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Prolonged linezolid therapy induces progressive mitochondrial dysfunction in human peripheral blood mononuclear cells
Marta Martínez-Guitián1, Francisco Cajade-Pascual1,2, Diana Carolina Castro-Fernández1
1FarmaCHUSLab, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, 15706, Spain.
Background:
Linezolid commonly causes hematologic toxicity, especially thrombocytopenia, during extended treatment. This effect is linked to the inhibition of mitochondrial protein synthesis, which impairs oxidative phosphorylation and cellular energy production. Although reduced complex IV activity has been observed in long-term therapy, the connection between treatment duration and mitochondrial dysfunction in humans remains insufficiently defined.
Methods:
Forty patients were included and stratified by treatment duration: 2-7 days (group 1), 8-14 days (group 2) and more than 14 days (group 3). To evaluate mitochondrial function in peripheral blood mononuclear cells (PBMCs) from patients treated with linezolid for different durations, Seahorse XF was used. To assess protein expression changes associated with mitochondrial toxicity, LC-MS/MS was used. Differentially expressed proteins were identified in R based on fold-change thresholds (|log₂FC|≥0.58) and p < 0.05, and results were visualized with volcano plots and STRING interaction networks.
Results:
All the groups were similar in terms of variables and characteristics. Mitochondrial respiration declined progressively with treatment duration and platelet counts showed a parallel reduction. Proteomic analysis identified one cluster of downregulated protein in group 2 of patients and two in group 3; they were involved in mitochondrial ATP synthesis-mainly subunits of complexes I and IV of the respiratory chain-supporting a concordant functional and molecular pattern of mitochondrial impairment.
Conclusions:
Prolonged linezolid treatment was associated with progressive mitochondrial dysfunction, as reflected by both functional assays and proteomic profiles. Concordant changes in respiration and protein expression support mitochondrial involvement in linezolid-related toxicity and suggest that, in addition to previously reported alterations in complex IV, complex I proteins may also be affected in treated patients.
Insights
Prolonged linezolid treatment progressively impairs mitochondrial function and reduces platelet counts. This study links linezolid
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Linezolid treatment can cause hematologic toxicity, particularly thrombocytopenia, linked to mitochondrial dysfunction.
- Inhibition of mitochondrial protein synthesis impairs cellular energy production, but human data on treatment duration and mitochondrial dysfunction are limited.
Purpose of the Study:
- To investigate the impact of linezolid treatment duration on mitochondrial function and protein expression in patients.
- To establish a correlation between linezolid therapy length, mitochondrial impairment, and hematologic toxicity.
Main Methods:
- Forty patients were stratified into three groups based on linezolid treatment duration (2-7, 8-14, >14 days).
- Mitochondrial function was assessed using Seahorse XF analysis of peripheral blood mononuclear cells (PBMCs).
- Protein expression changes related to mitochondrial toxicity were analyzed using LC-MS/MS.
Main Results:
- Mitochondrial respiration and platelet counts decreased progressively with increasing linezolid treatment duration.
- Proteomic analysis revealed downregulation of proteins involved in mitochondrial ATP synthesis, including subunits of respiratory chain complexes I and IV.
- Functional and molecular data showed a consistent pattern of mitochondrial impairment.
Conclusions:
- Prolonged linezolid treatment is associated with progressive mitochondrial dysfunction and hematologic toxicity.
- Mitochondrial involvement in linezolid toxicity is supported by concordant changes in respiration and protein expression.
- Complex I proteins, in addition to Complex IV, may be affected by linezolid therapy.
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