Influence of Mitochondrial Genetics on the Mitochondrial Toxicity of Linezolid in Blood Cells and Skin Nerve Fibers

Abstract

The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28-day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706A¡G, m.3197T¡C, and m.3010G¡A polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts.

Drug-Induced Alterations of Mitochondrial DNA Homeostasis in Steatotic and Nonsteatotic HepaRG Cells

“…This suggests the existence of an interindividual variability regarding imipramine and ritonavir-induced impairment of mitochondrial translation. Interestingly, genetic susceptibility was reported for antibiotic-induced alterations of mitochondrial protein synthesis and related adverse effects (Hobbie et al, 2008;Garrabou et al, 2017).…”

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

“…The potential toxicity of oxazolidinones has been recognized early in their preclinical development (23,24,38,39) and its clinical impact for linezolid underlined through an abundance of case reports (see, for example, references 10, 11, 12, 14, 17, 40, 41, 42, and 43), epidemiological studies (see, for example, references 16, 44, 45, 46, 47, and 48), and reviews (7,(49)(50)(51)(52), as well as through in-depth ex vivo analyses of samples from treated patients (17,18,42,53). Collectively, these studies point to mitochondria as key and selective toxicity targets in eukaryotic cells, with clear evidence of inhibition of the a The apparent cellular concentrations of oxazolidinones in HL-60 promyelocytes and THP-1 monocytes were determined upon incubation at extracellular concentrations corresponding to their total human C max (linezolid [LZD], 15 mg/liter [28]; tedizolid [TZD], 3 mg/liter [29,35]).…”

“…If this concept applies to HL-60 and THP-1 cells, it would explain why no mitochondrial depolarization was observed, because only a limited number of cells would be affected at any time point, making the global assay used here grossly insensitive. However, successive occurrence of stochastic effects in vivo may also explain why mitochondrial toxic effects of oxazolidinones eventually translate into overt organ toxicity (such as myelosuppressive effects) only after prolonged treatment times and why they may remain rare (such as neurotoxic effects, for which genetic predisposition may play a critical role [18,53]).…”

A Case of Linezolid Toxicity Presenting as a Sepsis Mimic

“…We faced challenges in management of possible MRSA infection in view of unclear history of vancomycin allergy. Mitochondrial genetics has been studied in linezolid toxicity, specifically for those related to shorter duration of therapy [30]. In presented cases, mitochondrial genetic can explain presentation of lactic acidosis.…”