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At least 415 records · Page 23Linked to original sources
PubMed2003

Tom40, the import channel of the mitochondrial outer membrane, plays an active role in sorting imported proteins.

The Translocase of the Outer Mitochondrial membrane (TOM complex) is centred on a channel, created by Tom40, serving as the only means of entry for proteins into the mitochondrion. Proteins destined for internal mitochondrial compartments interact subsequently with one of the two distinct protein Translocases of the Inner Mitochondrial membrane (TIM23 and TIM54 complexes) or follow specialized paths into the intermembrane space. To investigate the sorting of precursor proteins to these various sub-mitochondrial compartments, we created a library of tom40 mutants and screened for alleles selectively corrupt in protein sorting. One of the tom40 mutants, tom40-97, carries a single point mutation (W(243)R) resulting in an ineffective transfer of precursors to the TIM23 complex. There is no defect on transfer of precursors to the TIM54 complex or insertion of proteins into the outer membrane. The Tom40 channel is not a passive pore, but plays an active role in protein sorting for all sub-mitochondrial locations.

Amino Acid Sequence↗
PubMed2001

A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit of complex I abolishes assembly and activity of the complex in a patient with Leigh-like syndrome.

Sequence analysis of mitochondrial and nuclear candidate genes of complex I in children with deficiency of this complex and exhibiting Leigh-like syndrome has revealed, in one of them, a novel mutation in the NDUFS4 gene encoding the 18 kDa subunit. Phosphorylation of this subunit by cAMP-dependent protein kinase has previously been found to activate the complex. The present mutation consists of a homozygous G-->A transition at nucleotide position +44 of the coding sequence of the gene, resulting in the change of a tryptophan codon to a stop codon. Such mutation causes premature termination of the protein after only 14 amino acids of the putative mitochondrial targeting peptide. Fibroblast cultures from the patient exhibited severe reduction of the rotenone-sensitive NADH-->UQ oxidoreductase activity of complex I, which was insensitive to cAMP stimulation. Two-dimensional electrophoresis showed the absence of detectable normally assembled complex I in the inner mitochondrial membrane. These findings show that the expression of the NDUFS4 gene is essential for the assembly of a functional complex I.

Amino Acid Sequence↗
PubMed2001

Physiological basis for conservation of the signal recognition particle targeting pathway in Escherichia coli.

The Escherichia coli signal recognition particle (SRP) is a ribonucleoprotein complex that targets nascent inner membrane proteins (IMPs) to transport sites in the inner membrane (IM). Since SRP depletion only partially inhibits IMP insertion under some growth conditions, however, it is not clear why the particle is absolutely essential for viability. Insights into this question emerged from experiments in which we analyzed the physiological consequences of reducing the intracellular concentration of SRP below the wild-type level. We found that even moderate SRP deficiencies that have little effect on cell growth led to the induction of a heat shock response. Genetic manipulations that suppress the heat shock response were lethal in SRP-deficient cells, indicating that the elevated synthesis of heat shock proteins plays an important role in maintaining cell viability. Although it is conceivable that the heat shock response serves to increase the capacity of cells to target IMPs via chaperone-based mechanisms, SRP-deficient cells did not show an increased dependence on either GroEL or DnaK. By contrast, the heat shock-regulated proteases Lon and ClpQ became essential for viability when SRP levels were reduced. These results suggest that the heat shock response protects SRP-deficient cells by increasing their capacity to degrade mislocalized IMPs. Consistent with this notion, a model IMP that was mislocalized in the cytoplasm as the result of SRP depletion appeared to be more stable in a Deltalon DeltaclpQ strain than in control cells. Taken together, the data provide direct evidence that SRP is essential in E. coli and possibly conserved throughout prokaryotic evolution as well partly because efficient IMP targeting prevents a toxic accumulation of aggregated proteins in the cytoplasm.

ATP-Dependent Proteases↗
PubMed2005

Identification of an essential domain in the herpes simplex virus 1 UL34 protein that is necessary and sufficient to interact with UL31 protein.

