Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.

Mitochondrial Ca(2+) uptake governs metabolism and cell fate, yet how signals from other organelles shape this remains incompletely defined. Although lysosomes are relatively small Ca(2+) stores, their strategic positioning at organelle contact sites suggests they may amplify Ca(2+) transfer within nanodomains. Here, we show that activation of the lysosomal Two-pore channel 2 (TPC2) initiates rapid mitochondrial Ca(2+) uptake through an endoplasmic reticulum-dependent relay requiring IP(3) receptors and the mitochondrial calcium uniporter channel. The extent of mitochondrial Ca(2+) accumulation scales with TPC2 activity without affecting global Ca(2+) responses, identifying TPC2 as a specific amplifier of lysosome-mitochondria Ca(2+) exchange. Moderate TPC2 activation transiently enhances oxidative phosphorylation, whereas sustained enhancement increases susceptibility to Ca(2+)-induced mitochondrial permeability transition. In stroke models, hyperactivation of TPC2 exacerbates injury, while acute pharmacological inhibition at reperfusion confers neuroprotection, including in human iPSC-derived neurons. Thus, lysosomal Ca(2+) release acts as an upstream regulator of mitochondrial energetic resilience under stress.