Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to its toxic 1-methyl-4-phenylpyridinium (MPP+) metabolite catalyzed by monoamine oxidase (MAO) type B is likely to occur within glial cells in the central nervous system. In this study, primary cultures of mouse astrocytes were used to assess the biochemical and toxic consequences of exposure to MPTP. MPTP caused a concentration-dependent loss of cell viability. This effect was probably due to the intracellular generation of MPP+, because cytotoxicity was prevented by preincubation of astrocytes in the presence of MAO inhibitors. After addition of 250 microM MPTP, loss of cell viability was preceded by an increased rate of glucose utilization and lactate accumulation, and by depletion of ATP. The ratio between the rates of lactate production (0.37 mM/hr) and glucose consumption (0.2 mM/hr) was 1.85, indicating that most of the glucose present in the medium was stoichiometrically converted to lactate via glycolysis. A remarkable correlation was found between ATP depletion and cytotoxicity caused by MPTP, and, when astrocytes were incubated in glucose-free medium, both ATP depletion and loss of viability occurred more rapidly. Finally, even after exposure for several days, astrocyte death could be prevented by washing MPTP from the incubation medium, suggesting that MPP(+)-induced mitochondrial damage may be reversible. We conclude that prolonged exposure of astrocytes to MPTP may result in loss of viability via the MAO-dependent generation of MPP+ and the ability of this toxic metabolite to impair mitochondrial function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes. 156 Mar 84

Since the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, it has been postulated that (a) MPTP-like toxin(s) such as 1,2,3,4-tetrahydroisoquinoline (TIQ) may induce Parkinson's disease. As the neuronal degeneration in MPTP-induced parkinsonism is thought to be caused by the inhibition of the mitochondrial respiration by 1-methyl-4-phenylpyridinium ion (MPP+), we studied the effects of TIQ-like alkaloids including dopamine-derived ones on the mitochondrial respiration using mouse brains. TIQ, tetrahydropapaveroline (THP), and tetrahydropapaverine (THPV) produced significant inhibition of the state 3 and 4 respiration and respiratory control ratio supported by glutamate + malate, the activity of Complex I and the ATP synthesis. Among those compounds, THPV was most potent. Toxic properties of these compounds on mitochondria were quite similar to that of MPP+. Our results support the hypothesis that (a) MPTP- or MPP(+)-like substance(s) may be responsible for the nigral degeneration in Parkinson's disease.
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PMID:Inhibition of mitochondrial respiration by 1,2,3,4-tetrahydroisoquinoline-like endogenous alkaloids in mouse brain. 197 53

The relationships between mitochondrial transmembrane potential, ATP concentration, and cytotoxicity were evaluated after exposure of isolated rat hepatocytes to different mitochondrial poisons. Both the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its fully oxidized metabolite, the 1-methyl-4-phenylpyridinium (MPP+) ion, caused a concentration- and time-dependent depolarization of mitochondrial membranes which followed ATP depletion and preceded cytotoxicity. The effect of MPTP, but not that of MPP+, was prevented by deprenyl, an inhibitor of MPTP conversion to MPP+ via monoamine oxidase type B. Addition of fructose to the hepatocyte incubations treated with either MPTP or MPP+ counteracted the loss of mitochondrial transmembrane potential. Fructose was also effective in protecting against the mitochondrial membrane depolarization as well as ATP depletion and cytotoxicity induced by antimycin. A, carbonyl cyanide p-trifluoromethoxyphenyl hydrazone, and valinomycin. Data confirm the key role played by MPP(+)-induced mitochondrial damage in MPTP toxicity and indicate that (i) ATP produced via the glycolytic pathway can be utilized by hepatocytes to maintain mitochondrial electrochemical gradient, and (ii) a loss of mitochondrial membrane potential may occur only when supplies of ATP are depleted.
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PMID:Relationships between the mitochondrial transmembrane potential, ATP concentration, and cytotoxicity in isolated rat hepatocytes. 212 6