Previous results have indicated that the herpes simplex virus 1 UL31 and UL34 proteins interact and form a complex at the inner nuclear membranes of infected cells, where both play important roles in the envelopment of nucleocapsids at the inner nuclear membrane. In the work described here, mapping studies using glutathione S-transferase pull-down assays indicated that amino acids 137 to 181 of the UL34 protein are sufficient to mediate an interaction with the UL31 protein. A recombinant virus (v3480) lacking UL34 codons 138 to 181 was constructed. Similar to a UL34 null virus, v3480 failed to replicate on Vero cells and grew to a limited extent on rabbit skin cells. A UL34-expressing cell line restored v3480 growth and plaque formation. Similar to the localization of UL31 protein in cells infected with a UL34 null virus, the UL31 protein was present in the nuclei of Hep2 cells infected with v3480. Hep2 cells infected with v3480 contained the UL34 protein in the cytoplasm, the nucleus, and the nuclear membrane, and this was noted to be similar to the appearance of cells infected with a UL31 null virus. In transient expression assays, the interaction between UL34 amino acids 137 to 181 and the UL31 protein was sufficiently robust to target green fluorescent protein and emerin to intranuclear sites that contained the UL31 protein. These data indicate that amino acids 137 to 181 of the UL34 protein are (i) sufficient to mediate interactions with the UL31 protein in vitro and in vivo, (ii) necessary for the colocalization of UL31 and UL34 in infected cells, and (iii) essential for normal viral replication.

Animals↗
PubMed1992

Antimitochondrial antibodies in primary biliary cirrhosis and other disorders: definition and clinical relevance.

The nine different antimitochondrial antibody specificities found in non-hepatic and hepatic disorders are described. Anti-M1 and anti-M7 antibodies are associated with infectious disorders such as syphilis or myocarditis. Anti-M3 and anti-M6 have been found in the course of a drug allergic disease due to Venocuran and iproniazid, and anti-M5 antibodies seem to occur occasionally in some forms of ANA-positive and ANA-negative collagen disorders. The M1- and M7-antigens are biochemically defined as cardiolipin and sarcosine dehydrogenase, respectively. Anti-M2, anti-M4, anti-M8, anti-M9 are associated with primary biliary cirrhosis (PBC). M2 was identified as alpha-ketoacid-dehydrogenase complex of the inner mitochondrial membrane, anti-M4 as sulfite oxidase, an enzyme of the mitochondrial intermembrane space, and anti-M9 as glycogen phosphorylase, a cytoplasmic enzyme. M8 copurifies with outer mitochondrial membranes derived from pig kidney. Anti-M9 can occur in the absence of anti-M2 while anti-M4 and anti-M8 are always associated with anti-M2. A progressive course of PBC can be predicted with high probability even at early stages of the disease when complement fixing antibodies against M2, M4 and/or M8 are present in patients' sera. In contrast, the presence of anti-M2/M9 antibodies heralds a benign course. The etiopathogenesis of PBC is still unknown. In PBC contact persons a strong stimulation of naturally occurring mitochondrial antibodies (NOMA) has been observed which was in contrast to the lack of this antibody type in PBC patients. Considering the generally accepted role of those antibodies in protecting individuals from infections, the failure of NOMA production may be a predisposing factor to acquire PBC more easily.

Autoantibodies↗
PubMed2003

AKAP149 is a novel PP1 specifier required to maintain nuclear envelope integrity in G1 phase.

Reassembly of the nuclear envelope (NE) at the end of mitosis requires targeting of the B-type lamin protein phosphatase, PP1, to the envelope by A-kinase anchoring protein AKAP149. We show here that NE-associated AKAP149 is a novel PP1-specifying subunit involved in maintaining nuclear architecture through G1 phase. PP1 remains associated with NE-bound AKAP149 during G1 but is released from AKAP149 upon S phase entry, as AKAP149 becomes serine-phosphorylated. NE-associated AKAP149 inhibits PP1 activity towards glycogen phosphorylase but enhances PP1 phosphatase activity towards B-type lamins, indicating that AKAP149 is a B-type lamin specifying subunit of PP1. In vivo dissociation of PP1 from NE-bound AKAP149 in G1-phase nuclei triggers phosphorylation and depolymerization of A- and B-type lamins. The lamins solubilize intranuclearly without affecting the inner nuclear membrane or pore complex distribution. This correlates with the induction of a G1 arrest and, ultimately, apoptosis. We propose that AKAP149-regulated PP1 activity at the NE during G1 is required to maintain nuclear integrity and cell survival.

A Kinase Anchor Proteins↗
PubMed1980

Paracrystalline arrays in atypical cristae and mitochondrial division.

