Prolonged inhibition and incomplete recovery of mitochondrial function in oxazolidinone-treated megakaryoblastic cell lines.

Milosevic, Tamara [UCL] Vertenoeil, Gaëlle [UCL] Payen, Valéry [UCL] Sonveaux, Pierre [UCL] Tulkens, Paul M. [UCL] Constantinescu, Stefan N. [UCL] Van Bambeke, Françoise [UCL]

Thrombocytopenia is commonly seen in patients receiving linezolid for >14 days. Linezolid is also a reversible inhibitor of mitochondrial functions in various cell types. We have studied the inhibitory effects of linezolid and tedizolid and their potential recovery on (i) CYTox I expression (subunit I of cytochrome c-oxidase; encoded by the mitochondrial genome), (ii) cytochrome c-oxidase activity, and (iii) mitochondrial respiration (Seahorse bioanalysis) in two megakaryocytic cell lines (UT-7 WT [human acute megakaryoblastic leukemia cells] and UT-7 MPL [transduced to stably express the thrombopoietin (TPO) receptor]). Cells were exposed to linezolid (0.5-25 mg/L) or tedizolid (0.1-5 mg/L) for up to 5 days and recovery followed after drug removal. Both oxazolidinones caused a concentration- and time-dependent inhibition of CYTox I expression, cytochrome c-oxidase activity and mitochondrial spare capacity. In the electron microscope, mitochondria appeared dilated with a loss of cristae. Globally, tedizolid exerted stronger effects than linezolid. While the expression of CYTox I was completely recovered after 6 days of drug washout, we observed only a partial (linezolid) or no (tedizolid) recovery of cytochrome c-oxidase activity, and no rescue of mitochondrial spare capacity (after 3 days). Thus, and in contrast with previous studies using a variety of cell lines unrelated to megakaryocytic lineages, the inhibitory effects exerted by oxazolidinones on mitochondrial functions of megakaryoblastic cells appear to be particularly protracted. Given the dynamics of platelet production and destruction, these results may explain why oxazolidinone-induced thrombocytopenia emerges as one of the most frequent untoward effects in patients exposed to these antibiotics.