scholarly journals The MICOS component Mic60 displays a conserved membrane-bending activity that is necessary for normal cristae morphology

2017 ◽  
Vol 216 (4) ◽  
pp. 889-899 ◽  
Author(s):  
Daryna Tarasenko ◽  
Mariam Barbot ◽  
Daniel C. Jans ◽  
Benjamin Kroppen ◽  
Boguslawa Sadowski ◽  
...  
Keyword(s):  
Binding Capacity ◽  
Transmembrane Helix ◽  
Lipid Binding ◽  
Membrane Curvature ◽  
Intermembrane Space ◽  
Contact Site ◽  
Cellular Physiology ◽  
The Matrix ◽  
Membrane Bending ◽  
Boundary Membrane

The inner membrane (IM) of mitochondria displays an intricate, highly folded architecture and can be divided into two domains: the inner boundary membrane adjacent to the outer membrane and invaginations toward the matrix, called cristae. Both domains are connected by narrow, tubular membrane segments called cristae junctions (CJs). The formation and maintenance of CJs is of vital importance for the organization of the mitochondrial IM and for mitochondrial and cellular physiology. The multisubunit mitochondrial contact site and cristae organizing system (MICOS) was found to be a major factor in CJ formation. In this study, we show that the MICOS core component Mic60 actively bends membranes and, when inserted into prokaryotic membranes, induces the formation of cristae-like plasma membrane invaginations. The intermembrane space domain of Mic60 has a lipid-binding capacity and induces membrane curvature even in the absence of the transmembrane helix. Mic60 homologues from α-proteobacteria display the same membrane deforming activity and are able to partially overcome the deletion of Mic60 in eukaryotic cells. Our results show that membrane bending by Mic60 is an ancient mechanism, important for cristae formation, and had already evolved before α-proteobacteria developed into mitochondria.

Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

2019 ◽  
Vol 2 (1) ◽  
pp. 44-66 ◽  
Author(s):  
Dun-Xian Tan ◽  
Russel. J. Reiter
Keyword(s):  
Ischemia Reperfusion ◽  
Surface Membrane ◽  
Strong Association ◽  
Membrane Receptors ◽  
Melatonin Receptors ◽  
Metabolic Enzyme ◽  
Intermembrane Space ◽  
Antitumor Effects ◽  
The Matrix ◽  
Surprising Discovery

     It was a surprising discovery when mitochondria, as the power houses of cells, were also found to synthesize the potent mitochondrial targeted antioxidant, melatonin. The melatonin synthetic enzyme serotonin N-acetyltransferase (SNAT) was found in matrix and also in the intermembrane space of mitochondria. We hypothesize that the melatonin synthesis occurs in the matrix due to substrate (N-acetyl co-enzyme A) availability while the intermembrane space may serve as the recycling pool of SNAT to regulate the melatonin circadian rhythm. Another surprise was that the melatonin membrane receptors, including MT1 and MT2, were also present in mitochondria. The protective effects of melatonin against neuronal injury induced by brain ischemia/reperfusion were proven to be mainly mediated by mitochondrial melatonin receptors rather than the cell surface membrane receptors which is contrary to the classical principle. In addition, melatonin metabolic enzyme has also been identified in the mitochondria. This enzyme can convert melatonin to N-acetylserotonin to strengthen the antitumor effects of melatonin. Thus, mitochondria are the generator, battle ground and metabolic sites of melatonin. The biological significance of the strong association between mitochondria and melatonin should be intensively investigated. 

Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

2019 ◽  
Vol 2 (1) ◽  
pp. 44-66 ◽  
Author(s):  
Dun-Xian Tan ◽  
Russel. J. Reiter
Keyword(s):  
Ischemia Reperfusion ◽  
Surface Membrane ◽  
Strong Association ◽  
Membrane Receptors ◽  
Melatonin Receptors ◽  
Metabolic Enzyme ◽  
Intermembrane Space ◽  
Antitumor Effects ◽  
The Matrix ◽  
Surprising Discovery