Paracrystalline arrays in atypical cristae were observed in a few large mitochondria in the process of replication, in the follicular cell of the normal and gonadectomized rabbit thyroid gland. They were about 30 nm in diameter and spaced approximately 35-40 nm apart, and oblique sections showed parallel arrays which had a pitch of 25 nm. The number of inclusions varied in number and were similar to those reported in the normal follicular cell. The site of replication was often at the base of the mitochondrion and in some instances the continuity of the outer membrane was present. The helical nature of the inclusions suggests that they may be associated with the complex proteins of the inner mitochondrial membrane and space which have the capacity of helix formation. The cristae with the paracrystalline arrays appear to be in the orthodox configuration, a non-energized stage of the energy cycle. The mitochondria probably utilizes its unique ability to control respiration according to its functional requirement during replication.

Animals↗
PubMedDate not supplied

Diagnosis and treatment of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that predominantly occurs in middle-aged women of various ethnic and racial populations. The disease slowly progresses over decades and is supposed to be caused by immune reactions against host antigens. Histologically, it is characterized by inflammatory destruction of intrahepatic small bile ducts, subsequent fibrosis, and finally liver cirrhosis. It is more frequently diagnosed now than in the past probably because of a greater awareness of the disease. There is only week association of PBC with genetic markers. Liver function tests reveal an elevation of serum alkaline phosphatase and gamma-glutamyl transpeptidase levels with or without elevated aminotransferase levels. The hallmark of the disease is the presence of antimitochondrial antibodies (AMAs), which are found in 95% of patients with PBC. AMAs have been shown to be directed against the 2-oxo-acid dehydrogenase complexes located on the inner membrane of the mitochondria. However, AMA titers do not correlate with the disease severity of progression, and the role of AMAs in the pathogenesis of PBC has not been shown. The disease is frequently associated with other autoimmune diseases, including Sjögren's syndrome, scleroderma and thyroid disorders. Most therapeutic efforts have been directed at altering the immune response. Ursodeoxycholic acid (UDCA) appears to be effective therapy in preventing or delaying the need for liver transplantation and improving survival. However, a number of patients receiving UDCA still develop progressive disease and go on to transplantation, which is an effective therapy at the end stage of the disease. Various prognostic models have been proposed to estimate the survival probability and assist in the determination of the optimum timing of liver transplantation.

Autoantibodies↗
PubMed2001

Primary biliary cirrhosis: from induction to destruction.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that predominantly affects middle-aged women; fatigue and pruritus are the most common symptoms at presentation. Liver function tests are consistent with cholestasis and reveal an elevation of serum alkaline phosphatase and gamma-glutamyl transpeptidase with or without elevation of aminotransferase levels. Histologically, PBC is characterized by the destruction of the intrahepatic small bile ducts and subsequently fibrosis. The serological hallmark of the disease is the presence of antimitochondrial antibodies, which are found in 95% of patients with PBC. The antimitochondrial antibodies are directed against the 2-oxo-acid dehydrogenase complexes located on the inner membrane of the mitochondria. PBC generally slowly progresses, even over decades, and may lead to liver failure. In symptomatic patients, advanced age, elevated serum bilirubin levels, decreased serum albumin levels, and cirrhosis each correlate with shortened survival. Immunosuppressive and anti-inflammatory drugs have been used in the treatment of PBC based on the presumed autoimmune pathogenesis, but satisfactory agents leading to complete reversal or cure of the disease are not available. At present ursodeoxycholic acid appears to be the only effective therapy in preventing or delaying the need for liver transplantation and improving survival. However, a number of patients receiving ursodeoxycholic acid still develop progressive disease and require transplantation; transplantation is the only effective therapy at the end stage of the disease.

Adult↗
PubMed1994

Protoporphyrin IX, an endogenous ligand of the peripheral benzodiazepine receptor, potentiates induction of the mitochondrial permeability transition and the killing of cultured hepatocytes by rotenone.

