IP receptor-mediated Ca release from acidocalcisomes regulates mitochondrial bioenergetics and prevents autophagy in Trypanosoma cruzi.

In contrast to animal cells, the inositol 1,4,5-trisphosphate receptor of Trypanosoma cruzi (TcIPR) localizes to acidocalcisomes instead of the endoplasmic reticulum. Here, we present evidence that TcIPR is a Ca release channel gated by IP when expressed in DT40 cells knockout for all vertebrate IP receptors, and is required for Ca uptake by T. cruzi mitochondria, regulating pyruvate dehydrogenase dephosphorylation and mitochondrial O consumption, and preventing autophagy. Localization studies revealed its co-localization with an acidocalcisome marker in all life cycle stages of the parasite. Ablation of TcIPR by CRISPR/Cas9 genome editing caused: a) a reduction in O consumption rate and citrate synthase activity; b) decreased mitochondrial Ca transport without affecting the membrane potential; c) increased ammonia production and AMP/ATP ratio; d) stimulation of autophagosome formation, and e) marked defects in growth of culture forms (epimastigotes) and invasion of host cells by infective stages (trypomastigotes). Moreover, TcIPR overexpressing parasites showed decreased metacyclogenesis, trypomastigote host cell invasion and intracellular amastigote replication. In conclusion, the results suggest a modulatory activity of TcIPR-mediated acidocalcisome Ca release on cell bioenergetics in T. cruzi.