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

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Thrombocytopenia is a common side effect of linezolid therapy, particularly with prolonged use (>14 days).
• Linezolid is known to reversibly inhibit mitochondrial function across various cell types.
• Understanding the specific impact on megakaryocytic cells is crucial for explaining this adverse effect.

Purpose of the Study:

• To investigate the inhibitory effects of linezolid and tedizolid on mitochondrial function in megakaryocytic cell lines.
• To assess the potential for recovery of mitochondrial function after drug withdrawal.
• To correlate these cellular effects with the clinical observation of oxazolidinone-induced thrombocytopenia.

Main Methods:

• Utilized two megakaryocytic cell lines (UT-7 WT and UT-7 MPL) for in vitro studies.
• Exposed cells to varying concentrations of linezolid and tedizolid for up to 5 days.
• Assessed mitochondrial function through CYTox I expression, cytochrome c-oxidase activity, and Seahorse bioanalysis, including recovery experiments.

Main Results:

• Both linezolid and tedizolid demonstrated concentration- and time-dependent inhibition of mitochondrial function, including CYTox I expression and activity.
• Tedizolid exhibited stronger inhibitory effects compared to linezolid.
• While CYTox I expression recovered, cytochrome c-oxidase activity and mitochondrial spare capacity showed only partial or no recovery, particularly with tedizolid.

Conclusions:

• Oxazolidinones induce protracted inhibition of mitochondrial function in megakaryocytic cells, more so than previously observed in other cell types.
• These findings provide a cellular mechanism explaining the high incidence of thrombocytopenia associated with linezolid and tedizolid therapy.
• The limited recovery of mitochondrial function highlights potential long-term risks and informs clinical management strategies.