Artemisinin and its derivatives target mitochondrial c-type cytochromes in yeast and human cells

Publication date: Available online 25 January 2020Source: Biochimica et Biophysica Acta (BBA) - Molecular Cell ResearchAuthor(s): Anais Laleve, Cristina Panozzo, Inge Kühl, Alexa Bourand-Plantefol, Jelena Ostojic, Abdoulaye Sissoko, Déborah Tribouillard-Tanvier, David Cornu, Angélique Burg, Brigitte Meunier, Marc Blondel, Jerome Clain, Nathalie Bonnefoy, Romain Duval, Geneviève DujardinAbstractArtemisinin and its derivatives kill malaria parasites and inhibit the proliferation of cancer cells. In both processes, heme was shown to play a key role in artemisinin bioactivation. We found that artemisinin and clinical artemisinin derivatives are able to compensate for a mutation in the yeast Bcs1 protein, a key chaperon involved in biogenesis of the mitochondrial respiratory complex III. The equivalent Bcs1 variant causes an encephalopathy in human by affecting complex III assembly. We show that artemisinin derivatives decrease the content of mitochondrial cytochromes and disturb the maturation of the complex III cytochrome c1. This last effect is likely responsible for the compensation by decreasing the detrimental over-accumulation of the inactive pre-complex III observed in the bcs1 mutant. We further show that a fluorescent dihydroartemisinin probe rapidly accumulates in the mitochondrial network and targets cytochromes c and c1 in yeast, human cells and isolated mitochondria. In vitro this probe interacts with purified cytochrome c only under reducing conditions and we de...
Source: Biochimica et Biophysica Acta (BBA) Molecular Cell Research - Category: Molecular Biology Source Type: research