Showing papers on "Mitochondrial biogenesis published in 2000"
TL;DR: It is found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production.
Abstract: Cardiac mitochondrial function is altered in a variety of inherited and acquired cardiovascular diseases. Recent studies have identified the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) as a regulator of mitochondrial function in tissues specialized for thermogenesis, such as brown adipose. We sought to determine whether PGC-1 controlled mitochondrial biogenesis and energy-producing capacity in the heart, a tissue specialized for high-capacity ATP production. We found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increased cellular mitochondrial number, and stimulated coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands.
1,223 citations
TL;DR: Results demonstrate that expression of the PGC-1 gene in Epi muscle is induced not only by cold exposure but also by prolonged low-intensity physical exercise.
254 citations
TL;DR: It is demonstrated that serum induction of cytochrome c mRNA and processed protein in quiescent BALB/3T3 fibroblasts is associated with a marked increase in mitochondrial respiration and leads to enhanced mitochondrial respiratory capacity upon serum-induced entry to the cell cycle.
184 citations
TL;DR: The yeast ERV1 gene encodes a small polypeptide that is essential for mitochondrial function and for the viability of the cell and the enzymatic activity of this protein as a flavin‐linked sulfhydryl oxidase catalyzing the formation of disulfide bridges is reported.
176 citations
TL;DR: This data suggests that fat cell differentiation involves an interplay between the C/EBP family of transcription factors and PPARγ and the thermogenic program of brown fat cells may also include a contribution from a new coactivator, PGC-1.
Abstract: There has been a great deal of recent progress in our understanding of the transcriptional control of adipogenesis. Current data suggest that fat cell differentiation involves an interplay between the C/EBP family of transcription factors and PPARgamma. The thermogenic program of brown fat cells may also include a contribution from a new coactivator, PGC-1. Recent data suggests that this coactivator is responsible for activation of thermogenesis and oxidative metabolism in both brown fat and muscle. The PGC-1 dependent program includes both mitochondrial biogenesis and tissue-specific expression of uncoupling proteins.
103 citations
TL;DR: EPA and DHA have different effects on mitochondrial biogenesis, as indicated by the mean area occupied by the mitochondria and the size distribution of mitochondrial areas in both fiber types were highly similar in DHA‐treated and control animals.
70 citations
Journal Article•
TL;DR: Mitochondrial biogenesis occurs in muscle in response to chronic exercise, resulting in fatigue resistance, and is accompanied by alterations in mRNA stability, as well as increases in protein import and mitochondrial DNA copy number, leading to a greater muscle mitochondrial content.
Abstract: Mitochondrial biogenesis occurs in muscle in response to chronic exercise, resulting in fatigue resistance. The assembly of the organelle is initiated by contraction-induced signals, which lead to the transcriptional activation of nuclear genes. This is accompanied by alterations in mRNA stability, as well as increases in protein import and mitochondrial DNA copy number, leading to a greater muscle mitochondrial content.
60 citations
TL;DR: Tom20 is important in determining import during organelle biogenesis, but other mechanisms likely also play a role in establishing the final mitochondrial phenotype during normal muscle differentiation.
Abstract: Mitochondrial biogenesis is accompanied by an increased expression of components of the protein import machinery, as well as increased import of proteins destined for the matrix. We evaluated the role of the outer membrane receptor Tom20 by varying its expression and measuring changes in the import of malate dehydrogenase (MDH) in differentiating C2C12 muscle cells. Cells transfected with Tom20 had levels that were twofold higher than in control cells. Labeling of cells followed by immunoprecipitation of MDH revealed equivalent increases in MDH import. This parallelism between import rate and Tom20 levels was also evident as a result of thyroid hormone treatment. Using antisense oligodeoxynucleotides, we inhibited Tom20 expression by 40%, resulting in 40-60% reductions in MDH import. In vitro assays also revealed that import into the matrix was more sensitive to Tom20 inhibition than import into the outer membrane. These data indicate a close relationship between induced changes in Tom20 and the import of a matrix protein, suggesting that Tom20 is involved in determining the kinetics of import. However, this relationship was dissociated during normal differentiation, since the expression of Tom20 remained relatively constant, whereas imported MDH increased 12-fold. Thus Tom20 is important in determining import during organelle biogenesis, but other mechanisms (e.g., intramitochondrial protein degradation or nuclear transcription) likely also play a role in establishing the final mitochondrial phenotype during normal muscle differentiation.
54 citations
TL;DR: Data identify mDAP-3 as one of the first proapoptotic factors in the mitochondrial matrix and provide evidence for a critical, evolutionary conserved role of members of the D AP-3 protein family for mitochondrial biogenesis.
