Perilysosomal Ca2+ overload impairs autophagic degradation in β-cell lipotoxicity

Nguyen, H. T.; Ly, L. D.; Ngo, T. T. T.; Lee, S. K.; Noriega Polo, C.; Lee, S.; Lee, T.; Cha, S.-K.; Lee, M.-S.; Wiederkehr, A.; Wollheim, C. B.; Park, K.-S.

doi:10.1101/2025.01.27.635047

bioRxiv · 10.1101/2025.01.27.635047

Perilysosomal Ca2+ overload impairs autophagic degradation in β-cell lipotoxicity

Nguyen, H. T.·Ly, L. D.·Ngo, T. T. T.·Lee, S. K.·Noriega Polo, C.·Lee, S.·Lee, T.·Cha, S.-K.·Lee, M.-S.·Wiederkehr, A.·Wollheim, C. B.·Park, K.-S.

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Abstract

Saturated fatty acids impose lipotoxic stress on pancreatic {beta}-cells, leading to {beta}-cell failure and diabetes. In this study, we investigate the critical role of organellar Ca2+ disturbance on defective autophagy and {beta}-cell lipotoxicity. Palmitate, a saturated fatty acid, induced perilysosomal Ca2+ elevation, sustained mTORC1 activation on the lysosomal membrane, suppression of the lysosomal transient receptor potential mucolipin 1 (TRPML1) channel, and accumulation of undigested autophagosomes in {beta}-cells. These Ca2+ aberrations with autophagy defects by palmitate were prevented by a 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, restores TRPML1 activity, promotes autophagic flux, and improves survival of {beta}-cells exposed to palmitate-induced lipotoxicity. Our findings suggest oxidative stress-Ca2+ overload-mTORC1 pathway involves in TRPML1 suppression and defective autophagy during {beta}-cell lipotoxicity. Restoring perilysosomal Ca2+ homeostasis emerges as a promising therapeutic strategy for metabolic diseases.

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Nguyen, H. T., Ly, L. D., Ngo, T. T. T., Lee, S. K., Noriega Polo, C., Lee, S., Lee, T., Cha, S.-K., Lee, M.-S., Wiederkehr, A., Wollheim, C. B., Park, K.-S.. 2025-01-29. Perilysosomal Ca2+ overload impairs autophagic degradation in β-cell lipotoxicity. https://doi.org/10.1101/2025.01.27.635047

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