Mitochondrial protein synthesis

Certain antibiotics (for example, chloramphenicol) inhibit mitochondrial protein synthesis, but not cytoplasmic protein synthesis, because mitochondrial ribosomes are similar to prokaryotic ribosomes. 

Proliferation Inhibitor of DNA polymerase-gamma (e.g., nucleoside reverse transcriptase inhibitors) inhibition of mitochondrial protein synthesis (e.g., oxazolidinone antibiotics) mitochondrial DNA mutation (e.g.. oxidative injury by ethanol)... 

Drugs Inhibiting mtDNA Synthesis and Mitochondrial Protein Synthesis... 

Anandatheerthavarada, H.K. etal. (1999) Physiological role of the N-terminal processed P4501A1 targeted to mitochondria in erythromycin metabolism and reversal of erythromycin-mediated inhibition of mitochondrial protein synthesis./oumoi of Biological Chemistry, 274 (10), 6617-6625. 

De Vriese, A.S. et al. (2006) Linezolid-induced inhibition of mitochondrial protein synthesis. Clinical Infectious Diseases, 42 (8), 1111-1117. 

In many ways, mitochondria resemble bacteria for example, the mitochondrial ribosomal RNA genes of all eukaryotes have been traced back to the eubacteria [10]. This can explain why some antibacterial compounds with the target of inhibiting bacterial protein synthesis also inhibit mitochondrial protein synthesis [6, 11, 12], resulting in hematotoxicity. Tetracycline, chloramphemcol and some oxazolidinone antibiotics have been shown to induce hematotoxicity by inhibiting mitochondrial protein synthesis [13]. 

McKee, E.E., Furguson, M., Bentley, A.T. and Marks, T.A. (2006) Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones. Antimicrob Agents Chemotherapy, 50, 2042-2049. 

Mitochondrial diseases are caused by mutations in various mtDNA-encoded genes, most of which result in defective mitochondrial protein synthesis. 

Mostly chloramphenicol is well tolerated with only mild gastrointestinal disturbances. However this antibiotic inhibits mitochondrial protein synthesis in red blood cell precursors in the bone marrow and thus may cause dose-dependent anemia. This dose dependent reaction should not be confused with the idiosyncratic aplastic anemia which is dose-independent and usually fatal. The onset of this idiosyncrasy which has an incidence of about 1 20 000-1 50 000 may be during the treatment or weeks to months after therapy. 

The drug-induced inhibition of mitochondrial protein synthesis is probably responsible for the associated toxicity. 

The principal toxicity of linezolid is hematologic—reversible and generally mild. Thrombocytopenia is the most common manifestation (seen in approximately 3% of treatment courses), particularly when the drug is administered for longer than 2 weeks. Anemia and neutropenia may also occur, most commonly in patients with a predisposition to or underlying bone marrow suppression. Cases of optic and peripheral neuropathy and lactic acidosis have been reported with prolonged courses of linezolid. These side effects are thought to be related to linezolid-induced inhibition of mitochondrial protein synthesis. 

CHLORAMPHENICOL3 Inhibits prokaryotic peptldyltransferase. High levels may also inhibit mitochondrial protein synthesis. 

A3243G tRNAUu(UUR) Decrease in mitochondrial protein synthesis Cll, K4, K6... 

K3. King, M. P., Koga, Y., Davidson, M., and Schon, E. A., Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNALe (UUR> mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Mol. Cell. Biol. 12, 480-490 (1992). 

Kwast, K.E., and S.C. Hand (1996). Acute depression of mitochondrial protein synthesis during anoxia Contributions of oxygen sensing, matrix... 

Mutations in tRNALeu n UR) may be expected to have an important effect on protein synthesis in mitochondria. The MELAS-associated human mitochondrial tRNALeu <[ UR) mutation causes aminoacylation deficiency and a concomitant defect in translation initiation (Borner et al., 2000). The expected result would be a deficit in general mitochondrial protein synthesis with resulting deficiencies of multiple OXPHOS components. Patients with MELAS disorder have been found to have a marked decrease in the activity of respiratory Complex I with a secondary reduction in the activity of Complex IV... 

Pace, J.G., Watts, M.R., Canterbury, W.J. (1988). T-2 mycotoxin inhibits mitochondrial protein synthesis. Toxicon 26 77-85. 

Chloramphenicol causes two types of hematopoietic abnormality. The first is a dose-related toxic effect causing a bone marrow depression associated with inhibition of mitochondrial protein synthesis. Usually, discontinuing the antibiotic reverses this toxicity. 

Although a few subunits of mitochondrial membrane proteins are coded by mitochondrial DNA and synthesized in the mitochondrial matrix, most membrane proteins including the adenine nucleotide carrier are coded by nuclear genes and synthesized on cytoplasmic ribosomes [80,81], Chloramphenicol, an inhibitor of mitochondrial protein synthesis, does not inhibit incorporation of radioactive leucine into the carrier in growing Neurospora crassa, but cycloheximide, an inhibitor of cytoplasmic protein synthesis, does inhibit leucine incorporation [78]. Also, a yeast nuclear respiratory mutant has been shown to cause a defect in adenine nucleotide transport [81], and the nuclear gene responsible for coding the carrier in yeast is currently being cloned for further studies [82]. 

Although thiamphenicol penetrates the fetal circulation and is distributed evenly in fetal tissues, no fetal abnormalities have been related to thiamphenicol administration during pregnancy (18). Since mitochondrial protein synthesis in the fetal liver is inhibited by the drug concentrations normally attained, repeated administration of thiamphenicol to pregnant women is not recommended. 

Chloramphenicol - L-T reo chloramphenicol, an isomer which does not inhibit mitochondrial protein synthesis, did exert an effect on bone marrow in rats.147 Previous studies had related the two effects. A resistance factor elaborated by Pseudomonas aeruginosa K-102 was thought to control the function of membrane permeability of the cells.11 8... 

Mitochondria and chloroplasts are the two main eukaryotic cellular organelles that contain their own genome and undertake the semi-independent processes of transcription and translation. Most of the constituent proteins of these organelles are imported from the surrounding cytoplasm, but each organelle also synthesizes its own proteins. Here we shall limit our discussion to mitochondrial protein synthesis, because the chloroplast is not present in animal cells. 

Finally, lycorine inhibited the growth of rho+, mit and rho strains of Saccharomyces cerevisiae, while rho0 strains (devoid of mitochondrial DNA) were resistant to high concentrations of the alkaloid. Total protein synthesis and mitochondrial protein synthesis are only slightly inhibited by lycorine. It had, however, an inhibitory effect on DNA and RNA [172],... 

Dose-related erythroid suppression probably reflects inhibition of mitochondrial protein synthesis in erythroid precursors, which impairs iron incorporation into heme. Bone marrow suppression occurs regularly with plasma concentrations >25 pg/mL and is observed with large doses of chloramphenicol, prolonged treatment, or both. Dose-related bone marrow suppression may progress to aplasia if treatment is continued, but most cases of aplasia develop without prior dose-related marrow suppression. 

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