Abstract: Programmed cell death is essential for organ development and regeneration. To identify molecules relevant for this process, full length cDNA cloning of a short, developmentally regulated murine cDNA fragment, MERM-3, was performed and showed a 1.7 kb mRNA encoding a 45 kDa protein with an ATP/GTP binding motive (P-loop). Sequence analysis revealed an 82% amino acid identity to the human death associated protein 3 (hDAP-3), a positive mediator of apoptosis. The full length sequence being the murine orthologue of hDAP-3 is therefore referred to as mDAP-3. In situ hybridization and northern blot analysis showed an abundant mRNA expression with a pronounced expression in highly proliferative epithelial compartments. For mDAP-3, cytochrome c release and induction of cell death could be demonstrated by overexpression of a mDAP-3/EGFP fusion protein. DAP-3 mediated apoptosis was shown to depend on a functional P-loop. Intracellular localization studies using the mDAP-3/EGFP fusion protein, cell fractionation and protease protection experiments localized mDAP-3 to the mitochondrial matrix. DAP-3, in contrast to cytochrome c, retained its mitochondrial localization during apoptosis induction. A mutant of a putative yeast orthologue of mDAP-3, YGL129c, here referred to as yDAP-3, has been shown to exhibit disrupted mitochondrial function. yDAP-3 deficient mutants could be shown to progressively loose mitochondrial DNA. Loss of mitochondrial DNA in yDAP-3 was partially prevented by transfection of the yDAP-3 deficient mutant with mDAP-3, indicating functional complementation by murine DAP-3 in the yeast system. These data identify mDAP-3 as one of the first proapoptotic factors in the mitochondrial matrix and provide evidence for a critical, evolutionary conserved role of members of the DAP-3 protein family for mitochondrial biogenesis.
54 citations
TL;DR: The isolation of differentially expressed genes in RNA populations from four stages of L. edodes development indicates their involvement in homobasidiomycete development and suggests new directions for molecular studies on mechanisms of mushroom development.
Abstract: As part of an ongoing project to understand the molecular mechanisms of fruit body development in Lentinula edodes (Shiitake mushroom), RNA fingerprinting by arbitrarily primed PCR (RAP-PCR) was used to identify differentially expressed genes in RNA populations from four stages of L. edodes development – vegetative mycelium, primordium, young fruit body and mature fruit body. From 30 RNA fingerprints, we cloned and sequenced 33 RAP fragments after their differential expression patterns had been verified by reverse Northern dot-blot hybridization. Thirteen RAP fragments show high sequence similarity to known gene products which are involved in (1) transport across the plasma membrane (drug efflux pump and sugar transporter); (2) cell cycle control (cyclin B); (3) signal transduction and transcriptional regulation (mitogen-activated protein kinase, Cdc39/Not1, PriA, Jun-D); (4) intracellular molecule trafficking (ubiquitin, plasma membrane proton ATPase, and α-adaptin); (5) mitochondrial biogenesis (mitochondrial processing peptidase β-subunit, mitochondrial glycerol-3-phosphate dehydrogenase); and (6) intermediary metabolism (fructose 1,6 bisphosphatase). The transcript levels for plasma membrane proton ATPase and α-adaptin remained constant, whereas the other eleven genes were differentially expressed during L. edodes development. The expression profiles of the genes suggest that transport across the plasma membrane is important in the mycelial stage. Specific signal transduction and transcriptional controls may play important roles during the initiation of primordia and the formation of young fruiting bodies. When the mushroom matures, expression of genes involved in metabolic pathways becomes prominent. The isolation of these genes indicates their involvement in homobasidiomycete development and suggests new directions for molecular studies on mechanisms of mushroom development.
52 citations
TL;DR: Data indicate coordinated regulation of some nuclear-encoded (COX-IV and CS activity) and mitochondrial components ( COX-II and mtDNA) and strongly suggest that mitochondrial content increases particularly during the early fetal cardiac development and reveal a distinct pattern of regulation for mt-TFA.