Succinate dehydrogenase (EC 1.3.99.1) in the yeast Saccharomyces cerevisiae is a mitochondrial heterotetramer containing a flavoprotein subunit with an 8alpha-N(3)-histidyl-linked FAD cofactor. The covalent linkage of the FAD is necessary for activity. We have developed an in vitro assay that measures the flavinylation of the flavoprotein precursor in mitochondrial matrix fractions. Flavoprotein modification does not depend on translocation across a membrane, but it does require proteolytic processing by the mitochondrial processing peptidase prior to flavin attachment. Since ATP depletion, N-ethylmaleimide, or proteinase treatments of matrix fractions inhibit flavoprotein modification, at least one additional matrix protein component appears to be required. Having previously suggested that the flavoprotein begins folding before FAD attachment occurs, we tested whether the mitochondrial chaperonin, heat shock protein 60, might be necessary. Co-immunoprecipitation of the flavoprotein and the chaperonin demonstrate that the proteins do indeed interact. However, immunodepletion of the chaperonin from matrix fractions does not inhibit FAD attachment. Nonprotein components are also required for flavoprotein modification. In addition to ATP, effector molecules such as succinate, fumarate, or malate also stimulate modification. Together, these results suggest that FAD addition is an early event in succinate dehydrogenase assembly.
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PMID:A requirement for matrix processing peptidase but not for mitochondrial chaperonin in the covalent attachment of FAD to the yeast succinate dehydrogenase flavoprotein. 862 40

The mitochondrial processing peptidase (MPP) of Neurospora crassa consists of two subunits termed alpha-and beta-MPP. Here we present spectroscopic and chromatographic studies indicative of adenine nucleotide binding in the two MPP subunits. ADP was identified as the cofactor of alpha-MPP and ATP as the cofactor of beta-MPP. The nucleotides are not covalently bound and exert strong control on the conformational and functional properties of the subunits. The ADP cofactor of alpha-MPP seems to be of utmost importance for the proteolytic activity because no processing of the precursor protein was registered in the assay containing alpha-MPP depleted of ADP and native beta-MPP. On the contrary, with native alpha-MPP and depleted of ATP beta-MPP almost 100% processing activity could be measured. Very strong increase of the intensity and significant changes in the shape and maximum position of the protein fluorescence spectra were observed after removal of the adenine cofactors of alpha- and of beta-MPP.
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PMID:Evidences for adenine nucleotide binding in the subunits of Neurospora mitochondrial processing peptidase. 880 42

1-Methyl-4-phenylpyridinium (MPP+), the cytotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has been shown to be toxic to a variety of cell types in culture. The addition of media containing 1 mM MPP+ to cultures of Chinese hamster ovary (CHO) fibroblasts led to the gradual depletion of cellular ATP stores and subsequent cell death. A 12-min heat shock of the cells at 45 degrees C, 3 h prior to the addition of MPP(+)-containing media, significantly attenuated cell death. Heat shock pretreatment led to an increased synthesis of all the major heat shock proteins (HSPs) in CHO cells. Further, the addition of the protein synthesis inhibitor, cycloheximide, prevented the protective effect of heat shock pretreatment, indicating that this protection was dependent upon new protein synthesis. In additional experiments, a rat fibroblast cell line which has been stably transfected with, and constitutively expresses a cloned human HSP-70 gene, was found to be more resistant to the cytotoxic effects of MPP+ than the parental fibroblast cell line. These results indicate that HSPs are protective toward the deleterious effects of MPP+ and that their synthesis represents an important parameter in the neurotoxicity of MPTP.
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PMID:Heat shock proteins protect cultured fibroblasts from the cytotoxic effects of MPP+. 890 68

The synthetic precursor of the F(A)d subunit of mitochondrial ATP synthase was imported into isolated soybean cotyledon mitochondria. Import of the F(A)d precursor was accompanied by processing to a lower molecular weight mature form. The F(A)d precursor displayed the following import characteristics not seen before with plant mitochondria: efficient import in the absence of external ATP and import of wheat germ-translated precursor. Pretreatment of the F(A)d precursor with NEM did not inhibit import. Taken together with the lack of a requirement for external ATP, this indicates that this precursor does not require extramitochondrial ATP-dependent factors for import. Binding studies indicated that the F(A)d precursor bound to a proteinaceous component of the mitochondrial outer membrane. Inhibitor studies indicated that processing was most likely via the general mitochondrial processing peptidase. The results suggest that import of this subunit occurs via a pathway different from the general import pathway described for the majority of precursor proteins.
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PMID:Characterization of the import pathway of the F(A)d subunit of mitochondrial ATP synthase into isolated plant mitochondria. 891 33