     It was a surprising discovery when mitochondria, as the power houses of cells, were also found to synthesize the potent mitochondrial targeted antioxidant, melatonin. The melatonin synthetic enzyme serotonin N-acetyltransferase (SNAT) was found in matrix and also in the intermembrane space of mitochondria. We hypothesize that the melatonin synthesis occurs in the matrix due to substrate (N-acetyl co-enzyme A) availability while the intermembrane space may serve as the recycling pool of SNAT to regulate the melatonin circadian rhythm. Another surprise was that the melatonin membrane receptors, including MT1 and MT2, were also present in mitochondria. The protective effects of melatonin against neuronal injury induced by brain ischemia/reperfusion were proven to be mainly mediated by mitochondrial melatonin receptors rather than the cell surface membrane receptors which is contrary to the classical principle. In addition, melatonin metabolic enzyme has also been identified in the mitochondria. This enzyme can convert melatonin to N-acetylserotonin to strengthen the antitumor effects of melatonin. Thus, mitochondria are the generator, battle ground and metabolic sites of melatonin. The biological significance of the strong association between mitochondria and melatonin should be intensively investigated. 

scholarly journals Presequence and mature part of preproteins strongly influence the dependence of mitochondrial protein import on heat shock protein 70 in the matrix.

1993 ◽  
Vol 123 (1) ◽  
pp. 119-126 ◽  
Author(s):  
W Voos ◽  
B D Gambill ◽  
B Guiard ◽  
N Pfanner ◽  
E A Craig
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Fusion Protein ◽  
Fusion Proteins ◽  
Dual Role ◽  
Intermembrane Space ◽  
Heme Binding ◽  
Membrane Translocation ◽  
Amino Terminal ◽  
The Matrix

To test the hypothesis that 70-kD mitochondrial heat shock protein (mt-hsp70) has a dual role in membrane translocation of preproteins we screened preproteins in an attempt to find examples which required either only the unfoldase or only the translocase function of mt-hsp70. We found that a series of fusion proteins containing amino-terminal portions of the intermembrane space protein cytochrome b2 (cyt. b2) fused to dihydrofolate reductase (DHFR) were differentially imported into mitochondria containing mutant hsp70s. A fusion protein between the amino-terminal 167 residues of the precursor of cyt. b2 and DHFR was efficiently transported into mitochondria independently of both hsp70 functions. When the length of the cyt. b2 portion was increased and included the heme binding domain, the fusion protein became dependent on the unfoldase function of mt-hsp70, presumably caused by a conformational restriction of the heme-bound preprotein. In the absence of heme the noncovalent heme binding domain in the longer fusion proteins no longer conferred a dependence on the unfoldase function. When the cyt. b2 portion of the fusion protein was less than 167 residues, its import was still independent of mt-hsp70 function; however, deletion of the intermembrane space sorting signal resulted in preproteins that ended up in the matrix of wild-type mitochondria and whose translocation was strictly dependent on the translocase function of mt-hsp70. These findings provide strong evidence for a dual role of mt-hsp70 in membrane translocation and indicate that preproteins with an intermembrane space sorting signal can be correctly imported even in mutants with severely impaired hsp70 function.

Computational studies of the mitochondrial carrier family SLC25. Present status and future perspectives

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Andrea Pasquadibisceglie ◽  
Fabio Polticelli
Keyword(s):  
Transport Mechanism ◽  
Experimental Studies ◽  
Intermembrane Space ◽  
Mitochondrial Carrier ◽  
Mitochondrial Homeostasis ◽  
The Matrix ◽  
Mitochondrial Carrier Family ◽  
Mitochondrial Intermembrane Space ◽  
Computational Analyses

Abstract The members of the mitochondrial carrier family, also known as solute carrier family 25 (SLC25), are transmembrane proteins involved in the translocation of a plethora of small molecules between the mitochondrial intermembrane space and the matrix. These transporters are characterized by three homologous domains structure and a transport mechanism that involves the transition between different conformations. Mutations in regions critical for these transporters’ function often cause several diseases, given the crucial role of these proteins in the mitochondrial homeostasis. Experimental studies can be problematic in the case of membrane proteins, in particular concerning the characterization of the structure–function relationships. For this reason, computational methods are often applied in order to develop new hypotheses or to support/explain experimental evidence. Here the computational analyses carried out on the SLC25 members are reviewed, describing the main techniques used and the outcome in terms of improved knowledge of the transport mechanism. Potential future applications on this protein family of more recent and advanced in silico methods are also suggested.

scholarly journals Protein-Lipid Interaction of Cytolytic Toxin Cyt2Aa2 on Model Lipid Bilayers of Erythrocyte Cell Membrane

