Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia.
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.
Garrabou
Glòria
G
Mitochondrial Research Laboratory, Muscle Research Unit, Internal Medicine Department, Hospital Clinic of Barcelona, Villarroel 170, 08036 Barcelona, Catalonia, Spain.
Soriano
Alejandro
A
López
Sònia
S
Guallar
Jordi P
JP
Giralt
Marta
M
Villarroya
Francesc
F
Martínez
Jose A
JA
Casademont
Jordi
J
Cardellach
Francesc
F
Mensa
Josep
J
Miró
Oscar
O
D000081:Acetamides / Q000009:adverse effects*; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D004247:DNA / Q000032:analysis / Q000096:biosynthesis; D004579:Electron Transport / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006801:Humans; D007773:Lactates / Q000097:blood*; D000069349:Linezolid; D008137:Longitudinal Studies; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D023303:Oxazolidinones / Q000009:adverse effects*; D010084:Oxidation-Reduction; D011500:Protein Synthesis Inhibitors; D012313:RNA / Q000032:analysis / Q000096:biosynthesis
D000081:Acetamides; D000900:Anti-Bacterial Agents; D007773:Lactates; D023303:Oxazolidinones; D011500:Protein Synthesis Inhibitors; D012313:RNA; D004247:DNA; D003576:Electron Transport Complex IV; D000069349:Linezolid