RT Journal Article SR Electronic T1 Miltefosine Induces Apoptosis-Like Cell Death in Yeast via Cox9p in Cytochrome c Oxidase JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 476 OP 485 DO 10.1124/mol.111.072322 VO 80 IS 3 A1 Xiaoming Zuo A1 Julianne T. Djordjevic A1 Johanes Bijosono Oei A1 Desmarini Desmarini A1 Stephen D. Schibeci A1 Katrina A. Jolliffe A1 Tania C. Sorrell YR 2011 UL http://molpharm.aspetjournals.org/content/80/3/476.abstract AB Miltefosine has antifungal properties and potential for development as a therapeutic for invasive fungal infections. However, its mode of action in fungi is poorly understood. We demonstrate that miltefosine is rapidly incorporated into yeast, where it penetrates the mitochondrial inner membrane, disrupting mitochondrial membrane potential and leading to an apoptosis-like cell death. COX9, which encodes subunit VIIa of the cytochrome c oxidase (COX) complex in the electron transport chain of the mitochondrial membrane, was identified as a potential target of miltefosine from a genomic library screen of the model yeast Saccharomyces cerevisiae. When overexpressed in S. cerevisiae, COX9, but not COX7 or COX8, led to a miltefosine-resistant phenotype. The effect of miltefosine on COX activity was assessed in cells expressing different levels of COX9. Miltefosine inhibited COX activity in a dose-dependent manner in Cox9p-positive cells. This inhibition most likely contributed to the miltefosine-induced apoptosis-like cell death.