scholarly journals Mdm38 interacts with ribosomes and is a component of the mitochondrial protein export machinery

2006 ◽  
Vol 172 (4) ◽  
pp. 553-564 ◽  
Author(s):  
Ann E. Frazier ◽  
Rebecca D. Taylor ◽  
David U. Mick ◽  
Bettina Warscheid ◽  
Nadine Stoepel ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Protein Transport ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Complex Iii ◽  
Minor Role ◽  
Central Component ◽  
Inner Membrane ◽  
Mitochondrial Ribosomes ◽  
A Minor

Saccharomyces cerevisiae Mdm38 and Ylh47 are homologues of human Letm1, a protein implicated in Wolf-Hirschhorn syndrome. We analyzed the function of Mdm38 and Ylh47 in yeast mitochondria to gain insight into the role of Letm1. We find that mdm38Δ mitochondria have reduced amounts of certain mitochondrially encoded proteins and low levels of complex III and IV and accumulate unassembled Atp6 of complex V of the respiratory chain. Mdm38 is especially required for efficient transport of Atp6 and cytochrome b across the inner membrane, whereas Ylh47 plays a minor role in this process. Both Mdm38 and Ylh47 form stable complexes with mitochondrial ribosomes, similar to what has been reported for Oxa1, a central component of the mitochondrial export machinery. Our results indicate that Mdm38 functions as a component of an Oxa1-independent insertion machinery in the inner membrane and that Mdm38 plays a critical role in the biogenesis of the respiratory chain by coupling ribosome function to protein transport across the inner membrane.

scholarly journals The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis

2008 ◽  
Vol 183 (7) ◽  
pp. 1213-1221 ◽  
Author(s):  
Stephan Kutik ◽  
Michael Rissler ◽  
Xue Li Guan ◽  
Bernard Guiard ◽  
Guanghou Shui ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Respiratory Chain ◽  
Matrix Protein ◽  
Mitochondrial Protein ◽  
Pleiotropic Effects ◽  
Mitochondrial Matrix ◽  
Carrier Proteins ◽  
Inner Membrane ◽  
Mitochondrial Inner Membrane

The mitochondrial inner membrane contains different translocator systems for the import of presequence-carrying proteins and carrier proteins. The translocator assembly and maintenance protein 41 (Tam41/mitochondrial matrix protein 37) was identified as a new member of the mitochondrial protein translocator systems by its role in maintaining the integrity and activity of the presequence translocase of the inner membrane (TIM23 complex). Here we demonstrate that the assembly of proteins imported by the carrier translocase, TIM22 complex, is even more strongly affected by the lack of Tam41. Moreover, respiratory chain supercomplexes and the inner membrane potential are impaired by lack of Tam41. The phenotype of Tam41-deficient mitochondria thus resembles that of mitochondria lacking cardiolipin. Indeed, we found that Tam41 is required for the biosynthesis of the dimeric phospholipid cardiolipin. The pleiotropic effects of the translocator maintenance protein on preprotein import and respiratory chain can be attributed to its role in biosynthesis of mitochondrial cardiolipin.

scholarly journals MRPS25 mutations impair mitochondrial translation and cause encephalomyopathy

2019 ◽  
Vol 28 (16) ◽  
pp. 2711-2719 ◽  
Author(s):  
Enrico Bugiardini ◽  
Alice L Mitchell ◽  
Ilaria Dalla Rosa ◽  
Hue-Tran Horning-Do ◽  
Alan M Pitmann ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Protein ◽  
In Silico Analysis ◽  
Small Subunit ◽  
Mitochondrial Translation ◽  
Transgenic Expression ◽  
Mitochondrial Ribosomes ◽  
Mitochondrial Ribosome ◽  
Protein Components ◽  
Biochemical Analyses

