Abstract
Saturated fatty acids impose lipotoxic stress on pancreatic β cells, leading to β cell failure and diabetes. In this study, we investigate the critical role of organellar Ca2+ disturbance on defective autophagy and β cell lipotoxicity. Palmitate, a saturated fatty acid, induced perilysosomal Ca2+ elevation, sustained mTOR complex 1 (mTORC1) activation on the lysosomal membrane, suppression of the lysosomal transient receptor potential mucolipin 1 (TRPML1) channel, and accumulation of undigested autophagosomes in β cells. These Ca2+ aberrations with autophagy defects by palmitate were prevented by an mTORC1 inhibitor or a mitochondrial superoxide scavenger. To alleviate perilysosomal Ca2+ overload, strategies such as lowering extracellular Ca2+, employing voltage-gated Ca2+ channel blocker or ATP-sensitive K+ channel opener, effectively abrogated mTORC1 activation and preserved autophagy. Furthermore, redirecting perilysosomal Ca2+ into the endoplasmic reticulum (ER), with an ER Ca2+ ATPase activator, restored TRPML1 activity, promoted autophagic flux, and improved survival of β cells exposed to palmitate-induced lipotoxicity. Our findings suggest oxidative stress/Ca2+ overload/mTORC1 pathway involvement in TRPML1 suppression and defective autophagy during β cell lipotoxicity. Restoring perilysosomal Ca2+ homeostasis emerges as a promising therapeutic strategy for metabolic diseases.
Authors
Ha Thu Nguyen, Luong Dai Ly, Thuy Thi Thanh Ngo, Soo Kyung Lee, Carlos Noriega Polo, Subo Lee, Taesic Lee, Seung-Kuy Cha, Xaviera Riani Yasasilka, Kae Won Cho, Myung-Shik Lee, Andreas Wiederkehr, Claes B. Wollheim, Kyu-Sang Park
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