Membrane contact activation of Piezo2 drives lysosome–mitochondrion Ca 2+ transfer and signaling in Trypanosoma cruzi

Calcium ion (Ca 2+ ) transfer from other organelles is central to mitochondrial metabolism and cell survival, yet how mechanical forces regulate interorganelle communication remains unclear. Here we report a lysosome-to-mitochondrion pathway in Trypanosoma cruzi , the etiologic agent of Chagas disease, mediated by the mechano/osmosensitive channel TcPiezo2. Using ultrastructural, biochemical, and live-cell superresolution imaging, we define lysosome–mitochondrion contact sites (LMCs) that enable direct Ca 2+ transfer. TcPiezo2 triggers Ca 2+ release, which generates perilysosomal nanodomains that drives mitochondrial Ca 2+ uptake via the voltage-dependent anion channel and the mitochondrial Ca 2+ uniporter complex. Disruption of TcPiezo2-dependent Ca 2+ transfer impairs mitochondrial metabolism, perturbs redox homeostasis, induces autophagy, and eventually leads to parasite death. These findings establish LMCs as a signaling platform that directly regulates interorganelle Ca 2+ transfer and mitochondrial bioenergetics.