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.

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.

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.

Two Forms of a Mitochondrial Endonuclease in Neurospora crassa

1975 ◽  
Vol 53 (7) ◽  
pp. 823-825 ◽  
Author(s):  
Charles E. Martin ◽  
Robert P. Wagner
Keyword(s):  
Molecular Weight ◽  
Neurospora Crassa ◽  
Mitochondrial Membrane ◽  
Nuclease Activity ◽  
Inner Mitochondrial Membrane ◽  
Detergent Treatment ◽  
Approximate Molecular Weight ◽  
Membrane Bound

Mitochondrial nuclease activity in Neurospora crassa occurs in membrane-bound and soluble forms in approximately equal proportions. These activities apparently are due to the same enzyme, which has an approximate molecular weight of 120 000. A portion of the insoluble enzyme appears to be associated with the inner mitochondrial membrane and is resistant to solubilization by detergent treatment as well as by physical disruption methods.

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 Bax and Bak Coalesce into Novel Mitochondria-Associated Clusters during Apoptosis

2001 ◽  
Vol 153 (6) ◽  
pp. 1265-1276 ◽  
Author(s):  
Amotz Nechushtan ◽  
Carolyn L. Smith ◽  
Itschak Lamensdorf ◽  
Soo-Han Yoon ◽  
Richard J. Youle
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Cluster Formation ◽  
Family Members ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Membranes ◽  
Mitochondrial Translocation ◽  
Novel Structure ◽  
Large Clusters ◽  
Confocal And Electron Microscopy

Bax is a member of the Bcl-2 family of proteins known to regulate mitochondria-dependent programmed cell death. Early in apoptosis, Bax translocates from the cytosol to the mitochondrial membrane. We have identified by confocal and electron microscopy a novel step in the Bax proapoptotic mechanism immediately subsequent to mitochondrial translocation. Bax leaves the mitochondrial membranes and coalesces into large clusters containing thousands of Bax molecules that remain adjacent to mitochondria. Bak, a close homologue of Bax, colocalizes in these apoptotic clusters in contrast to other family members, Bid and Bad, which circumscribe the outer mitochondrial membrane throughout cell death progression. We found the formation of Bax and Bak apoptotic clusters to be caspase independent and inhibited completely and specifically by Bcl-XL, correlating cluster formation with cytotoxic activity. Our results reveal the importance of a novel structure formed by certain Bcl-2 family members during the process of cell death.

scholarly journals Stilbene derivatives inhibit the activity of the inner mitochondrial membrane chloride channels

2007 ◽  
Vol 12 (4) ◽  
Author(s):  
Izabela Koszela-Piotrowska ◽  
Katarzyna Choma ◽  
Piotr Bednarczyk ◽  
Krzysztof Dołowy ◽  
Adam Szewczyk ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Mitochondrial Membrane ◽  
Disulfonic Acid ◽  
Mitochondrial Membranes ◽  
Rat Skeletal Muscle ◽  
Inner Mitochondrial Membrane ◽  
Stilbene Derivatives ◽  
Rat Heart Mitochondria

AbstractIon channels selective for chloride ions are present in all biological membranes, where they regulate the cell volume or membrane potential. Various chloride channels from mitochondrial membranes have been described in recent years. The aim of our study was to characterize the effect of stilbene derivatives on single-chloride channel activity in the inner mitochondrial membrane. The measurements were performed after the reconstitution into a planar lipid bilayer of the inner mitochondrial membranes from rat skeletal muscle (SMM), rat brain (BM) and heart (HM) mitochondria. After incorporation in a symmetric 450/450 mM KCl solution (cis/trans), the chloride channels were recorded with a mean conductance of 155 ± 5 pS (rat skeletal muscle) and 120 ± 16 pS (rat brain). The conductances of the chloride channels from the rat heart mitochondria in 250/50 mM KCl (cis/trans) gradient solutions were within the 70–130 pS range. The chloride channels were inhibited by these two stilbene derivatives: 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) and 4-acetamido-4′-isothiocyanostilbene-2,2′-disulfonic acid (SITS). The skeletal muscle mitochondrial chloride channel was blocked after the addition of 1 mM DIDS or SITS, whereas the brain mitochondrial channel was blocked by 300 μM DIDS or SITS. The chloride channel from the rat heart mitochondria was inhibited by 50–100 μM DIDS. The inhibitory effect of DIDS was irreversible. Our results confirm the presence of chloride channels sensitive to stilbene derivatives in the inner mitochondrial membrane from rat skeletal muscle, brain and heart cells.

scholarly journals Cardiolipin, Non-Bilayer Structures and Mitochondrial Bioenergetics: Relevance to Cardiovascular Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1721
Author(s):  
Edward S. Gasanoff ◽  
Lev S. Yaguzhinsky ◽  
Győző Garab
Keyword(s):  
Electron Transport Chain ◽  
Mitochondrial Membrane ◽  
Mitochondrial Bioenergetics ◽  
Mitochondrial Membranes ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Functional Roles ◽  
Transport Chain ◽  
Energy Converting

