scholarly journals Mitochondrial Alterations (Inhibition of Mitochondrial Protein Expression, Oxidative Metabolism, and Ultrastructure) Induced by Linezolid and Tedizolid at Clinically Relevant Concentrations in Cultured Human HL-60 Promyelocytes and THP-1 Monocytes

2017 ◽  
Vol 62 (3) ◽  
Author(s):  
Tamara V. Milosevic ◽  
Valéry L. Payen ◽  
Pierre Sonveaux ◽  
Giulio G. Muccioli ◽  
Paul M. Tulkens ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Oxidative Metabolism ◽  
Oxidase Activity ◽  
Potent Inhibitor ◽  
Mitochondrial Protein ◽  
Mitochondrial Protein Synthesis ◽  
Once Daily ◽  
Content Type ◽  
Mitochondrial Alterations ◽  
Mitochondrial Oxidative Metabolism

ABSTRACTLinezolid, the first clinically available oxazolidinone antibiotic, causes potentially severe toxicities (myelosuppression, lactic acidosis, and neuropathies) ascribed to impairment of mitochondrial protein synthesis and consecutive mitochondrial dysfunction. Tedizolid, a newly approved oxazolidinone, shows an enhanced activity compared to linezolid but is also a more potent inhibitor of mitochondrial protein synthesis. We compared linezolid and tedizolid for (i) inhibition of the expression of subunit I of cytochromec-oxidase (CYTox I; Western blot analysis), (ii) cytochromec-oxidase activity (biochemical assay), (iii) mitochondrial oxidative metabolism (Seahorse technology), and (iv) alteration of mitochondrial ultrastructure (electron microscopy) using HL-60 promyelocytes and THP-1 monocytes exposed to microbiologically (multiples of modal MIC againstStaphylococcus aureus) and therapeutically (Cmin−Cmax) pertinent concentrations. Both drugs caused a rapid and complete (48 to 72 h) inhibition of CYTox I expression, cytochromec-oxidase activity, and spare respiratory capacity, with conspicuous swelling of the mitochondrial matrix and loss of their cristae. Globally, tedizolid was a more potent inhibitor than linezolid. For both drugs, all effects were quickly (48 to 72 h) and fully reversible upon drug withdrawal. Using an alternation of exposure to and withdrawal from drug mimicking their approved schedule of administration (twice daily and once daily [qD] for linezolid and tedizolid, respectively), only partial inhibition of CYTox I expression was noted for up to 96 h. Thus, rapid reversal of toxic effects upon discontinuous administration may mitigate oxazolidinone toxicity. Since tedizolid is given qD, this may help to explain its reported lower preclinical and clinical toxicity.

Oxytetracycline inhibition of mitochondrial protein synthesis in bovine lymphocytes infected withTheileria parvaor stimulated by mitogen

Parasitology ◽  
1990 ◽  
Vol 101 (3) ◽  
pp. 387-393 ◽  
Author(s):  
P. R. Spooner
Keyword(s):  
Protein Synthesis ◽  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Oxidase Activity ◽  
Mitochondrial Protein ◽  
Inhibitory Effect ◽  
Mitochondrial Protein Synthesis ◽  
Drug Concentrations ◽  
Bovine Lymphocytes

SUMMARYOxytetracycline (OTC) significantly inhibited cytochrome c oxidase activity in bovine lymphocytes infected withTheileria parvaand in uninfected mitogen-stimulated lymphocytes. The inhibitory effect was detectedin vitrowithin 24 h of treatment with drug concentrations as low as 1 µg/ml. Following mitogen stimulation of lymphocytes, concentrations of 3 and 10 µg/ml OTC completely inhibited an increase in cytochrome c oxidase activity for 48–72 h. This inhibitory activity was considered to be due to a direct effect on lymphoblast mitochondrial protein synthesis. As a consequence, adenosine triphosphate activity was significantly reduced in lymphocytes stimulated either by infection withT. parvasporozoites or by mitogen and then treated with OTC. The results also indicated that parasite mitochondrial protein synthesis was inhibited by OTC. The activity of OTC reported in this study could explain the suppression of disease following ‘infection and treatment’ immunization against East Coast fever and thein vitrodrug-inhibition of schizont development.

scholarly journals Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 674
Author(s):  
Francesco Capriglia ◽  
Francesca Rizzo ◽  
Giuseppe Petrosillo ◽  
Veronica Morea ◽  
Giulia d’Amati ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Molecular Mechanisms ◽  
Mitochondrial Protein ◽  
Trna Synthetase ◽  
Mitochondrial Protein Synthesis ◽  
Mitochondrial Translation ◽  
Terminal Domain ◽  
Carboxy Terminal Domain ◽  
Mitochondrial Functions ◽  
Carboxy Terminal

The m.3243A>G mutation within the mitochondrial mt-tRNALeu(UUR) gene is the most prevalent variant linked to mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome. This pathogenic mutation causes severe impairment of mitochondrial protein synthesis due to alterations of the mutated tRNA, such as reduced aminoacylation and a lack of post-transcriptional modification. In transmitochondrial cybrids, overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) has proven effective in rescuing the phenotype associated with m.3243A>G substitution. The rescuing activity resides in the carboxy-terminal domain (Cterm) of the enzyme; however, the precise molecular mechanisms underlying this process have not been fully elucidated. To deepen our knowledge on the rescuing mechanisms, we demonstrated the interactions of the Cterm with mutated mt-tRNALeu(UUR) and its precursor in MELAS cybrids. Further, the effect of Cterm expression on mitochondrial functions was evaluated. We found that Cterm ameliorates de novo mitochondrial protein synthesis, whilst it has no effect on mt-tRNALeu(UUR) steady-state levels and aminoacylation. Despite the complete recovery of cell viability and the increase in mitochondrial translation, Cterm-overexpressing cybrids were not able to recover bioenergetic competence. These data suggest that, in our MELAS cell model, the beneficial effect of Cterm may be mediated by factors that are independent of the mitochondrial bioenergetics.

