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PubMed1996

From expressed sequence tags to peroxisome biogenesis disorder genes.

Isolation of human disease genes is a challenging process and can often only be achieved by labor-intensive positional cloning techniques. Fortunately, there are alternative strategies for isolation of peroxisome biogenesis disorder genes. The first, functional complementation, was established as a viable approach by Fujiki and colleagues, who identified PAF-1, the first known peroxisome biogenesis disorder gene. The second strategy, computer-based homology probing, relies on (1) the fact that peroxisome assembly has been conserved throughout the evolution of eukaryotes, (2) knowledge of the amino acid sequences of an increasing number of yeast peroxisome assembly (PAS) genes, and (3) the existence of sequence data from large numbers of human genes. The recent development of the expressed sequence tag (EST) database (dbEST) is fulfilling the last of these requirements. We have applied the homology probing strategy in the search for candidate genes for the peroxisome biogenesis disorders by routinely screening the database of ESTs for genes with significant sequence similarity to yeast PAS genes. The validity of this approach is demonstrated by its use in identifying PXR1 as the human orthologue of the Pichia pastoris PAS8 gene and PXAAA1 as a human homologue of the Pichia pastoris PAS5 gene. Furthermore, detailed analysis of PXR1 has revealed that mutations in this gene are responsible for complementation group 2 of the peroxisome biogenesis disorders. The demonstration that human homologues of yeast PAS genes exist and that mutations in these genes cause peroxisome biogenesis disorders demonstrates that yeast pas mutants are accurate and useful models for the analysis of these diseases.

Adenosine Triphosphate↗
PubMed2004

The usher N terminus is the initial targeting site for chaperone-subunit complexes and participates in subsequent pilus biogenesis events.

Pilus biogenesis on the surface of uropathogenic Escherichia coli requires the chaperone/usher pathway, a terminal branch of the general secretory pathway. In this pathway, periplasmic chaperone-subunit complexes target an outer membrane (OM) usher for subunit assembly into pili and secretion to the cell surface. The molecular mechanisms of protein secretion across the OM are not well understood. Mutagenesis of the P pilus usher PapC and the type 1 pilus usher FimD was undertaken to elucidate the initial stages of pilus biogenesis at the OM. Deletion of residues 2 to 11 of the mature PapC N terminus abolished the targeting of the usher by chaperone-subunit complexes and rendered PapC nonfunctional for pilus biogenesis. Similarly, an intact FimD N terminus was required for chaperone-subunit binding and pilus biogenesis. Analysis of PapC-FimD chimeras and N-terminal fragments of PapC localized the chaperone-subunit targeting domain to the first 124 residues of PapC. Single alanine substitution mutations were made in this domain that blocked pilus biogenesis but did not affect targeting of chaperone-subunit complexes. Thus, the usher N terminus does not function simply as a static binding site for chaperone-subunit complexes but also participates in subsequent pilus assembly events.

Amino Acid Sequence↗
PubMed2005

Identification of a TcpC-TcpQ outer membrane complex involved in the biogenesis of the toxin-coregulated pilus of Vibrio cholerae.

The toxin-coregulated pilus (TCP) of Vibrio cholerae and the soluble TcpF protein that is secreted via the TCP biogenesis apparatus are essential for intestinal colonization. The TCP biogenesis apparatus is composed of at least nine proteins but is largely uncharacterized. TcpC is an outer membrane lipoprotein required for TCP biogenesis that is a member of the secretin protein superfamily. In the present study, analysis of TcpC in a series of strains deficient in each of the TCP biogenesis proteins revealed that TcpC was absent specifically in a tcpQ mutant. TcpQ is a predicted periplasmic protein required for TCP biogenesis. Fractionation studies revealed that the protein is not localized to the periplasm but is associated predominantly with the outer membrane fraction. An analysis of the amount of TcpQ present in the series of tcp mutants demonstrated the inverse of the TcpC result (absence of TcpQ in a tcpC deletion strain). Complementation of the tcpQ deletion restored TcpC levels and TCP formation, and similarly, complementation of tcpC restored TcpQ. Metal affinity pull-down experiments performed using His-tagged TcpC or TcpQ demonstrated a direct interaction between TcpC and TcpQ. In the presence of TcpQ, TcpC was found to form a high-molecular-weight complex that is stable in 2% sodium dodecyl sulfate and at temperatures below 65 degrees C, a characteristic of secretin complexes. Fractionation studies in which TcpC was overexpressed in the absence of TcpQ showed that TcpQ is also required for proper localization of TcpC to the outer membrane.

