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 IP₃ 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.