Leishmania exploits the macrophage endoplasmic reticulum-shaping protein CLIMP-63 to modulate mitochondrial biogenesis and bioenergetics

In Leishmania-infected macrophages, interactions between parasitophorous vacuoles and the host cell endoplasmic reticulum are central to parasite replication. Whether the complex architecture of this organelle impacts these interactions remains however unknown. Here, we identify the macrophage endoplasmic reticulum-shaping protein CLIMP-63 as a host factor promoting Leishmania infection. Following parasite internalization, we observed a redistribution of CLIMP-63 to the vicinity of parasitophorous vacuoles in a process dependent on the virulence glycolipid lipophosphoglycan, and its dissociation from the mitochondrial network. Mechanistically, we found that CLIMP-63 is required for Leishmania-induced mitochondrial DNA replication, cristae biogenesis, and enhanced mitochondrial respiration, which are critical for the ability of the parasite to colonize macrophages. Collectively, our findings uncover a role for CLIMP-63 in supporting macrophage colonization by Leishmania and illustrate how this intracellular pathogen exploits the host cell endoplasmic reticulum to reprogram mitochondrial functions and bioenergetics. AUTHOR SUMMARYThe protozoan parasite Leishmania replicates in macrophages within parasitophorous vacuoles. These vacuoles establish interactions with various organelles and modulate their properties and functionality to adapt the host cell to their own needs. In this regard, Leishmania rewires host cell mitochondria to produce key metabolites and to modify their bioenergetic profile. We obtained evidence that Leishmania exploits the role of the macrophage endoplasmic reticulum architectural protein CLIMP-63 to stimulate mitochondrial biogenesis and respiration. The fact that CLIMP-63 plays a central role in the ability of Leishmania to colonize macrophage illustrates how this parasite manipulates the host cell endoplasmic reticulum to modulatet the function and properties of other organelles.