Mitochondria and lipid raft-located FOF1-ATP synthase as major therapeutic targets in the antileishmanial and anticancer activities of ether lipid edelfosine

Abstract

[EN]Leishmaniasis is a major health problem worldwide, and can result in loss of human life or a lifelong stigma because of bodily scars. According to World Health Organization, leishmaniasis is considered as an emerging and uncontrolled disease, and its current treatment is far from ideal, with only a few drugs available that could lead to drug resistance or cause serious side-effects. Here, we have found that mitochondria and raft-located FOF1-ATPase synthase are efficient druggable targets, through which an ether lipid named edelfosine exerts its antileishmanial action. Edelfosine effectively kills Leishmania spp. promastigotes and amastigotes. Our experimental animal models demonstrate that oral administration of edelfosine exerts a potent antileishmanial activity, while inhibits macrophage pro-inflammatory responses. Our results show that both Leishmania and tumor cells share mitochondria and raft-located FOF1-ATPase synthase as major druggable targets in leishmaniasis and cancer therapy. These data, showing a potent antileishmanial activity of edelfosine and unveiling its mechanism of action, together with the inhibition of the inflammatory responses elicited by macrophages, suggest that the ether lipid edelfosine is a promising oral drug for leishmaniasis, and highlight mitochondria and lipid raft-located FOF1-ATP synthase as major therapeutic targets for the treatment of this disease.