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Antimicrobial Agents and Chemotherapy, March 2007, p. 962-967, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01190-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Reversible Inhibition of Mitochondrial Protein Synthesis during Linezolid-Related Hyperlactatemia{triangledown}

Glòria Garrabou,1 Alejandro Soriano,2 Sònia López,1 Jordi P. Guallar,3 Marta Giralt,3 Francesc Villarroya,3 Jose A. Martínez,2 Jordi Casademont,1 Francesc Cardellach,1 Josep Mensa,2 and Òscar Miró1*

Mitochondrial Research Laboratory, IDIBAPS, Internal Medicine Department,1 Infectious Diseases Department, Hospital Clinic of Barcelona,2 Biochemical and Molecular Biology Department, University of Barcelona, Barcelona, Catalonia, Spain3

Received 22 September 2006/ Returned for modification 2 November 2006/ Accepted 18 December 2006

The objective of the present study was to determine the mitochondrial toxicity mechanisms of linezolid-related hyperlactatemia. Five patients on a long-term schedule of linezolid treatment were studied during the acute phase of hyperlactatemia and after clinical recovery and lactate normalization following linezolid withdrawal. Mitochondrial studies were performed with peripheral blood mononuclear cells and consisted of measurement of mitochondrial mass, mitochondrial protein synthesis homeostasis (cytochrome c oxidase [COX] activity, COX-II subunit expression, COX-II mRNA abundance, and mitochondrial DNA [mtDNA] content), and overall mitochondrial function (mitochondrial membrane potential and intact-cell oxidative capacity). During linezolid-induced hyperlactatemia, we found extremely reduced protein expression (16% of the remaining content compared to control values [100%], P < 0.001) for the mitochondrially coded, transcribed, and translated COX-II subunit. Accordingly, COX activity was also found to be decreased (51% of the remaining activity, P < 0.05). These reductions were observed despite the numbers of COX-II mitochondrial RNA transcripts being abnormally increased (297%, P = 0.10 [not significant]) and the mitochondrial DNA content remaining stable. These abnormalities persisted even after the correction for mitochondrial mass, which was mildly decreased during the hyperlactatemic phase. Most of the mitochondrial abnormalities returned to control ranges after linezolid withdrawal, lactate normalization, and clinical recovery. Linezolid inhibits mitochondrial protein synthesis, leading to decreased mitochondrial enzymatic activity, which causes linezolid-related hyperlactatemia, which resolves upon discontinuation of linezolid treatment.

* Corresponding author. Mailing address: Mitochondrial Research Laboratory, Muscle Research Unit, Internal Medicine Department, Hospital Clinic of Barcelona, Villarroel 170, 08036 Barcelona, Catalonia, Spain. Phone: 34.93.227.98.33. Fax: 34.93.227.56.93. E-mail: omiro{at}clinic.ub.es.

{triangledown} Published ahead of print on 28 December 2006.

Antimicrobial Agents and Chemotherapy, March 2007, p. 962-967, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01190-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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  • Soriano, A., Ortega, M., Garcia, S., Penarroja, G., Bove, A., Marcos, M., Martinez, J. C., Martinez, J. A., Mensa, J. (2007). Comparative Study of the Effects of Pyridoxine, Rifampin, and Renal Function on Hematological Adverse Events Induced by Linezolid. Antimicrob. Agents Chemother. 51: 2559-2563 [Abstract] [Full Text]  


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