Amino Acid Sequence↗
PubMed2005

An evolutionarily conserved coiled-coil protein implicated in polycystic kidney disease is involved in basal body duplication and flagellar biogenesis in Trypanosoma brucei.

Trypanosoma brucei is a flagellated protozoan with a highly polarized cellular structure. TbLRTP is a trypanosomal protein containing multiple SDS22-class leucine-rich repeats and a coiled-coil domain with high similarity to a mammalian testis-specific protein of unknown function. Homologues are present in a wide range of higher eukaryotes including zebra fish, where the gene product has been implicated in polycystic kidney disease. Western blot analysis and immunofluorescence with antibodies against recombinant TbLRTP indicate that the protein is expressed throughout the trypanosome life cycle and localizes to distal zones of the basal bodies. Overexpression and RNA interference demonstrate that TbLRTP is important for faithful basal body duplication and flagellum biogenesis. Expression of excess TbLRTP suppresses new flagellum assembly, while reduction of TbLRTP protein levels often results in the biogenesis of additional flagellar axonemes and paraflagellar rods that, most remarkably, are intracellular and fully contained within the cytoplasm. The mutant flagella are devoid of membrane and are often associated with four microtubules in an arrangement similar to that observed in the normal flagellar attachment zone. Aberrant basal body and flagellar biogenesis in TbLRTP mutants also influences cell size and cytokinesis. These findings demonstrate that TbLRTP suppresses basal body replication and subsequent flagellar biogenesis and indicate a critical role for the LRTP family of proteins in the control of the cell cycle. These data further underscore the role of aberrant flagellar biogenesis as a disease mechanism.

Amino Acid Sequence↗
PubMed2006

Pyruvate induces mitochondrial biogenesis by a PGC-1 alpha-independent mechanism.

Oxidative cells increase mitochondrial mass in response to stimuli such as changes in energy demand or cellular differentiation. This plasticity enables the cell to adapt dynamically to achieve the necessary oxidative capacity. However, the pathways involved in triggering mitochondrial biogenesis are poorly defined. The present study examines the impact of altering energy provision on mitochondrial biogenesis in muscle cells. C2C12 myoblasts were chronically treated with supraphysiological levels of sodium pyruvate for 72 h. Treated cells exhibited increased mitochondrial protein expression, basal respiratory rate, and maximal oxidative capacity. The increase in mitochondrial biogenesis was independent of increases in peroxisomal proliferator activator receptor-gamma coactivator-1alpha (PGC-1alpha) and PGC-1beta mRNA expression. To further assess whether PGC-1alpha expression was necessary for pyruvate action, cells were infected with adenovirus containing shRNA for PGC-1alpha before treatment with pyruvate. Despite a 70% reduction in PGC-1alpha mRNA, the effect of pyruvate was preserved. Furthermore, pyruvate induced mitochondrial biogenesis in primary myoblasts from PGC-1alpha null mice. These data suggest that regulation of mitochondrial biogenesis by pyruvate in myoblasts is independent of PGC-1alpha, suggesting the existence of a novel energy-sensing pathway regulating oxidative capacity.

Adaptation, Physiological↗
PubMed2006

TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents.

Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-alpha. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was associated with less body weight gain than in obese wild-type controls. Furthermore, TNF-alpha downregulated eNOS expression and mitochondrial biogenesis in cultured white and brown adipocytes and muscle satellite cells of mice. The NO donors DETA-NO and SNAP prevented the reduction of mitochondrial biogenesis observed with TNF-alpha. Our findings demonstrate that TNF-alpha impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity.

