Mitochondria-lysosome contacts regulate mitochondrial Ca 2+ dynamics via lysosomal TRPML1

Significance Mitochondria and lysosomes are critical for cellular homeostasis and defects in both organelles are observed in several diseases. Recently, contact sites between mitochondria and lysosomes were identified and found to modulate mitochondrial dynamics. However, whether mitochondria–lysosome contacts have additional functions is unknown. Here, we identify a function of mitochondria–lysosome contacts in facilitating the direct transfer of calcium from lysosomes to mitochondria. Transfer of calcium at mitochondria–lysosome contacts is mediated by the lysosomal channel TRPML1 and is disrupted in mucolipidosis type IV, a lysosomal storage disorder caused by loss-of-function mutations in TRPML1. Calcium transfer from lysosomes to mitochondria at mitochondria–lysosome contacts thus presents an additional mechanism of intracellular calcium regulation that may further contribute to various disorders.