Abstract: Previous studies in our laboratory demonstrated significant changes in bovine heart mitochondrial bioenergetics during fetal growth and development. To further understand mitochondrial biogenesis in early human development, the activity and subunit content levels of specific mitochondrial enzymes in fetal and neonatal heart were determined. Comparing early gestation (EG, 45-65 day) later gestation (LG, 85-110 day) and neonate (birth-1 month), specific activity of citrate synthase (CS), a Krebs cycle enzyme showed a 2 fold increase from EG to LG and a 2 fold increase from LG to neonate. Specific activities of complex IV and complex V increased similarly 1.8-2 fold from EG to LG. However during the later fetal period from LG to neonate, complex IV activity increased only 1.3 fold and complex V showed no significant increase. Peptide content of COX-II subunit increased 2 fold from EG to LG and by 3.5 fold from LG to neonate. Levels of COX-IV and ATP synthase α subunits were undetectable in EG hearts, clearly detectable in LG heart and 3 fold increased from LG to neonate. Unexpectedly, mitochondrial transcription factor A (mt-TFA) levels were not significantly different during these developmental stages. Mitochondrial DNA (mtDNA) levels increased 1.8 fold from EG to LG, and 3.8 fold increase from EG to neonate and correlated with CS activity levels. In conclusion, these data indicate coordinated regulation of some nuclear-encoded (COX-IV and CS activity) and mitochondrial components (COX-II and mtDNA), and strongly suggest that mitochondrial content increases particularly during the early fetal cardiac development and reveal a distinct pattern of regulation for mt-TFA.
TL;DR: The results suggest that the Adr1p transcriptional activator is also required in CYB2 transcription control, which provides new data which allows a better understanding of the molecular mechanisms implicated in the co‐regulation at the transcriptional level of the genes encoding proteins involved in various aspects of oxidative metabolism.
Abstract: Expression of the Saccharomyces cerevisiae nuclear gene CYB2 encoding the mitochondrial enzyme L-(+)-lactate-cytochrome c oxidoreductase (EC 1.2.2.3) is subject to several strict metabolic controls at the transcriptional level: repression due to glucose fermentation, derepression by ethanol, induction by lactate and inhibition under anaerobic conditions or in response to deficiency of haem biosynthesis. In this respect, the data obtained from the transcriptional analysis of the CYB2 gene contribute to a better understanding of the control of mitochondrial biogenesis. In this study, we show that Hap1p is the main transcriptional activator involved in the control of CYB2 transcription. We found that Hap1p activity, known to be oxygen dependent, is effected by DNA-protein interaction with two binding sites present in the CYB2 promoter. Control is moreover dependent on carbon sources. This regulation by the carbon substrates is subordinate to the activity of the complex Hap2/3/4/5p, which counteracts the negative effect of the URS1 element. Finally, our results suggest that the Adr1p transcriptional activator is also required in CYB2 transcription control. This work provides new data which allows a better understanding of the molecular mechanisms implicated in the co-regulation at the transcriptional level of the genes encoding proteins involved in various aspects of oxidative metabolism.
TL;DR: The mitochondrial biosynthetic capacity correlates with the rate of organelle biogenesis rather than the steady-state concentration of a marker enzyme, and the copy number of mitochondrial DNA does not seem to play a major role in determining either mitochondrial transcript levels or functional mass.
Abstract: The biogenesis of giant mitochondria in flight muscle of Locusta migratoria (L.) was analyzed at the molecular level. During the 2 weeks between the beginning of the last larval stage and the imago capable of sustained flight, individual mitochondria have been shown to enlarge 30-fold and the fractional mitochondrial volume of muscle cells increases fourfold [Brosemer, R.W., Vogell, W. and Bucher, Th. (1963) Biochem. Z. 338, 854–910]. Within the same period, the activity of cytochrome c oxidase, containing subunits encoded on mitochondrial DNA, increased twofold. However, no significant change in mitochondrial DNA copy number, and even a threefold decrease in mitochondrial transcripts, was observed. Mitochondrial translation rate, measured in isolated organelles, was twofold higher in larval muscle, which can be explained only partly by the higher content of mitochondrial RNAs. Thus, rather unusually, in this system of mitochondrial differentiation, the mitochondrial biosynthetic capacity correlates with the rate of organelle biogenesis rather than the steady-state concentration of a marker enzyme. The copy number of mitochondrial DNA does not seem to play a major role in determining either mitochondrial transcript levels or functional mass.
TL;DR: It appears that intramitochondrial PS does not limit the extent of chronic contractiles activity-induced mitochondrial biogenesis, and acute contractile activity exerts differential effects on protein turnover in IMF and SS mitochondria.
Abstract: To determine the role of intramitochondrial protein synthesis (PS) and degradation (PD) in contractile activity-induced mitochondrial biogenesis, we evaluated rates of [35S]methionine incorporation...
TL;DR: Specific examples of the regulation of expression of mitochondrial proteins with development and among tissues are outlined which indicate the complexity of factors that interplay to achieve regulation of mitochondrial biogenesis.