Adenosine Triphosphate↗
PubMed2003

Modeling human peroxisome biogenesis disorders in the nematode Caenorhabditis elegans.

Peroxisomes are ubiquitous eukaryotic organelles. The proteins required for peroxisome biogenesis are called peroxins, and mutations in the peroxin genes cause the devastating human developmental syndromes called the peroxisome biogenesis disorders. Our interest is in elaborating the roles that peroxisomes play in Caenorhabditis elegans development, and in establishing an invertebrate model system for the human peroxisome biogenesis disorders. The genome of C. elegans encodes homologs of 11 of the 13 human peroxins. We disrupted five nematode peroxins using RNA interference (RNAi) and found that RNAi knockdown of each one causes an early larval arrest at the L1 stage. Using a green fluorescent protein reporter targeted to the peroxisome, we establish that peroxisomal import is impaired in prx-5(RNAi) nematodes. prx-5(RNAi) animals are blocked very early in the L1 stage and do not initiate normal postembryonic cell divisions, similar to starvation-arrested larvae. Cell and axonal migrations that normally occur during the L1 stage also appear blocked. We conclude that peroxisome function is required for C. elegans postembryonic development and that disruption of peroxisome assembly by prx-5(RNAi) prevents scheduled postembryonic cell divisions. Defects in the cellular localization of peroxisomal proteins and in development are shared features of human and nematode peroxisome biogenesis disorders. In setting up a C. elegans model of peroxisomal biogenesis disorders, we suggest that genetic screens for suppression of the Prx developmental block will facilitate identification of novel intervention strategies and may provide new insights into human disease pathogenesis.

Animals↗
PubMed1989

Mechanism of action of thyroxine (T4) on the biogenesis of mitochondria using antibiotic-free system: a gerontological survey.

For the biogenesis of mitochondria from rat liver two different genetic systems are responsible, the nucleo-cytoplasmic system, covering 85-90% of the protein, and the mitochondrial system (10-15%). These data have been confirmed by experiment. Both protein fractions were separated by phosphate buffer (pH 11.5), in which only one of them is soluble. The experiments were performed with 3 age groups of rat: 1, 3 and 24 months. The ratio of both protein fractions was not dependent on rat age. The activities of the two genetic systems were examined by the in-vivo incorporation rate of 14 C-leucine. For the mitochondrial genetic system this rate was approximately equal in all of the age groups, while that for the nucleo-cytoplasmic genetic system was reduced in the 24 month group. Hence an age-dependence is demonstrated for the nucleo-cytoplasmic genetic system. The results of our investigation permit the conclusion that the role of the mitochondrial genetic system increases at senescence. To investigate the effect of T4 on the biogenesis of mitochondria, both protein fractions were estimated also in liver of rats treated with T4. The result showed that there was an increase for all the age groups for protein only of nucleo-cytoplasmic origin. Since it is known that T4 stimulates the biogenesis of mitochondria and increases its protein content, it could be inferred that the action of T4 is channelled through the nucleo-cytoplasmic system independent on age, and that the nucleus plays the major regulatory role in the biogenesis of mitochondria.

Aging↗
PubMedDate not supplied

Proteomic snapshot analyses of preribosomal ribonucleoprotein complexes formed at various stages of ribosome biogenesis in yeast and mammalian cells.

Proteomic technologies powered by advancements in mass spectrometry and bioinformatics and coupled with accumulated genome sequence data allow a comprehensive study of cell function through large-scale and systematic protein identifications of protein constituents of the cell and tissues, as well as of multi-protein complexes that carry out many cellular function in a higher-order network in the cell. One of the most extensively analyzed cellular functions by proteomics is the production of ribosome, the protein-synthesis machinery, in the nucle(ol)us--the main site of ribosome biogenesis. The use of tagged proteins as affinity bait, coupled with mass spectrometric identification, enabled us to isolate synthetic intermediates of ribosomes that might represent snapshots of nascent ribosomes at particular stages of ribosome biogenesis and to identify their constituents--some of which showed dynamic changes for association with the intermediates at various stages of ribosome biogenesis. In this review, in conjunction with the results from yeast cells, our proteomic approach to analyze ribosome biogenesis in mammalian cells is described.

