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Regulation of autophagy by perilysosomal calcium : a new player in β-cell lipotoxicity

Nguyen, Ha Thu ; Wiederkehr, Andreas ; Wollheim, Claes B. LU and Park, Kyu Sang (2024) In Experimental and Molecular Medicine 56(2). p.273-288
Abstract

Autophagy is an essential quality control mechanism for maintaining organellar functions in eukaryotic cells. Defective autophagy in pancreatic beta cells has been shown to be involved in the progression of diabetes through impaired insulin secretion under glucolipotoxic stress. The underlying mechanism reveals the pathologic role of the hyperactivation of mechanistic target of rapamycin (mTOR), which inhibits lysosomal biogenesis and autophagic processes. Moreover, accumulating evidence suggests that oxidative stress induces Ca2+ depletion in the endoplasmic reticulum (ER) and cytosolic Ca2+ overload, which may contribute to mTOR activation in perilysosomal microdomains, leading to autophagic defects and β-cell... (More)

Autophagy is an essential quality control mechanism for maintaining organellar functions in eukaryotic cells. Defective autophagy in pancreatic beta cells has been shown to be involved in the progression of diabetes through impaired insulin secretion under glucolipotoxic stress. The underlying mechanism reveals the pathologic role of the hyperactivation of mechanistic target of rapamycin (mTOR), which inhibits lysosomal biogenesis and autophagic processes. Moreover, accumulating evidence suggests that oxidative stress induces Ca2+ depletion in the endoplasmic reticulum (ER) and cytosolic Ca2+ overload, which may contribute to mTOR activation in perilysosomal microdomains, leading to autophagic defects and β-cell failure due to lipotoxicity. This review delineates the antagonistic regulation of autophagic flux by mTOR and AMP-dependent protein kinase (AMPK) at the lysosomal membrane, and both of these molecules could be activated by perilysosomal calcium signaling. However, aberrant and persistent Ca2+ elevation upon lipotoxic stress increases mTOR activity and suppresses autophagy. Therefore, normalization of autophagy is an attractive therapeutic strategy for patients with β-cell failure and diabetes.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental and Molecular Medicine
volume
56
issue
2
pages
16 pages
publisher
Springer Nature
external identifiers
  • scopus:85183733175
  • pmid:38297165
ISSN
1226-3613
DOI
10.1038/s12276-024-01161-x
language
English
LU publication?
yes
id
18cf633d-d2c0-442e-8d87-6a8b5d0aad98
date added to LUP
2024-03-01 14:44:37
date last changed
2025-08-20 00:44:17
@article{18cf633d-d2c0-442e-8d87-6a8b5d0aad98,
  abstract     = {{<p>Autophagy is an essential quality control mechanism for maintaining organellar functions in eukaryotic cells. Defective autophagy in pancreatic beta cells has been shown to be involved in the progression of diabetes through impaired insulin secretion under glucolipotoxic stress. The underlying mechanism reveals the pathologic role of the hyperactivation of mechanistic target of rapamycin (mTOR), which inhibits lysosomal biogenesis and autophagic processes. Moreover, accumulating evidence suggests that oxidative stress induces Ca<sup>2+</sup> depletion in the endoplasmic reticulum (ER) and cytosolic Ca<sup>2+</sup> overload, which may contribute to mTOR activation in perilysosomal microdomains, leading to autophagic defects and β-cell failure due to lipotoxicity. This review delineates the antagonistic regulation of autophagic flux by mTOR and AMP-dependent protein kinase (AMPK) at the lysosomal membrane, and both of these molecules could be activated by perilysosomal calcium signaling. However, aberrant and persistent Ca<sup>2+</sup> elevation upon lipotoxic stress increases mTOR activity and suppresses autophagy. Therefore, normalization of autophagy is an attractive therapeutic strategy for patients with β-cell failure and diabetes.</p>}},
  author       = {{Nguyen, Ha Thu and Wiederkehr, Andreas and Wollheim, Claes B. and Park, Kyu Sang}},
  issn         = {{1226-3613}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{273--288}},
  publisher    = {{Springer Nature}},
  series       = {{Experimental and Molecular Medicine}},
  title        = {{Regulation of autophagy by perilysosomal calcium : a new player in β-cell lipotoxicity}},
  url          = {{http://dx.doi.org/10.1038/s12276-024-01161-x}},
  doi          = {{10.1038/s12276-024-01161-x}},
  volume       = {{56}},
  year         = {{2024}},
}