Lysosomal Ca(2+) as a mediator of palmitate-induced lipotoxicity

While the mechanism of lipotoxicity by palmitic acid (PA), an effector of metabolic stress in vitro and in vivo, has been extensively investigated, molecular details of lipotoxicity are still not fully characterized. Since recent studies reported that PA can exert lysosomal stress in addition to well-known ER and mitochondrial stress, we studied the role of lysosomal events in lipotoxicity by PA, focusing on lysosomal Ca(2+). We found that PA induced accumulation of mitochondrial ROS and that mitochondrial ROS induced release of lysosomal Ca(2+) due to lysosomal Ca(2+) exit channel activation. Lysosomal Ca(2+) release led to increased cytosolic Ca(2+) which induced mitochondrial permeability transition (mPT). Chelation of cytoplasmic Ca(2+) or blockade of mPT with olesoxime or decylubiquinone (DUB) suppressed lipotoxicity. Lysosomal Ca(2+) release led to reduced lysosomal Ca(2+) content which was replenished by ER Ca(2+), the largest intracellular Ca(2+) reservoir (ER → lysosome Ca(2+) refilling), which in turn activated store-operated Ca(2+) entry (SOCE). Inhibition of ER → lysosome Ca(2+) refilling by blockade of ER Ca(2+) exit channel using dantrolene or inhibition of SOCE using BTP2 inhibited lipotoxicity in vitro. Dantrolene or DUB also inhibited lipotoxic death of hepatocytes in vivo induced by administration of ethyl palmitate together with LPS. These results suggest a novel pathway of lipotoxicity characterized by mPT due to lysosomal Ca(2+) release which was supplemented by ER → lysosome Ca(2+) refilling and subsequent SOCE, and also suggest the potential role of modulation of ER → lysosome Ca(2+) refilling by dantrolene or other blockers of ER Ca(2+) exit channels in disease conditions characterized by lipotoxicity such as metabolic syndrome, diabetes, cardiomyopathy or nonalcoholic steatohepatitis.