Animals↗
PubMed1997

Lysosomal biogenesis in lysosomal storage disorders.

Lysosomal biogenesis is an orchestration of the structural and functional elements of the lysosome to form an integrated organelle and involves the synthesis, targeting, functional residence, and turnover of the proteins that comprise the lysosome. We have investigated lysosomal biogenesis during the formation and dissipation of storage vacuoles in two model systems. One involves the formation of sucrosomes in normal skin fibroblasts and the other utilizes storage disorder-affected skin fibroblasts; both of these systems result in an increase in the size and the number of lysosomal vacuoles. Lysosomal proteins, beta-hexosaminidase, alpha-mannosidase, N-acetylgalactosamine-4-sulfatase, acid phosphatase, and the lysosome-associated membrane protein, LAMP-1, were shown to be elevated between 2- and 28-fold above normal during lysosomal storage. Levels of mRNA for the lysosome-associated membrane proteins LAMP-1 and LAMP-2, N-acetylgalactosamine-4-sulfatase, and the 46- and 300-kDa mannose-6-phosphate receptors were also elevated 2- to 8-fold. The up-regulation of protein and mRNA lagged 2-4 days behind the formation of lysosomal storage vacuoles. Correction of storage, in both systems, resulted in the rapid decline of the mRNA to basal levels, with a slower decrease in the levels of lysosomal proteins. Lysosomal biogenesis in storage disorders is shown to be a regulated process which is partially controlled at, or prior to, the level of mRNA. Although lysosomal proteins were differentially regulated, the coordination of these events in lysosomal biogenesis would suggest that a common mechanism(s) may be in operation.

Antibodies, Monoclonal↗
PubMed1998

Biogenesis of synaptic-like microvesicles in perforated PC12 cells.

We have established a system that reconstitutes the biogenesis of synaptic-like microvesicles (SLMVs) in perforated cells of the rat neuroendocrine cell line PC12. The system is based on the biotinylation of synaptophysin, a marker of synaptic vesicles and SLMVs. Biotinylation is performed at 18 degrees C, a temperature at which formation of SLMVs is blocked and biotinylated synaptophysin accumulates in the SLMV donor compartment. The biotinylated PC12 cells are then perforated by scraping and incubated at 37 degrees C in the presence of ATP and cytosolic proteins, conditions required for SLMV biogenesis. After the perforated-cell reaction, the newly formed SLMVs are isolated by differential centrifugation followed by either glycerol gradient centrifugation or a simple single-glycerol-step centrifugation. The latter allows the analysis of many perforated-cell reactions in parallel and, hence, the dissection of the molecular machinery mediating SLMV biogenesis. Using this system, we have found that clathrin, dynamin, phosphatidylinositol transfer protein, and SH3P4 are involved in SLMV biogenesis.

Adenosine Triphosphate↗
PubMed1987

Nuclear functions required for cytochrome c oxidase biogenesis in Saccharomyces cerevisiae: multiple trans-acting nuclear genes exert specific effects on expression of each of the cytochrome c oxidase subunits encoded on mitochondrial DNA.