Abstract Mitochondrial disorders are clinically and genetically heterogeneous and are associated with a variety of disease mechanisms. Defects of mitochondrial protein synthesis account for the largest subgroup of disorders manifesting with impaired respiratory chain capacity; yet, only a few have been linked to dysfunction in the protein components of the mitochondrial ribosomes. Here, we report a subject presenting with dyskinetic cerebral palsy and partial agenesis of the corpus callosum, while histochemical and biochemical analyses of skeletal muscle revealed signs of mitochondrial myopathy. Using exome sequencing, we identified a homozygous variant c.215C>T in MRPS25, which encodes for a structural component of the 28S small subunit of the mitochondrial ribosome (mS25). The variant segregated with the disease and substitutes a highly conserved proline residue with leucine (p.P72L) that, based on the high-resolution structure of the 28S ribosome, is predicted to compromise inter-protein contacts and destabilize the small subunit. Concordant with the in silico analysis, patient’s fibroblasts showed decreased levels of MRPS25 and other components of the 28S subunit. Moreover, assembled 28S subunits were scarce in the fibroblasts with mutant mS25 leading to impaired mitochondrial translation and decreased levels of multiple respiratory chain subunits. Crucially, these abnormalities were rescued by transgenic expression of wild-type MRPS25 in the mutant fibroblasts. Collectively, our data demonstrate the pathogenicity of the p.P72L variant and identify MRPS25 mutations as a new cause of mitochondrial translation defect.

scholarly journals Cl− concentration changes and desensitization of GABAA and glycine receptors

2011 ◽  
Vol 138 (6) ◽  
pp. 609-626 ◽  
Author(s):  
Urban Karlsson ◽  
Michael Druzin ◽  
Staffan Johansson
Keyword(s):  
Information Transfer ◽  
Critical Role ◽  
Minor Role ◽  
Current View ◽  
Glycine Receptors ◽  
Gaba A ◽  
Current Decay ◽  
Central Neurons ◽  
Concentration Changes ◽  
A Minor

Desensitization of ligand-gated ion channels plays a critical role for the information transfer between neurons. The current view on γ-aminobutyric acid (GABA)A and glycine receptors includes significant rapid components of desensitization as well as cross-desensitization between the two receptor types. Here, we analyze the mechanism of apparent cross-desensitization between native GABAA and glycine receptors in rat central neurons and quantify to what extent the current decay in the presence of ligand is a result of desensitization versus changes in intracellular Cl− concentration ([Cl−]i). We show that apparent cross-desensitization of currents evoked by GABA and by glycine is caused by changes in [Cl−]i. We also show that changes in [Cl−]i are critical for the decay of current in the presence of either GABA or glycine, whereas changes in conductance often play a minor role only. Thus, the currents decayed significantly quicker than the conductances, which decayed with time constants of several seconds and in some cells did not decay below the value at peak current during 20-s agonist application. By taking the cytosolic volume into account and numerically computing the membrane currents and expected changes in [Cl−]i, we provide a theoretical framework for the observed effects. Modeling diffusional exchange of Cl− between cytosol and patch pipettes, we also show that considerable changes in [Cl−]i may be expected and cause rapidly decaying current components in conventional whole cell or outside-out patch recordings. The findings imply that a reevaluation of the desensitization properties of GABAA and glycine receptors is needed.

scholarly journals Mitochondrial protein import: Mia40 facilitates Tim22 translocation into the inner membrane of mitochondria

2013 ◽  
Vol 24 (5) ◽  
pp. 543-554 ◽  
Author(s):  
Lidia Wrobel ◽  
Agata Trojanowska ◽  
Malgorzata E. Sztolsztener ◽  
Agnieszka Chacinska
Keyword(s):  
Disulfide Bonds ◽  
Protein Import ◽  
Noncovalent Interactions ◽  
Mitochondrial Protein ◽  
Central Component ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
Inner Membrane ◽  
Oxidative Folding ◽  
Mitochondrial Intermembrane Space

