Leishmania donovani restricts mitochondrial dynamics to enhance miRNP stability and target RNA repression in host macrophages

Abstract

MicroRNAs (miRNAs), the tiny regulatory RNAs, form complexes with Argonaute (Ago) proteins and inhibit gene expression in metazoan cells. While studying parasite-invaded macrophages, we identify a unique mode of gene regulation in which the parasite Leishmania donovani (Ld) causes mitochondrial depolarization, reduces mitochondrial dynamics, and restricts turnover of cellular microRNA ribonucleoprotein (miRNP) complexes in infected host cells. This leads to increased stability of miRNPs along with elevated levels of Ago2-bound cytokine mRNA in Ld-infected macrophages. Thus the increase of miRNP stability in Ld-infected cells curtails production of proinflammatory cytokines, which are otherwise detrimental for survival of the parasite within the infected macrophages. Loss of mitochondrial membrane potential is accompanied by reduced juxtaposition of endoplasmic reticulum (ER) and mitochondria as well as endosomes. This is likely coupled with enhanced sequestration and stabilization of ER- associated miRNPs observed in infected macrophage cells. Mitofusin 2 (Mfn2), a membrane protein implicated in ER-mitochondria tethering, also shows reduced expression in Ld-infected cells. A mitochondrial role in Ld-induced alteration of miRNA activity and stability is further corroborated by impaired compartmentalization and stabilization of miRNP components in Mfn2-depleted mammalian cells.