Abstract: Although mitochondria play a central role in energy production in all plant tissues, the amount and activity of mitochondria differs among tissues and with development. These differences are due to the changing demands of various tissues for energy during development and the presence of different metabolic pathways in mitochondria from a variety of tissues. As mitochondria contain proteins encoded in both the nuclear and mitochondrial genomes the expression of these genomes must be coordinated. Progress has been achieved in understanding transcription of genes in both genomes. It appears from investigations to date that: i) transcriptional regulation is not a major feature of control of mitochondrial-encoded genes, and ii) the transcription of nuclear- and mitochondrial-encoded genes for proteins of a multi-subunit complex are not coordinated. Rather several post-transcriptional and/or post-translational mechanisms exist to achieve the desired coordination between the two genomes. Specific examples of the regulation of expression of mitochondrial proteins with development and among tissues are outlined which indicate the complexity of factors that interplay to achieve regulation of mitochondrial biogenesis.
TL;DR: Some of the mtDNA defects discovered by the laboratory and others in patients with neurologic disorders are described and their potential relationship with the pathways and mechanisms involved in mitochondrial biogenesis is analyzed.
TL;DR: Observations suggested that Uth1p could be involved as a connection step between pathways controlling growth and those controlling division.
Abstract: UTH1 and SIM1 are two of four ‘SUN’ genes (SIM1, UTH1, NCA3 and SUN4/SCW3) whose products are involved in different cellular processes such as DNA replication, lifespan, mitochondrial biogenesis or cell septation. UTH1 or SIM1 inactivation did not affect cell growth, shape or nuclear migration, whereas the double null mutant presented phenotypes of numerous binucleate cells and benomyl sensitivity, suggesting that microtubule function could be altered; the uth1Δsim1Δ strain also presented defects which could be related to the Ras/cAMP pathway: pet phenotype, heat shock sensitivity, inability to store glycogen, sensitivity to starvation and failure of spores to germinate. These observations suggested that Uth1p could be involved as a connection step between pathways controlling growth and those controlling division.
TL;DR: The detailed molecular characterization of the effects produced by different mutations that cause mitochondrial cytopathies will be critical for designing rational therapeutic strategies for this group of devastating diseases.
TL;DR: Results suggest that certain components of the mitochondrial biogenesis program are activated in hearts of copper-deficient rats, and F(1)F(0)-ATP synthase beta subunit and MCAD transcript levels remain low, which may contribute to impaired mitochondrial respiratory function, decreased fatty acid utilization and lipid droplet accumulation in hearts.
Abstract: The mechanism(s) by which impaired mitochondrial respiratory function and the accumulation of lipid droplets and mitochondria in hearts of copper-deficient rats occur remains unclear. It is not known whether specific components of the regulatory pathway involved in mitochondrial biogenesis, such as mitochondrial transcription factor A (mtTFA) and nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2), are activated in copper deficiency. Little is known about gene expression of enzymes involved in fatty acid oxidation (FAO) in hearts of copper-deficient rats. Male weanling rats were fed copper-adequate (CuA), copper-deficient (CuD) or pair-fed (CuP) diets for 5 wk. Mitochondria and lipid droplet volume densities from electron micrographs were greater and there was an elevation in the mtTFA protein level in hearts of copper-deficient rats. DNA binding activities of NRF-1 and NRF-2 did not differ among the groups. Northern blot analysis of cardiac tissue revealed that transcripts of F(1)F(0)-ATP synthase subunit c were greater, but mRNA levels of ATP synthase beta subunit and the FAO enzyme, medium-chain acyl-CoA dehydrogenase (MCAD), were lower in hearts of copper-deficient rats. Long-chain acyl-CoA dehydrogenase (LCAD) mRNA levels did not differ among treatment groups. These results suggest that certain components of the mitochondrial biogenesis program are activated in hearts of copper-deficient rats. F(1)F(0)-ATP synthase beta subunit and MCAD transcript levels remain low, which may contribute to impaired mitochondrial respiratory function, decreased fatty acid utilization and lipid droplet accumulation in hearts of copper-deficient rats.
TL;DR: Most proteins involved in mitochondrial biogenesis are encoded by the genome of the nucleus and have to be transported toward and, subsequently, imported into the organelle through the import channel.
Abstract: Most proteins involved in mitochondrial biogenesis are encoded by the genome of the nucleus. They are synthesized in the cytosol and have to be transported toward and, subsequently, imported into the organelle. This targeting and import process is initiated by the specific mitochondrial targeting signal, which differs pending on the final localization of the protein. The preprotein will be recognized by cytosolic proteins, which function in transport toward the mitochondria and in maintaining the import competent state of the preprotein. The precursor will be transferred onto a multicomponent complex on the outer mitochondrial membrane, formed by receptor proteins and the general insertion pore (GIP). Some proteins are directly sorted into the outer membrane whereas the majority will be transported over the outer membrane through the import channel followed by further distribution of those proteins.