The peripheral benzodiazepine receptor (PBzR) is associated with the outer mitochondrial membrane. Protoporphyrin IX (PPIX), an endogenous substance with high affinity for the PBzR, induced the inner membrane permeability transition (MPT) in respiring liver mitochondria de-energized by carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Cyclosporin A (CyA), an inhibitor of the permeability transition, prevented this effect. In cultured hepatocytes, the MPT was measured as an increased [3H]sucrose-accessible space sensitive to CyA. Nanomolar concentrations of PPIX potentiated the induction of the MPT and the extent of cell killing in hepatocyte cultures de-energized by rotenone. CyA prevented the enhanced cell killing by PPIX. PPIX did not increase the rate or extent of ATP depletion, the loss of the mitochondrial membrane potential, or the accumulation of long chain acyl-CoA thioesters. The association of the PBzR with the voltage-dependent anion channel of the outer mitochondrial membrane and with the adenine nucleotide carrier of the inner membrane suggests that this complex mediates the transport of PPIX across the mitochondrial membranes. In turn, this same complex participates in the MPT. Thus, the same structural complex (PBzR, voltage-dependent anion channel, and adenine nucleotide carrier) can interact with the endogenous substrate PPIX to result in different functional consequences depending on the state of mitochondrial energization.

Adenosine Triphosphate↗
PubMed1997

Multiantibiotic resistance caused by active drug extrusion in Pseudomonas aeruginosa and other gram-negative bacteria.

All living organisms have been exposed to noxious compounds throughout their long evolutionary history and those surviving have evolved to fabricate devices that detoxicate and extrude these life threatening substances. It is likely, therefore, that all viable organisms, from bacteria to mammals, are equipped with active extrusion machinery. When bacteria are attacked by antibiotics, they use these tactics to combat the drugs and to develop resistance. Drugs extrusion machinery in Gram-negative bacteria is complex, consisting of the inner membrane transporter which acts as an energy-dependent extrusion pump; a binding protein which presumably connect both membranes; and the outer membrane exit channel. The extrusion pump assemblies are often encoded by chromosomal genes and might be expressed by mutation(s) or induced in the presence of drug(s).

Anti-Bacterial Agents↗
PubMed1983

Dissociation of intermolecular linkages of the sperm head and tail by primary amines, aldehydes, sulphydryl reagents and detergents.

Primary amines, pyridoxal and thiols induced separation of the mammalian sperm head and tail at specific sites across the head-tail junction. Primary amines and pyridoxal induced head detachment by allowing separation of the inner and outer nuclear envelope membranes adjacent to the tail basal plates. This detachment was prevented by prior reduction with sodium cyanoborohydride. The chemistry of amine-induced head separation and the similar action of pyridoxal indicate that the head and tail are joined by Schiff bases formed between proteins within the nuclear membranes. Head detachment with thiols occurred at two sites: across the connecting filaments linking the basal plate and the capitulum of the tail-neck complex and between the inner nuclear membrane and the nuclear chromatin. Mammalian epididymal spermatozoa exhibited species differences in susceptibility to head detachment induced by hydromechanical shear. The heads of mouse epididymal spermatozoa readily separated from the tails during vortexing whereas those from the vas deferens were resistant to shear. Head separation occurred at the same site as induced by primary amines. Rabbit spermatozoa from all parts of the epididymis were resistant to mechanical shear. Species differences in the mechanical stability of the head-tail junction suggest that the intermolecular Schiff bases linking the head and tail can be formed before or during sperm transport in the epididymis and that their formation probably occurs after the appearance of the periodic structures which bridge the inner and outer membranes of the nucleus in the region of the tail basal plate.

Aldehydes↗
PubMed1994

The mitochondrial processing peptidase from potato: a self-processing enzyme encoded by two differentially expressed genes.

Cytochrome c reductase from potato is a bifunctional protein complex located in the inner mitochondrial membrane, which is involved in respiratory electron transport and processing of mitochondrial precursor proteins. The three largest subunits of the complex share the highest degree of sequence identity with the alpha- and beta-subunits of the soluble processing peptidase (MPP) from fungi and mammals. Evidence is provided that another substoichiometric polypeptide of the cytochrome c reductase complex resembles the alpha-subunit of MPP. A cDNA clone corresponding to the second alpha-MPP protein (alpha-II MPP) encodes a polypeptide of 504 amino acids which is 84% identical to alpha-I MPP. The two different alpha-MPP polypeptides have similar sizes on SDS-polyacrylamide gels but can be distinguished with an antibody raised against a decapeptide that is specific for alpha-II MPP. The presequences of both alpha-subunits of MPP are proteolytically removed by the integrated processing enzyme complex indicating that it acts on the targeting signals of its own precursor proteins. Gene-specific oligonucleotides reveal that the genes encoding alpha-subunit I and alpha-subunit II of MPP are differentially expressed in all tissues analysed but the transcript levels do not vary between tissues.