The mitochondrial intermembrane space assembly (MIA) pathway is generally considered to be dedicated to the redox-dependent import and biogenesis of proteins localized to the intermembrane space of mitochondria. The oxidoreductase Mia40 is a central component of the pathway responsible for the transfer of disulfide bonds to intermembrane space precursor proteins, causing their oxidative folding. Here we present the first evidence that the function of Mia40 is not restricted to the transport and oxidative folding of intermembrane space proteins. We identify Tim22, a multispanning membrane protein and core component of the TIM22 translocase of inner membrane, as a protein with cysteine residues undergoing oxidation during Tim22 biogenesis. We show that Mia40 is involved in the biogenesis and complex assembly of Tim22. Tim22 forms a disulfide-bonded intermediate with Mia40 upon import into mitochondria. Of interest, Mia40 binds the Tim22 precursor also via noncovalent interactions. We propose that Mia40 not only is responsible for disulfide bond formation, but also assists the Tim22 protein in its integration into the inner membrane of mitochondria.

scholarly journals Loss of CCR5 results in glucose intolerance in diet-induced obese mice

2013 ◽  
Vol 305 (7) ◽  
pp. E897-E906 ◽  
Author(s):  
Arion Kennedy ◽  
Corey D. Webb ◽  
Andrea A. Hill ◽  
Marnie L. Gruen ◽  
Laurel G. Jackson ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cell ◽  
Critical Role ◽  
Cell Infiltration ◽  
Minor Role ◽  
Immune Cell Infiltration ◽  
T Cell Infiltration ◽  
Mild Reduction ◽  
Plasma Insulin Levels ◽  
A Minor

Macrophage and T cell infiltration into metabolic tissues contributes to obesity-associated inflammation and insulin resistance (IR). C-C chemokine receptor 5 (CCR5), expressed on macrophages and T cells, plays a critical role in the recruitment and activation of proinflammatory M1 and TH1 immune cells to tissues and is elevated in adipose tissue (AT) and liver of obese humans and mice. Thus, we hypothesized that deficiency of CCR5 would protect against diet-induced inflammation and IR. CCR5-deficient (CCR5−/−) mice and C57BL/6 (WT) controls were fed 10% low-fat (LF) or 60% high-fat (HF) diets for 16 wk. HF feeding increased adiposity, blood glucose, and plasma insulin levels equally in both genotypes. Opposing our hypothesis, HF-fed CCR5−/− mice were significantly more glucose intolerant than WT mice. In AT, there was a significant reduction in the M1-associated gene CD11c, whereas M2 associated genes were not different between genotypes. In addition, HF feeding caused a twofold increase in CD4+ T cells in the AT of CCR5−/− compared with WT mice. In liver and muscle, no differences in immune cell infiltration or inflammatory cytokine expression were detected. However, in AT and muscle, there was a mild reduction in insulin-induced phosphorylation of AKT and IRβ in CCR5−/− compared with WT mice. These findings suggest that whereas CCR5 plays a minor role in regulating immune cell infiltration and inflammation in metabolic tissues, deficiency of CCR5 impairs systemic glucose tolerance as well as AT and muscle insulin signaling.

scholarly journals Coi1 is a novel assembly factor of the yeast complex III–complex IV supercomplex

2017 ◽  
Vol 28 (20) ◽  
pp. 2609-2622 ◽  
Author(s):  
Ravi K. Singhal ◽  
Christine Kruse ◽  
Juliana Heidler ◽  
Valentina Strecker ◽  
Klaus Zwicker ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Protein ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Complex Iv ◽  
Reading Frame ◽  
Fermentative Growth ◽  
Assembly Factor ◽  
Steady State Levels ◽  
The Individual

The yeast bc1 complex (complex III) and cytochrome oxidase (complex IV) are mosaics of core subunits encoded by the mitochondrial genome and additional nuclear-encoded proteins imported from the cytosol. Both complexes build various supramolecular assemblies in the mitochondrial inner membrane. The formation of the individual complexes and their supercomplexes depends on the activity of dedicated assembly factors. We identified a so far uncharacterized mitochondrial protein (open reading frame YDR381C-A) as an important assembly factor for complex III, complex IV, and their supercomplexes. Therefore we named this protein Cox interacting (Coi) 1. Deletion of COI1 results in decreased respiratory growth, reduced membrane potential, and hampered respiration, as well as slow fermentative growth at low temperature. In addition, coi1Δ cells harbor reduced steady-state levels of subunits of complexes III and IV and of the assembled complexes and supercomplexes. Interaction of Coi1 with respiratory chain subunits seems transient, as it appears to be a stoichiometric subunit neither of complex III nor of complex IV. Collectively this work identifies a novel protein that plays a role in the assembly of the mitochondrial respiratory chain.

