcholine (PC) membranes enriched with 2.5 and 5.0 mol% of cardiolipin (CL), a phospholipid composition that mimics that in the outer mitochondrial membrane (OMM). These experiments revealed that CTII converted a higher percentage of bilayer phospholipids to a non-bilayer and immobilized state and both cardiotoxins utilized CL and PC molecules to form non-bilayer structures. Furthermore, in order to gain further understanding on how cardiotoxins bind to mitochondrial membranes, we employed molecular dynamics (MD) and molecular docking simulations to investigate the molecular mechanisms by which CTII and CTI interactively bind with an in silico phospholipid membrane that models the composition similar to the OMM. In brief, MD studies suggest that CTII utilized the N-terminal region to embed the phospholipid bilayer more avidly in a horizontal orientation with respect to the lipid bilayer and thereby penetrate at a faster rate compared with CTI. Molecular dynamics along with the Autodock studies identified critical amino acid residues on the molecular surfaces of CTII and CTI that facilitated the long-range and short-range interactions of cardiotoxins with CL and PC. Based on our compiled data and our published findings, we provide a conceptual model that explains a molecular mechanism by which snake venom cardiotoxins, including CTI and CTII, interact with mitochondrial membranes to alter the mitochondrial membrane structure to either upregulate ATP-synthase activity or disrupt mitochondrial function.

scholarly journals Energy Landscape of the Domain Movement in Staphylococcus aureus UDP-N-acetylglucosamine 2-epimerase

2019 ◽  
Author(s):  
Erika Chang de Azevedo ◽  
Alessandro S. Nascimento
Keyword(s):  
Staphylococcus Aureus ◽  
Conformational Changes ◽  
Energy Landscape ◽  
Teichoic Acid ◽  
Bound State ◽  
Wall Teichoic Acid ◽  
Antibiotic Resistant ◽  
Simulation Techniques ◽  
Dynamics Simulations ◽  
Healthcare Associated

AbstractStaphylococcus aureus is an important cause of resistant healthcare-associated infections. It has been shown that the Wall Teichoic Acid (WTA) may be an important drug target acting on antibiotic-resistant cells. The UDP-N-Acetylglucosamine 2-epimerase, MnaA, is one of the first enzymes on the pathway for the biosynthesis of the WTA. Here, detailed molecular dynamics simulations of S. aureus MnaA were used to characterize the conformational changes that occur in the presence of UDP and UDP-GlcNac and also the energetic landscape associated with these changes. Using different simulation techniques, such as ABMD and GAMD, it was possible to assess the energetic profile for the protein with and without ligands in its active site. We found that there is a dynamic energy landscape that has its minimum changed by the presence of the ligands, with a closed structure of the enzyme being more frequently observed for the bound state while the unbound enzyme favors an opened conformation. Further structural analysis indicated that positively charged amino acids associated with UDP and UDP-GlcNac interactions play a major role in the enzyme opening movement. Finally, the energy landscape profiled in this work provides important conclusions for the design of inhibitor candidates targeting S. aureus MnaA.

scholarly journals The GDP-Bound State of Mitochondrial Mfn1 Induces Membrane Adhesion of Apposing Lipid Vesicles through a Cooperative Binding Mechanism

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1085 ◽  
Author(s):  
Andrés Tolosa-Díaz ◽  
Víctor G. Almendro-Vedia ◽  
Paolo Natale ◽  
Iván López-Montero
Keyword(s):  
Membrane Fusion ◽  
Mitochondrial Membrane ◽  
Lipid Vesicles ◽  
Bound State ◽  
Cooperative Binding ◽  
Outer Mitochondrial Membrane ◽  
Binding Mechanism ◽  
Adhesion Forces ◽  
Gtp Hydrolysis ◽  
Membrane Adhesion

Mitochondria are double-membrane organelles that continuously undergo fission and fusion. Outer mitochondrial membrane fusion is mediated by the membrane proteins mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2), carrying a GTP hydrolyzing domain (GTPase) and two coiled-coil repeats. The detailed mechanism on how the GTP hydrolysis allows Mfns to approach adjacent membranes into proximity and promote their fusion is currently under debate. Using model membranes built up as giant unilamellar vesicles (GUVs), we show here that Mfn1 promotes membrane adhesion of apposing lipid vesicles. The adhesion forces were sustained by the GDP-bound state of Mfn1 after GTP hydrolysis. In contrast, the incubation with the GDP:AlF 4 − , which mimics the GTP transition state, did not induce membrane adhesion. Due to the flexible nature of lipid membranes, the adhesion strength depended on the surface concentration of Mfn1 through a cooperative binding mechanism. We discuss a possible scenario for the outer mitochondrial membrane fusion based on the modulated action of Mfn1.

scholarly journals SERS uncovers the link between conformation of cytochrome c heme and mitochondrial membrane potential

2021 ◽  
Author(s):  
Nadezda A. Brazhe ◽  
Evelina I. Nikelshparg ◽  
Adil A. Baizhumanov ◽  
Vera G. Grivennikova ◽  
Anna A. Semenova ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Conformational Changes ◽  
Mitochondrial Membrane ◽  
Atp Synthesis ◽  
Surface Enhanced Raman Spectroscopy ◽  
Complex Iii ◽  
Label Free ◽  
Inner Mitochondrial Membrane ◽  
The Impact

AbstractCytochrome c is an essential component of the electron transport chain (ETC), which regulates respiratory chain activity, oxygen consumption, and ATP synthesis. But the impact of conformational changes in cytochrome c on its function is not understood for lack of access to these changes in intact mitochondria. Here we describe a label-free tool that identifies conformational changes in cytochrome c heme and elucidates their function. We verify that molecule bond vibrations assessed by surface-enhanced Raman spectroscopy (SERS) is a reliable indicator of the planar heme configuration during activation of ETC and decrease in inner mitochondrial membrane potential. The planar conformation of cytochrome c heme enables its optimal orientation towards the heme of cytochrome c1 in complex III. This ensures a faster electron transfer, which is important during ETC speed-ups and acceleration of ATP synthesis. The ability of our tool to track mitochondrial function opens wide perspectives on cell bioenergetics.

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