Amino Acid Sequence↗
PubMed2006

Respiratory chain supercomplexes in the plant mitochondrial membrane.

The intricate, heavily folded inner membrane of mitochondria houses the respiratory chain complexes. These complexes, together with the ATP synthase complex, are responsible for energy production, which is stored as ATP. The structure of the individual membrane-bound protein components has been well characterized. In particular, the use of Blue-native polyacrylamide gel electrophoresis has been instrumental in recent years in providing evidence that these components are organized into supercomplexes. Single particle electron microscopy studies have enabled a structural characterization of some of the mitochondrial supercomplexes. This has provided the opportunity to define a functional role for these supercomplexes for the first time, in particular for the dimeric ATP synthase complex, which appears to be responsible for the folding of the inner mitochondrial membrane.

Electron Transport↗
PubMed2005

A-type lamin complexes and regenerative potential: a step towards understanding laminopathic diseases?

The lamins are nuclear intermediate filament-type proteins forming the nuclear lamina meshwork at the inner nuclear membrane as well as complexes in the nucleoplasm. The recent discoveries that mutated A-type lamins and lamin-binding nuclear membrane proteins can be linked to numerous rare human diseases (laminopathies) affecting a multitude of tissues has changed the cell biologist's view of lamins as mere structural nuclear scaffold proteins. It is still unclear how mutations in these ubiquitously expressed proteins give rise to tissue-restricted pathological phenotypes. Potential disease models include mutation-caused defects in lamin structure and stability, the deregulation of gene expression, and impaired cell cycle control. This review brings together various previously proposed ideas and suggests a novel, more general, disease model based on an impairment of adult stem cell function and thus compromised tissue regeneration in laminopathic diseases.

Animals↗
PubMed2000

Membrane protein import in yeast mitochondria.

The protein import pathway that targets proteins to the mitochondrial matrix has been extensively characterized in the past 15 years. Variations of this import pathway account for the sorting of proteins to other compartments as well, but the insertion of integral inner membrane proteins lacking a presequence is mediated by distinct translocation machinery. This consists of a complex of Tim9 and Tim10, two homologous, Zn(2+)-binding proteins that chaperone the passage of the hydrophobic precursor across the aqueous intermembrane space. The precursor is then targeted to another, inner-membrane-bound, complex of at least five subunits that facilitates insertion. Biochemical and genetic experiments have identified the key components of this process; we are now starting to understand the molecular mechanism. This review highlights recent advances in this new membrane protein insertion pathway.

Biological Transport↗
PubMed1984

Relationship between lateral diffusion, collision frequency, and electron transfer of mitochondrial inner membrane oxidation-reduction components.

Fluorescence recovery after photobleaching was used to determine the diffusion coefficients of the oxidation-reduction (redox) components ubiquinone, complex III (cytochromes b-c1), cytochrome c, and complex IV (cytochrome oxidase) of the mitochondrial inner membrane. All redox components diffuse in two dimensions as common-pool electron carriers. Cytochrome c diffuses in two and three dimensions concomitantly, and its diffusion rate, unlike that of all other redox components, is modulated along with its activity by ionic strength. The diffusion coefficients established in this study reveal that the theoretical diffusion-controlled collision frequencies of all redox components are greater than their experimental maximum (uncoupled) turnover numbers. Since electron transport is slower than the theoretical limit set by the lateral diffusion of the redox components, ordered chains, assemblies, or aggregates of redox components are not necessary to account for electron transport. Rather, mitochondrial electron transport is diffusion coupled, consistent with a "random-collision model" for electron transport.

Animals↗
PubMed1975

Receptor synapses without synaptic ribbons in the cochlea of the cat.

This report describes recepto-neural junctions thought to be chemical synapses without synaptic ribbons or vesicle aggregates. Such synapses occur in the cat between the outer hair cells of the cochlea and auditory nerve fibers. These synapses are formed by flat or indented junctions having symmetric membrane complexes associated with smooth endoplasmic reticulum and coated vesicles in the outer hair cell cytoplasm. Inner hair cells have receptoneural junctions with asymmetric membrane complexes; synaptic ribbons and vesicles gather at one type of junction, while the other type associates with endoplasmic reticulum. Gap junctions are not seen at cochlear synapses but do link supporting cells. The results suggest that inner and outer hair cell synapses have different properties and raise questions about the role of synaptic vesicles and endoplasmic reticulum in the storage and release of transmitters.

Animals↗