scholarly journals Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis

2020 ◽  
Vol 133 (14) ◽  
pp. jcs240374 ◽  
Author(s):  
Richard G. Lee ◽  
Junjie Gao ◽  
Stefan J. Siira ◽  
Anne-Marie Shearwood ◽  
Judith A. Ermer ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Stress Responses ◽  
Protein Complexes ◽  
Mitochondrial Protein ◽  
Mitochondrial Morphology ◽  
Mitochondrial Translation ◽  
Inner Membrane ◽  
Mitochondrial Ribosomes ◽  
Mitochondrial Inner Membrane ◽  
Mitochondrial Ribosome

ABSTRACTThe mitochondrial inner membrane contains a unique phospholipid known as cardiolipin (CL), which stabilises the protein complexes embedded in the membrane and supports its overall structure. Recent evidence indicates that the mitochondrial ribosome may associate with the inner membrane to facilitate co-translational insertion of the hydrophobic oxidative phosphorylation (OXPHOS) proteins into the inner membrane. We generated three mutant knockout cell lines for the CL biosynthesis gene Crls1 to investigate the effects of CL loss on mitochondrial protein synthesis. Reduced CL levels caused altered mitochondrial morphology and transcriptome-wide changes that were accompanied by uncoordinated mitochondrial translation rates and impaired respiratory chain supercomplex formation. Aberrant protein synthesis was caused by impaired formation and distribution of mitochondrial ribosomes. Reduction or loss of CL resulted in divergent mitochondrial and endoplasmic reticulum stress responses. We show that CL is required to stabilise the interaction of the mitochondrial ribosome with the membrane via its association with OXA1 (also known as OXA1L) during active translation. This interaction facilitates insertion of newly synthesised mitochondrial proteins into the inner membrane and stabilises the respiratory supercomplexes.

scholarly journals Saccharomyces cerevisiae Is Dependent on Vesicular Traffic between the Golgi Apparatus and the Vacuole When Inositolphosphorylceramide Synthase Aur1 Is Inactivated

2015 ◽  
Vol 14 (12) ◽  
pp. 1203-1216 ◽  
Author(s):  
Natalia S. Voynova ◽  
Carole Roubaty ◽  
Hector M. Vazquez ◽  
Shamroop K. Mallela ◽  
Christer S. Ejsing ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Protein Transport ◽  
Reactive Oxygen ◽  
Cytosolic Calcium ◽  
Minor Role ◽  
Vesicular Traffic ◽  
Vacuolar Acidification ◽  
Aureobasidin A ◽  
Vacuolar Protein ◽  
A Minor

ABSTRACTInositolphosphorylceramide (IPC) and its mannosylated derivatives are the only complex sphingolipids of yeast. Their synthesis can be reduced by aureobasidin A (AbA), which specifically inhibits the IPC synthase Aur1. AbA reportedly, by diminishing IPC levels, causes endoplasmic reticulum (ER) stress, an increase in cytosolic calcium, reactive oxygen production, and mitochondrial damage leading to apoptosis. We found that when Aur1 is gradually depleted by transcriptional downregulation, the accumulation of ceramides becomes a major hindrance to cell survival. Overexpression of the alkaline ceramidaseYPC1rescues cells under this condition. We established hydroxylated C26fatty acids as a reliable hallmark of ceramide hydrolysis. Such hydrolysis occurs only whenYPC1is overexpressed. In contrast, overexpression ofYPC1has no beneficial effect when Aur1 is acutely repressed by AbA. A high-throughput genetic screen revealed that vesicle-mediated transport between Golgi apparatus, endosomes, and vacuole becomes crucial for survival when Aur1 is repressed, irrespective of the mode of repression. In addition, vacuolar acidification becomes essential when cells are acutely stressed by AbA, and quinacrine uptake into vacuoles shows that AbA activates vacuolar acidification. The antioxidantN-acetylcysteine does not improve cell growth on AbA, indicating that reactive oxygen radicals induced by AbA play a minor role in its toxicity. AbA strongly induces the cell wall integrity pathway, but osmotic support does not improve the viability of wild-type cells on AbA. Altogether, the data support and refine current models of AbA-mediated cell death and add vacuolar protein transport and acidification as novel critical elements of stress resistance.

