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Antimicrob Agents Chemother. 2017 Aug 24;61(9). pii: e00542-17. doi: 10.1128/AAC.00542-17. Print 2017 Sep.

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

Author information

1
Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences-University of Barcelona, Barcelona, Spain garrabou@clinic.ub.es.
2
Centro de Investigación Biomédica en Red en Enfermedades Raras‡.
3
Infectious Diseases Department, Hospital Clinic of Barcelona, Barcelona, Spain.
4
Mitochondrial and Neuromuscular Pathology Department, CIBBIM, Laboratory, Institute of Research, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
5
Neurology Department, Hospital Clinic of Barcelona, Barcelona, Spain.
6
Biochemical, Molecular and Cellular Biology Department, University of Zaragoza, Zaragoza, Spain.
7
Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences-University of Barcelona, Barcelona, Spain.
8
Internal Medicine Department, Hospital Clinic of Barcelona, Barcelona, Spain.

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.

KEYWORDS:

16S rRNA; genetic polymorphisms; haplogroups; linezolid; mitochondrial genetics; mitochondrial protein synthesis; single nucleotide polymorphisms; toxicity

PMID:
28674062
PMCID:
PMC5571298
DOI:
10.1128/AAC.00542-17
[Indexed for MEDLINE]
Free PMC Article

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