Abstract
ABSTRACTThe voltage-dependent anion channel (VDAC) is a ubiquitous channel in the outer membrane of the mitochondrion with multiple roles in protein, metabolite and small molecule transport. In mammalian cells, VDAC protein, as part of a larger complex including the inositol triphosphate receptor, has been shown to have a role in mediating contacts between the mitochondria and endoplasmic reticulum (ER). We identify VDAC of the pathogenic apicomplexan Toxoplasma gondii and demonstrate its importance for parasite growth. We show that VDAC is involved in protein import and metabolite transfer to mitochondria. Further, depletion of VDAC resulted in significant morphological changes in the mitochondrion and ER, suggesting a role in mediating contacts between these organelles in T. gondii. This article has an associated First Person interview with the first author of the paper.
Highlights
Toxoplasma gondii is the causative agent of toxoplasmosis and a member of the parasitic apicomplexan family, which includes Plasmodium, the causative agent of malaria, and Cryptosporidium, which causes the diarrheal disease cryptosporidiosis
voltage-dependent anion channel (VDAC) is conserved between Apicomplexa, and sequence identity between orthologues can drop below 30% (Fig. S1B), VDAC is nearly ubiquitously conserved across all eukaryotes (Wideman et al, 2013)
Given that ∼20% VDAC expression is maintained under ATc, it is possible that the residual VDAC is able to perform some of this function under these conditions, explaining the relatively mild defect compared to other systems (Maldonado et al, 2013)
Summary
Toxoplasma gondii is the causative agent of toxoplasmosis and a member of the parasitic apicomplexan family, which includes Plasmodium, the causative agent of malaria, and Cryptosporidium, which causes the diarrheal disease cryptosporidiosis. VDAC clusters in domains of ER–mitochondria contacts (Rapizzi et al, 2002; Shoshan-Barmatz et al, 2004), where it interacts directly with the ER-resident inositol trisphosphate receptor (IP3R) via the chaperone Grp (Honrath et al, 2017; Szabadkai et al, 2006) This close apposition of membranes allows direct transfer of Ca2+ between the ER and the mitochondria, where the close association of the mitochondrial inner membrane Ca2+ uniporter (MCU) and associated protein MICU on the inner membrane of the mitochondria allows uptake of Ca2+ into the organelle (De Stefani et al, 2016; Liao et al, 2015). This contact has been shown to have important roles in Ca2+ homeostasis in survival and proliferation in mammalian cells (De Stefani et al, 2016; Rieusset et al, 2016; Rizzuto et al, 2009)
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