Fourteen nuclear complementation groups of mutants that specifically affect the three mitochondrially-encoded subunits of yeast cytochrome c oxidase have been characterized. Genes represented by these complementation groups are not required for mitochondrial transcription, transcript processing, or translation per se but are required for the expression of one of the three genes--COX1, COX2, or COX3--which encode the cytochrome c oxicase subunits I, II, or III, respectively. Five of these genes affect the biogenesis of cytochrome c oxidase subunit I, 3 affect the biogenesis of subunit II, 3 affect the biogenesis of subunit III and 3 affect the biogenesis of both cytochrome c oxidase subunit I and cytochrome b, the product of COB. Among the 5 complementation groups of mutants that affect the expression of COX1, 2 lack COX1 transcripts, 1 produces incompletely processed COX1 transcripts, and 2 contain normal levels of normal-sized COX1 transcripts. In contrast, all 3 complementation groups which affect the expression of COX2 and all 3 complementation groups which affect the expression of COX3 exhibit no, or little, detectable difference with respect to the wild type pattern of transcripts. The 3 complementation groups which affect the expression of both COX1 and COB all have aberrant COX1 and COB transcript patterns. These findings indicate that multiple trans-acting nuclear genes are required for specific expression of each COX gene encoded on mitochondrial DNA and suggest that their products act at different steps in the expression of these mitochondrial genes.

Cell Nucleus↗
PubMed2002

Mitochondrial biogenesis in brown adipose tissue is associated with differential expression of transcription regulatory factors.

The differentiation of brown adipocytes during late fetal development or in cell culture is associated with enhanced mitochondrial biogenesis and increased gene expression for components of the respiratory chain/oxidative phosphorylation system. We have shown that this is due to a rise in mitochondrial DNA abundance and the corresponding increase in mitochondrial genome transcripts and gene products, as well as to the coordinate induction of nuclear-encoded genes for mitochondrial proteins. We studied how the expression of key components of the transcriptional regulation of mitochondrial biogenesis is regulated during this process. Changes in the expression of nuclear respiratory factor-2/GA-binding protein a and peroxisome proliferator-activated-receptor gamma coactivator-1 (increase) were opposite to those of nuclear respiratory factor-1 and Sp1 (decrease) during the developmental and differentiation-dependent induction of mitochondrial biogenesis in brown fat. These results indicate that the relative roles of transcription factors and coactivators in mediating mitochondrial biogenesis 'in vivo' are highly specific according to the cell type and stimulus that mediate the mitochondriogenic process.

Adipocytes↗
PubMed2003

Peroxisome biogenesis.

Peroxisome biogenesis conceptually consists of the (a) formation of the peroxisomal membrane, (b) import of proteins into the peroxisomal matrix and (c) proliferation of the organelles. Combined genetic and biochemical approaches led to the identification of 25 PEX genes-encoding proteins required for the biogenesis of peroxisomes, so-called peroxins. Peroxisomal matrix and membrane proteins are synthesized on free ribosomes in the cytosol and posttranslationally imported into the organelle in an unknown fashion. The protein import into the peroxisomal matrix and the targeting and insertion of peroxisomal membrane proteins is performed by distinct machineries. At least three peroxins have been shown to be involved in the topogenesis of peroxisomal membrane proteins. Elaborate peroxin complexes form the machinery which in a concerted action of the components transports folded, even oligomeric matrix proteins across the peroxisomal membrane. The past decade has significantly improved our knowledge of the involvement of certain peroxins in the distinct steps of the import process, like cargo recognition, docking of cargo-receptor complexes to the peroxisomal membrane, translocation, and receptor recycling. This review summarizes our knowledge of the functional role the known peroxins play in the biogenesis and maintenance of peroxisomes. Ideas on the involvement of preperoxisomal structures in the biogenesis of the peroxisomal membrane are highlighted and special attention is paid to the concept of cargo protein aggregation as a presupposition for peroxisomal matrix protein import.

Animals↗
PubMed1977

Involvement of iron in the biogenesis of the cyanide-insensitive respiration in the yeast Saccharomycopsis lipolytica.

The involvement of iron in the biogenesis of the cyanide-insensitive respiration in the yeast Saccharomycopsis lipolytica has been established on the following basis: (1) endogenous metal chelation by either benzyl- or salicylhydroxamic acid, EDTA or nitrilotriacetate prevented the biogenesis of the cyanide-insensitive respiratory pathway in S. lipolytica. (2) Addition of Fe(III) during the biogenesis increased both the rate of the appearance of the alternative respiratory pathway and its extent. Neither Fe(II), nor Co(II), Cu(II), Al(III), La(III), Mn(II) or Mg(II) could substitute for Fe(III). (3) The biogenesis of the alternative respiratory pathway could be dissociated into two steps: (a) a first one, slow, cycloheximide-sensitive, temperature-dependent, iron-independent, leading to cells still fully cyanide-sensitive, presumably involving the de novo biosynthesis of an inactive protein moiety and (b) a second step, fast, iron-dependent, temperature-independent, cycloheximide-insensitive, leading to cells with a cyanide-insensitive respiration, presumably the activation by iron of the inactive precursor.

