Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Palmitate impairs autophagic degradation via oxidative stress/perilysosomal Ca2+ overload/mTORC1 activation pathway in pancreatic β cells

Nguyen, Ha Thu ; Ly, Luong Dai ; Ngo, Thuy Thi Thanh ; Lee, Soo Kyung ; Noriega Polo, Carlos LU orcid ; Lee, Subo ; Lee, Taesic ; Cha, Seung-Kuy ; Yasasilka, Xaviera Riani and Cho, Kae Won , et al. (2025) In JCI Insight 10(24).
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Mechanistic Target of Rapamycin Complex 1/metabolism, Insulin-Secreting Cells/metabolism, Oxidative Stress/drug effects, Animals, Lysosomes/metabolism, Autophagy/drug effects, Calcium/metabolism, Mice, Transient Receptor Potential Channels/metabolism, Palmitates/pharmacology, Endoplasmic Reticulum/metabolism, Signal Transduction/drug effects, Humans
in
JCI Insight
volume
10
issue
24
publisher
The American Society for Clinical Investigation
external identifiers
  • pmid:41217849
  • scopus:105025430524
ISSN
2379-3708
DOI
10.1172/jci.insight.192827
language
English
LU publication?
yes
id
6a1d9194-0b71-4869-836c-6ea89d79904b
date added to LUP
2026-01-29 09:58:14
date last changed
2026-01-30 04:01:46
@article{6a1d9194-0b71-4869-836c-6ea89d79904b,
  abstract     = {{<p>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.</p>}},
  author       = {{Nguyen, Ha Thu and Ly, Luong Dai and Ngo, Thuy Thi Thanh and Lee, Soo Kyung and Noriega Polo, Carlos and Lee, Subo and Lee, Taesic and Cha, Seung-Kuy and Yasasilka, Xaviera Riani and Cho, Kae Won and Lee, Myung-Shik and Wiederkehr, Andreas and Wollheim, Claes B and Park, Kyu-Sang}},
  issn         = {{2379-3708}},
  keywords     = {{Mechanistic Target of Rapamycin Complex 1/metabolism; Insulin-Secreting Cells/metabolism; Oxidative Stress/drug effects; Animals; Lysosomes/metabolism; Autophagy/drug effects; Calcium/metabolism; Mice; Transient Receptor Potential Channels/metabolism; Palmitates/pharmacology; Endoplasmic Reticulum/metabolism; Signal Transduction/drug effects; Humans}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{24}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{JCI Insight}},
  title        = {{Palmitate impairs autophagic degradation via oxidative stress/perilysosomal Ca2+ overload/mTORC1 activation pathway in pancreatic β cells}},
  url          = {{http://dx.doi.org/10.1172/jci.insight.192827}},
  doi          = {{10.1172/jci.insight.192827}},
  volume       = {{10}},
  year         = {{2025}},
}