Journal Article•
TL;DR: This article focuses on the recent advances in the field of mitochondrial disorders with respect to the consequences for an advanced clinical and genetic diagnostics.
Abstract: Defects in structures or functions of mitochondria, mainly involving the oxidative phosphorylation, mitochondrial biogenesis and other metabolic pathways have been shown to be associated with a wide spectrum of clinical phenotypes. The ubiquitous nature of mitochondria and their unique genetic features contribute to the clinical, biochemical and genetic heterogenecity of mitochondrial diseases. This article focuses on the recent advances in the field of mitochondrial disorders with respect to the consequences for an advanced clinical and genetic diagnostics. In addition, an overview on recently identified genetic defects and their pathogenic molecular mechanisms are given.
TL;DR: In conclusion, mito chondria are able to maintain high rates of mitochondrial transcription even in the presence of reduced mtTFA protein and mtDNA levels, but it is not sufficient for an increase of mtDNA copy number and other, yet unknown, factors have to be postulated.
Abstract: Mitochondrial proliferation was studied in chronically stimulated rabbit skeletal muscle over a period of 50 days. After this time, subunits of COX had increased about fourfold. Corresponding mRNAs, encoded on mitochondrial DNA as well as on nuclear genes, were unchanged when related to total tissue RNA, however, they were elevated two- to fivefold when the massive increase of ribosomes per unit mass of muscle was taken into account. The same was true for the mRNA encoding mitochondrial transcription factor A. Surprisingly, tissue levels of mtTFA protein were reduced about twofold, together with mitochondrial DNA. In conclusion, mitochondria are able to maintain high rates of mitochondrial transcription even in the presence of reduced mtTFA protein and mtDNA levels. Therefore, stimulated mtTFA gene expression accompanies stimulated mitochondrial transcription, as in other models, but it is not sufficient for an increase of mtDNA copy number and other, yet unknown, factors have to be postulated.
TL;DR: High levels of similarity throughout the proteins, in particular in regions involved in enzyme activity, co-factor and regulator binding, are revealed, suggesting non-conserved residues between the subunits from the two yeasts are candidates for involvement in the interaction with RNA.
Abstract: Krebs cycle NAD+-isocitrate dehydrogenase (Idh) binds to the 5-UTRs of all mitochondrial mRNAs in Saccharomyces cerevisiae. We hypothesize that this leader-binding activity plays a role in translational regulation, thereby linking mitochondrial biogenesis to the need for respiratory function. Analysis of effects of leader binding on mitochondrial translation is complicated by the involvement of the enzyme in mitochondrial metabolism. We have therefore searched for an Idh altered in RNA binding, but retaining full enzyme activity. Idh from Kluyveromyces lactis and Schizosaccharomyces pombe was partially purified and examined for the ability to bind Cox2 mRNA. Sch. pombe Idh, like the S. cerevisiae enzyme, has high affinity for both its own, K. lactis and S. cerevisiaeCOX2 leaders. In contrast, Idh purified from K. lactis shows only low affinity for all mRNAs tested. To determine what distinguishes K. lactis Idh from S. cerevisiae Idh, genes encoding the two subunits of Idh in K. lactis were cloned and sequenced. Sequence comparison revealed high levels of similarity throughout the proteins, in particular in regions involved in enzyme activity, co-factor and regulator binding. Non-conserved residues between the subunits from the two yeasts are candidates for involvement in the interaction with RNA.
TL;DR: It is suggested that a secondary form of mitochondrial biogenesis, involving the massive participation of other organelles and independent of the classical mechanisms inherent in mitosis, occurs in parietal cells at the beginning of G1 phase during the 6 days of their maturation.
Patent•
13 Nov 2000
TL;DR: In this paper, a comparison and methods for the treatment of diseases associated with altered mitochondrial function, and in particular for type 2 diabetes mellitus, are provided for different types of mutations.
Abstract: Compositions and methods are provided for the treatment of diseases associated with altered mitochondrial function, and in particular, for type 2 diabetes mellitus. Administration of an agent that increases mitochondrial mass, including promotion of mitochondrial biogenesis by induction of a PGC gene e.g., PGC-1), a UCP gene and/or a nuclear regulatory factor gene e.g., NRF-1), is also disclosed. Screening assays for agents that regulate such genes involved in mitochondiral biogenesis, and for genes and gene products that are regulated by such genes involved in mitochondrial biogenesis, are also provided.