An invited article: Phonological recoding and reading acquisition

1983 ◽  
Vol 4 (2) ◽  
pp. 103-147 ◽  
Author(s):  
Anthony F. Jorm ◽  
David L. Share
Keyword(s):  
Phonological Processing ◽  
Word Identification ◽  
Critical Role ◽  
Minor Role ◽  
Phonological Recoding ◽  
Adult Reading ◽  
A Minor ◽  
Developmental Analysis ◽  
Teaching Implications

ABSTRACTPhonological recoding is commonly viewed as a back-up mechanism when word identification using the visual pathway fails. A second more important role for phonological recoding is as a self-teaching mechanism by which the child learns to identify words visually. Although phonological recoding may play a minor role in skilled adult reading, it plays a critical role in helping the child become a skilled reader. This article reviews the evidence relevant to these issues. The first section examines evidence on the role of phonological recoding in the development of word identification skills and reading comprehension. The next section reviews evidence showing that children with reading disabilities often have deficits in basic phonological processing skills. The third section deals with the nature of the reading problem in such children which, it is argued, is consistent with the proposed developmental analysis of the importance of phonological recoding in learning to read. The article concludes with a discussion of the teaching implications of these conclusions.

scholarly journals Gene expression during inactivity-induced muscle atrophy: effects of brief bouts of a forceful contraction countermeasure

2008 ◽  
Vol 105 (4) ◽  
pp. 1246-1254 ◽  
Author(s):  
Soo J. Kim ◽  
Roland R. Roy ◽  
Jung A. Kim ◽  
Hui Zhong ◽  
Fadia Haddad ◽  
...  
Keyword(s):  
High Resistance ◽  
Muscle Protein ◽  
Critical Role ◽  
Ring Finger ◽  
Specific Protein ◽  
Medial Gastrocnemius ◽  
Minor Role ◽  
Isometric Contractions ◽  
Adult Rats ◽  
A Minor

Anabolic and catabolic markers of muscle protein metabolism were examined in inactivity-induced atrophying muscles with and without daily short-duration, high-resistance isometric contractions. Inactivity was achieved via spinal cord isolation (SI), which results in near inactivity of the hindlimb musculature without compromising the motoneuron-muscle connectivity. Adult rats were assigned to a control (Con) or SI group in which one limb was stimulated (SI-Stim, 5 consecutive days of brief bouts of high-load isometric contractions) while the other served as a SI control (SI). Both the medial gastrocnemius (MG) and soleus weights (relative to body weight) were ∼71% of Con in the SI, but maintained at Con in the SI-Stim group. Activity of the IGF-1/phosphatidylinositol 3-kinase (PI3K)/Akt pathway of protein synthesis was similar among all groups in the MG. Expression of atrogin-1 and muscle RING finger-1 (MuRF-1), markers of protein degradation, were higher in the MG and soleus of the SI than Con and maintained at Con in the SI-Stim. Compared with Con, the anti-growth factor myostatin was unaffected in the MG and soleus in the SI but was lower in the MG of the SI-Stim. These results demonstrate that upregulation of specific protein catabolic pathways plays a critical role in SI-induced atrophy, while this response was blunted by 4 min of daily high-resistance electromechanical stimulation and was able to preserve most of the muscle mass. Although the protein anabolic pathway (IGF-1/PI3K/Akt) appears to play a minor role in regulating mass in the SI model, increased translational capacity may have contributed to mass preservation in response to isometric contractions.

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