Toxins ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 226
Author(s):  
Sudarat Tharad ◽  
Boonhiang Promdonkoy ◽  
José L. Toca-Herrera
Keyword(s):  
Lipid Bilayers ◽  
Erythrocyte Membrane ◽  
Hemolytic Activity ◽  
Membrane Lipids ◽  
Binding Capacity ◽  
Lipid Binding ◽  
Force Microscopy ◽  
Specific Effects ◽  
Atomic Force ◽  
Cytolytic Action

Cytolytic toxin (Cyt) is a toxin among Bacillus thuringiensis insecticidal proteins. Cyt toxin directly interacts with membrane lipids for cytolytic action. However, low hemolytic activity is desired to avoid non-specific effects in mammals. In this work, the interaction between Cyt2Aa2 toxin and model lipid bilayers mimicking the erythrocyte membrane was investigated for Cyt2Aa2 wild type (WT) and the T144A mutant, a variant with lower hemolytic activity. Quartz crystal microbalance with dissipation (QCM-D) results revealed a smaller lipid binding capacity for the T144A mutant than for the WT. In particular, the T144A mutant was unable to bind to the phosphatidylcholine lipid (POPC) bilayer. However, the addition of cholesterol (Chol) or sphingomyelin (SM) to the POPC bilayer promoted binding of the T144 mutant. Moreover, atomic force microscopy (AFM) images unveiled small aggregates of the T144A mutant on the 1:1 sphingomyelin/POPC bilayers. In contrast, the lipid binding trend for WT and T144A mutant was comparable for the 1:0.4 POPC/cholesterol and the 1:1:1 sphingomyelin/POPC/cholesterol bilayers. Furthermore, the binding of WT and T144A mutant onto erythrocyte cells was investigated. The experiments showed that the T144A mutant and the WT bind onto different areas of the erythrocyte membrane. Overall the results suggest that the T144 residue plays an important role for lipid binding.

scholarly journals Protein sorting between mitochondrial membranes specified by position of the stop-transfer domain.

1988 ◽  
Vol 106 (5) ◽  
pp. 1499-1505 ◽  
Author(s):  
M Nguyen ◽  
A W Bell ◽  
G C Shore
Keyword(s):  
G Protein ◽  
Simple Extension ◽  
Intermembrane Space ◽  
Mitochondrial Membranes ◽  
Inner Mitochondrial Membrane ◽  
The Matrix ◽  
Targeting Signal ◽  
Vesicular Stomatitis ◽  
Matrix Precursor ◽  
Identical Fashion

Recently, we fused a matrix-targeting signal to a large fragment of vesicular stomatitis virus G protein, which contains near its COOH-terminus a well-characterized endoplasmic reticulum (ER) stop-transfer sequence; the hybrid G protein was sorted to the inner mitochondrial membrane (Nguyen, M., and G. C. Shore. 1987. J. Biol. Chem. 262:3929-3931). Here, we show that the 19 amino acid G stop-transfer domain functions in an identical fashion when inserted toward the COOH-terminus of an otherwise normal matrix precursor protein, pre-ornithine carbamyl transferase; after import, the mutant protein was found anchored in the inner membrane via the stop-transfer sequence, with its NH2 terminus facing the matrix and its short COOH-terminal tail located in the intermembrane space. However, when the G stop-transfer sequence was placed near the NH2 terminus, the protein was inserted into the outer membrane, in the reverse orientation (NH2 terminus facing out, with a large COOH-terminal fragment located in the intermembrane space). These observations for mitochondrial topogenesis can be explained by a simple extension of existing models for ER sorting.

Chlorpromazine modulates the morphological macro- and microstructure of endothelial cells

2000 ◽  
Vol 278 (5) ◽  
pp. C873-C878 ◽  
Author(s):  
I. S. Hueck ◽  
H. G. Hollweg ◽  
G. W. Schmid-Schönbein ◽  
G. M. Artmann
Keyword(s):  
Endothelial Cells ◽  
Antipsychotic Agent ◽  
Membrane Curvature ◽  
Phospholipid Bilayer ◽  
Aortic Endothelial Cells ◽  
Bovine Aortic Endothelial Cells ◽  
Cellular Attachment ◽  
Transmission Electron ◽  
Membrane Adhesion ◽  
Membrane Bending