Oxa1p, a nuclear-encoded protein of the mitochondrial inner membrane with five predicted transmembrane (TM) segments is synthesized as a precursor (pOxa1p) with an N-terminal presequence. It becomes imported in a process requiring the membrane potential, matrix ATP, mt-Hsp70 and the mitochondrial processing peptidase (MPP). After processing, the negatively charged N-terminus of Oxa1p (approximately 90 amino acid residues) is translocated back across the inner membrane into the intermembrane space and thereby attains its native N(out)-C(in) orientation. This export event is dependent on the membrane potential. Chimeric preproteins containing N-terminal stretches of increasing lengths of Oxa1p fused on mouse dehydrofolate reductase (DHFR) were imported into isolated mitochondria. In each case, their DHFR moieties crossed the inner membrane into the matrix. Thus Oxa1p apparently does not contain a stop transfer signal. Instead the TM segments are inserted into the membrane from the matrix side in a pairwise fashion. The sorting pathway of pOxa1p is suggested to combine the pathways of general import into the matrix with a bacterial-type export process. We postulate that at least two different sorting pathways exist in mitochondria for polytopic inner membrane proteins, the evolutionarily novel pathway for members of the ADP/ATP carrier family and a conserved Oxa1p-type pathway.
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PMID:Insertion into the mitochondrial inner membrane of a polytopic protein, the nuclear-encoded Oxa1p. 917 37

The biogenesis of the ATP-dependent PIM1 protease of mitochondria was studied by mutational analysis. The ATPase and proteolytic activities of PIM1 were shown to be essential for mitochondrial function. A proteolytically inactive mutant form of PIM1 protease accumulated as a pro-form in mitochondria, revealing a two-step processing of PIM1: the matrix targeting signal is removed by the mitochondrial processing peptidase and then a pro-region of 61 amino acids is cleaved off in an autocatalytic reaction. This latter process depended on the ATP-dependent assembly of PIM1 protease subunits and can occur by an intermolecular and, most probably, also an intramolecular pathway. The respiratory competence of cells harboring mutant PIM1 protease lacking the pro-region was strongly impaired. Subcellular fractionation revealed a cytosolic localization of mutant PIM1 protease. This demonstrates the requirement for the propeptide for efficient sorting of PIM1 protease to mitochondria.
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PMID:Autocatalytic processing of the ATP-dependent PIM1 protease: crucial function of a pro-region for sorting to mitochondria. 940 61

Nuclear-encoded mitochondrial precursor proteins are proteolytically processed inside the mitochondrion after import. The general mitochondrial processing activity in plant mitochondria has been shown to be integrated into the cytochrome bc1 complex of the respiratory chain. Here we investigate the occurrence of an additional, matrix-located processing activity by incubation of the precursors of the soybean mitochondrial proteins, alternative oxidase, the FAd subunit of the ATP synthetase and the tobacco F1 beta subunit of the ATP synthase, with the membrane and soluble components of mitochondria isolated from soybean cotyledons and spinach leaves. A matrix-located peptidase specifically processed the precursors to the predicted mature form in a reaction which was sensitive to orthophenanthroline, a characteristic inhibitor of mitochondrial processing peptidase (MPP). The specificity of the matrix peptidase was illustrated by the inhibition of processing of the alternative oxidase precursor in both soybean and spinach matrix extracts upon altering a single amino acid residue in the targeting presequence (-2 Arg to Gly). Additionally, there was no evidence for general proteolysis of precursor proteins incubated with the matrix. The purity of the matrix fractions was ascertained by spectrophotometric and immunological analyses. The results demonstrate that there is a specific processing activity in the matrix of soybean and spinach in addition to the previously well characterized membrane-bound MPP integrated into the cytochrome bcl complex of the respiratory chain.
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PMID:A matrix-located processing peptidase of plant mitochondria. 948 72


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