Chelating Agents↗
PubMed1996

A role for ADP-ribosylation factor 1, but not COP I, in secretory vesicle biogenesis from the trans-Golgi network.

A synthetic N-myristoylated peptide corresponding to the amino-terminal domain of ADP-ribosylation factor 1 (ARF1) markedly increases, in a cell-free system using post-nuclear supernatant from PC12 cells, the biogenesis of constitutive secretory vesicles and immature secretory granules from the trans-Golgi network (TGN). The related N-myristoylated ARF4 peptide only weakly stimulates, and the non-myristoylated ARF1 and ARF4 peptides inhibit, the biogenesis of these secretory vesicles. In a modified cell-free system using TGN membranes, coatomer-depleted cytosol supports the biogenesis of TGN-derived secretory vesicles to the same extent as control cytosol. These results suggest a role for ARF1, but not the COP I coat, in secretory vesicle biogenesis from the TGN, possibly via the activation of phospholipase D.

ADP-Ribosylation Factor 1↗
PubMed2005

Reactive oxygen species mediates homocysteine-induced mitochondrial biogenesis in human endothelial cells: modulation by antioxidants.

It has been proposed that homocysteine (Hcy)-induces endothelial dysfunction and atherosclerosis by generation of reactive oxygen species (ROS). A previous report has shown that Hcy promotes mitochondrial damage. Considering that oxidative stress can affect mitochondrial biogenesis, we hypothesized that Hcy-induced ROS in endothelial cells may lead to increased mitochondrial biogenesis. We found that Hcy-induced ROS (1.85-fold), leading to a NF-kappaB activation and increase the formation of 3-nitrotyrosine. Furthermore, expression of the mitochondrial biogenesis factors, nuclear respiratory factor-1 and mitochondrial transcription factor A, was significantly elevated in Hcy-treated cells. These changes were accompanied by increase in mitochondrial mass and higher mRNA and protein expression of the subunit III of cytochrome c oxidase. These effects were significantly prevented by pretreatment with the antioxidants, catechin and trolox. Taken together, our results suggest that ROS is an important mediator of mitochondrial biogenesis induced by Hcy, and that modulation of oxidative stress by antioxidants may protect against the adverse vascular effects of Hcy.

Antioxidants↗
PubMed2005

The mitochondrial biogenesis regulatory program in cardiac adaptation to ischemia--a putative target for therapeutic intervention.

The resurgence of mitochondrial biology research stems from the realization that the distinct regulation of mitochondria to meet diverse homeostatic demands is driven by exquisite biochemical and molecular control mechanisms. This program termed mitochondrial biogenesis is integral to orchestrating mitochondrial function and appears to exhibit adaptive remodeling following biomechanical and oxidative stress. The major bioenergetic function of mitochondria partitions the final utilization of oxygen between oxidative phosphorylation and reactive oxygen species. As disruption in oxidative phosphorylation and excessive reactive oxygen species contribute to cardiac ischemia-reperfusion injury, we hypothesize that the mitochondrial biogenesis regulatory program is an explicit target for cardiac therapeutic interventions. The objectives of this review are to (a) define the advances in understanding the mitochondrial biogenesis regulatory program integrated to its control of mitochondrial bioenergetics and oxygen utilization, (b) reveal how this program is modulated by chronic hypoxia and ischemic preconditioning, and (c) examine the therapeutic potential of modulating the regulation of mitochondrial biogenesis as a strategy to attenuate ischemia-reperfusion injury.

Adaptation, Physiological↗