Chlorpromazine (CP), an amphipathic, antipsychotic agent, causes concave membrane bending in red blood cells with formation of stomatocytic shapes by modulation of the phospholipid bilayer. This study was designed to investigate the effects of CP on the shape of bovine aortic endothelial cells (BAEC) and their membranes in confluent monolayers with phase-contrast and transmission electron microscopy. Exposure of BAECs to nanomolar levels of CP leads to membrane curvature changes. With increasing CP concentrations, the membrane assumed a shape with enhanced numbers of intracellular caveolae and projection of pseudopodia at all junctions. At higher CP concentrations (up to 150 μM), the endothelial cells assumed almost spherical shapes. The evidence suggests that CP may affect lipid bilayer bending of BAECs in analogy with previous observations on erythrocytes, supporting the formation of caveolae and pseudopodia in BAECs due to the induction of concave membrane bending, as well as an effect on endothelial cell membrane adhesion at higher CP concentrations with loss of cellular attachment at junctions.

scholarly journals Mutational Analysis of the Saccharomyces cerevisiae Cytochrome c Oxidase Assembly Protein Cox11p

2006 ◽  
Vol 5 (3) ◽  
pp. 568-578 ◽  
Author(s):  
Graham S. Banting ◽  
D. Moira Glerum
Keyword(s):  
Hydrogen Peroxide ◽  
Cytochrome Oxidase ◽  
Solution Structure ◽  
Sinorhizobium Meliloti ◽  
Mutational Analysis ◽  
Intermembrane Space ◽  
Copper Binding ◽  
Inner Mitochondrial Membrane ◽  
The Matrix

ABSTRACT Cox11p is an integral protein of the inner mitochondrial membrane that is essential for cytochrome c oxidase assembly. The bulk of the protein is located in the intermembrane space and displays high levels of evolutionary conservation. We have analyzed a collection of site-directed and random cox11 mutants in an effort to further define essential portions of the molecule. Of the alleles studied, more than half had no apparent effect on Cox11p function. Among the respiration deficiency-encoding alleles, we identified three distinct phenotypes, which included a set of mutants with a misassembled or partially assembled cytochrome oxidase, as indicated by a blue-shifted cytochrome aa 3 peak. In addition to the shifted spectral signal, these mutants also display a specific reduction in the levels of subunit 1 (Cox1p). Two of these mutations are likely to occlude a surface pocket behind the copper-binding domain in Cox11p, based on analogy with the Sinorhizobium meliloti Cox11 solution structure, thereby suggesting that this pocket is crucial for Cox11p function. Sequential deletions of the matrix portion of Cox11p suggest that this domain is not functional beyond the residues involved in mitochondrial targeting and membrane insertion. In addition, our studies indicate that Δcox11, like Δsco1, displays a specific hypersensitivity to hydrogen peroxide. Our studies provide the first evidence at the level of the cytochrome oxidase holoenzyme that Cox1p is the in vivo target for Cox11p and suggest that Cox11p may also have a role in the response to hydrogen peroxide exposure.

scholarly journals Tim23–Tim50 pair coordinates functions of translocators and motor proteins in mitochondrial protein import

2009 ◽  
Vol 184 (1) ◽  
pp. 129-141 ◽  
Author(s):  
Yasushi Tamura ◽  
Yoshihiro Harada ◽  
Takuya Shiota ◽  
Koji Yamano ◽  
Kazuaki Watanabe ◽  
...  
Keyword(s):  
Motor Proteins ◽  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
Inner Membrane ◽  
The Matrix ◽  
General Protein ◽  
Mitochondrial Hsp70

Mitochondrial protein traffic requires coordinated operation of protein translocator complexes in the mitochondrial membrane. The TIM23 complex translocates and inserts proteins into the mitochondrial inner membrane. Here we analyze the intermembrane space (IMS) domains of Tim23 and Tim50, which are essential subunits of the TIM23 complex, in these functions. We find that interactions of Tim23 and Tim50 in the IMS facilitate transfer of precursor proteins from the TOM40 complex, a general protein translocator in the outer membrane, to the TIM23 complex. Tim23–Tim50 interactions also facilitate a late step of protein translocation across the inner membrane by promoting motor functions of mitochondrial Hsp70 in the matrix. Therefore, the Tim23–Tim50 pair coordinates the actions of the TOM40 and TIM23 complexes together with motor proteins for mitochondrial protein import.

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