Gender dimorphism in rat liver mitochondrial oxidative metabolism and biogenesis

2005 ◽  
Vol 289 (2) ◽  
pp. C372-C378 ◽  
Author(s):  
Roberto Justo ◽  
Jordi Boada ◽  
Margalida Frontera ◽  
Jordi Oliver ◽  
Jordi Bermúdez ◽  
...  
Keyword(s):  
Gender Differences ◽  
Protein Content ◽  
Rat Liver ◽  
Oxidative Metabolism ◽  
Mitochondrial Protein ◽  
Electron Microscopic ◽  
Gender Dimorphism ◽  
Protein Levels ◽  
Mitochondrial Fractions ◽  
Mitochondrial Oxidative Metabolism

In the present study, we have investigated gender differences in rat liver mitochondrial oxidative metabolism. Total mitochondrial population (M) as well as the heavy (M1), medium (M3), and light (M8) mitochondrial fractions obtained by means of differential centrifugation steps at 1,000, 3,000, and 8,000 g, respectively, were isolated. Electron microscopic analysis was performed and mitochondrial protein content and cardiolipin levels, mitochondrial O2 flux, ATP synthase activity, mitochondrial membrane potential, and mitochondrial transcription factor A (TFAM) protein levels were measured in each sample. Our results indicate that mitochondria from females have higher protein content and higher cardiolipin levels, greater respiratory and phosphorylative capacities, and more-energized mitochondria in respiratory state 3. Moreover, protein levels of TFAM were four times greater in females than in males. Gender differences in the aforementioned parameters were more patent in the isolated heavy M1 and M3 mitochondrial fractions. The present study demonstrates that gender-related differences in liver mitochondrial function are due mainly to a higher capacity and efficiency of substrate oxidation, likely related to greater mitochondrial machinery in females than in males, which is in accord with greater mitochondrial differentiation in females.

scholarly journals Skeletal muscle mitochondrial protein synthesis and respiration in response to the energetic stress of an ultra-endurance race

2017 ◽  
Vol 123 (6) ◽  
pp. 1516-1524 ◽  
Author(s):  
Adam R. Konopka ◽  
William M. Castor ◽  
Christopher A. Wolff ◽  
Robert V. Musci ◽  
Justin J. Reid ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Endurance Exercise ◽  
Mitochondrial Respiration ◽  
Endurance Athlete ◽  
Control Period ◽  
Mitochondrial Protein ◽  
Mitochondrial Bioenergetics ◽  
Mitochondrial Protein Synthesis ◽  
Ultra Endurance

The 2016 Colorado Trail Race (CTR) was an ultra-endurance mountain bike race in which competitors cycled for up to 24 h/day between altitudes of 1,675 and 4,025 m to complete 800 km and 21,000 m of elevation gain. In one athlete, we had the unique opportunity to characterize skeletal muscle protein synthesis and mitochondrial respiration in response to a normal activity control period (CON) and the CTR. We hypothesized that mitochondrial protein synthesis would be elevated and mitochondrial respiration would be maintained during the extreme stresses of the CTR. Titrated and bolus doses of ADP were provided to determine substrate-specific oxidative phosphorylation (OXPHOS) and electron transport system (ETS) capacities in permeabilized muscle fibers via high-resolution respirometry. Protein synthetic rates were determined by daily oral consumption of deuterium oxide (2H2O). The endurance athlete had OXPHOS (226 pmol·s−1·mg tissue−1) and ETS (231 pmol·s−1·mg tissue−1) capacities that rank among the highest published to date in humans. Mitochondrial (3.2-fold), cytoplasmic (2.3-fold), and myofibrillar (1.5-fold) protein synthesis rates were greater during CTR compared with CON. With titrated ADP doses, the apparent Km of ADP, OXPHOS, and ETS increased after the CTR. With provision of ADP boluses after the CTR, the addition of fatty acids (−12 and −14%) mitigated the decline in OXPHOS and ETS capacity during carbohydrate-supported respiration (−26 and −31%). In the face of extreme stresses during the CTR, elevated rates of mitochondrial protein synthesis may contribute to rapid adaptations in mitochondrial bioenergetics. NEW & NOTEWORTHY The mechanisms that maintain skeletal muscle function during extreme stresses remain incompletely understood. In the current study, greater rates of mitochondrial protein synthesis during the energetic demands of ultra-endurance exercise may contribute to rapid adaptations in mitochondrial bioenergetics. The endurance athlete herein achieved mitochondrial respiratory capacities among the highest published for humans. Greater mitochondrial protein synthesis during ultra-endurance exercise may contribute to improved mitochondrial respiration and serve as a mechanism to resist cellular energetic stresses.

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