The present review is an attempt to conceptualize a contemporary understanding about the roles that cardiolipin, a mitochondrial specific conical phospholipid, and non-bilayer structures, predominantly found in the inner mitochondrial membrane (IMM), play in mitochondrial bioenergetics. This review outlines the link between changes in mitochondrial cardiolipin concentration and changes in mitochondrial bioenergetics, including changes in the IMM curvature and surface area, cristae density and architecture, efficiency of electron transport chain (ETC), interaction of ETC proteins, oligomerization of respiratory complexes, and mitochondrial ATP production. A relationship between cardiolipin decline in IMM and mitochondrial dysfunction leading to various diseases, including cardiovascular diseases, is thoroughly presented. Particular attention is paid to the targeting of cardiolipin by Szeto–Schiller tetrapeptides, which leads to rejuvenation of important mitochondrial activities in dysfunctional and aging mitochondria. The role of cardiolipin in triggering non-bilayer structures and the functional roles of non-bilayer structures in energy-converting membranes are reviewed. The latest studies on non-bilayer structures induced by cobra venom peptides are examined in model and mitochondrial membranes, including studies on how non-bilayer structures modulate mitochondrial activities. A mechanism by which non-bilayer compartments are formed in the apex of cristae and by which non-bilayer compartments facilitate ATP synthase dimerization and ATP production is also presented.

scholarly journals Protease OMA1 Modulates Mitochondrial Bioenergetics and Ultrastructure through Dynamic Association with MICOS Complex

2020 ◽  
Author(s):  
Martonio Ponte Viana ◽  
Roman M. Levytskyy ◽  
Ruchika Anand ◽  
Andreas S. Reichert ◽  
Oleh Khalimonchuk
Keyword(s):  
Mitochondrial Membrane ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Ultrastructure ◽  
Mitochondrial Membranes ◽  
Complex Dynamic ◽  
Contact Site ◽  
Outer Membranes ◽  
Mitochondrial Functions ◽  
Membrane Contacts ◽  
Dynamic Association

ABSTRACTRemodeling of mitochondrial ultrastructure is a complex dynamic process that is critical for a variety of mitochondrial functions and apoptosis. Although the key regulators of this process - mitochondrial contact site and cristae junction organizing system (MICOS) and GTPase Optic Atrophy 1 (OPA1) have been characterized, the mechanisms behind this regulation remain incompletely defined. Here, we found that in addition to its role in mitochondrial division, metallopeptidase OMA1 is required for maintenance of contacts between the inner and outer membranes through a dynamic association with MICOS. This association is independent of OPA1, appears to be mediated via the MICOS subunit MIC60, and is important for stability of MICOS machinery and the inner-outer mitochondrial membrane contacts. We find that OMA1-MICOS relay is required for stability of respiratory supercomplexes, optimal bioenergetic output in response to cellular insults, and apoptosis. Loss of OMA1 affects these activities; remarkably it can be partially compensated for by an artificial MICOS-emulating tether protein that bridges the inner and outer mitochondrial membranes. Our data show that OMA1-mediated support of mitochondrial ultrastructure is required for maintenance of mitochondrial architecture and bioenergetics under both basal and homeostasis-challenging conditions, and suggest a previously unrecognized role for this protease in mitochondrial physiology.

scholarly journals Structural studies of thyroid peroxidase show the monomer interacting with autoantibodies in thyroid autoimmune disease

2019 ◽  
Author(s):  
Daniel E. Williams ◽  
Sarah N. Le ◽  
David E. Hoke ◽  
Peter G. Chandler ◽  
Monika Gora ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Thyroid Peroxidase ◽  
Autoimmune Thyroid Diseases ◽  
Autoimmune Thyroid ◽  
Structural Characterisation ◽  
Negative Stain ◽  
Thyroid Autoimmune Disease ◽  
Negative Stain Electron Microscopy ◽  
Membrane Bound ◽  
Dynamics Simulations

AbstractThyroid peroxidase (TPO) is a critical membrane-bound enzyme involved in the biosynthesis of multiple thyroid hormones, and is a major autoantigen in autoimmune thyroid diseases such as Graves’ disease and Hashimoto’s thyroiditis. Here we report the biophysical and structural characterisation of two novel TPO constructs containing only the ectodomain of TPO and lacking the propeptide. Both constructs were enzymatically active and able to bind the patient-derived TR1.9 autoantibody. Analytical ultra-centrifugation data suggests that TPO can exist as both a monomer and a dimer. Combined with negative stain electron microscopy and molecular dynamics simulations, these data show that TR1.9 autoantibody preferentially binds the TPO monomer, revealing conformational changes that bring together previously disparate residues into a continuous epitope. In addition to providing plausible structural models of a TPO-autoantibody complex, this study provides validated TPO constructs that will facilitate further characterization, and advances our understanding of the structural, functional and antigenic characteristics of TPO, a molecule behind some of the most common autoimmune diseases.

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