Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.
- 1School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen 15503, Bahrain.
- 2Research Department, Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen 15503, Bahrain.
Abstract
Pancreatic β-cell failure is central to the pathogenesis of type 2 diabetes (T2D), developing when chronic metabolic stress overwhelms the adaptive capacity of these cells. Because insulin biosynthesis and glucose-stimulated secretion depend on tightly coordinated organelle function, crosstalk between the endoplasmic reticulum (ER) and mitochondria strongly influences β-cell fate. The two organelles are physically coupled at mitochondria-associated membranes (MAMs), contact sites that synchronize ER Ca²⁺ release with mitochondrial Ca²⁺ uptake and adenosine triphosphate (ATP) production, and that help regulate redox balance, autophagy, mitophagy and the unfolded protein response. This review draws together evidence on three questions. First, which stresses converge on the β-cell: ER stress, oxidative stress and dysregulated autophagy and mitophagy. Second, how ER-mitochondria crosstalk sustains β-cell health through Ca²⁺ handling and the proteins that maintain MAM integrity, including inositol 1,4,5-trisphosphate (IP₃) receptors, voltage-dependent anion channel 1 (VDAC1), mitofusin 2 (Mfn2) and the ER stress sensors IRE1α and PERK. Third, how glucolipotoxic and inflammatory stress remodels these contacts and pushes communication towards a maladaptive state marked by mitochondrial Ca²⁺ overload, ROS accumulation, defective organelle quality control, cellular senescence and apoptosis. We contrast rodent and human data, where MAM composition and glucotoxic responses diverge, and consider therapeutic strategies, such as incretin-based agents and the mitochondrial-derived peptide MOTS-c, that target this interface to preserve β-cell function in diabetes.
Related
- In vivo Nupr1 regulates oxidative stress–endoplasmic reticulum stress crosstalk and mitochondria-dependent apoptosis in varicocele-related testicular injury
- Unveiling FKBP7 as an early endoplasmic reticulum sentinel in pancreatic stellate cell activation, collagen remodeling and tumor progression
- Mitochondria and Pancreatic β-Cells: Central Role in Insulin Secretion and Therapeutic Target for Diabetes
- PRKACA modulates endoplasmic reticulum stress-associated dysfunction in granulosa cell models relevant to polycystic ovary syndrome
- Polycystin-2 functions as a calcium leak channel under endoplasmic reticulum stress to protect against myocardial ischemia
BibTeX
@article{niinuma2026mitochondriaendoplasmic,
title = {{Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.}},
author = {Sara Anjum Niinuma and Ashleigh Suzu-Nishio Takemoto and William Junior Khalil and Alexandra E Butler and Abu Saleh Md Moin},
journal = {Cells},
year = {2026},
month = sep,
doi = {10.3390/cells15191733},
url = {https://europepmc.org/article/MED/42882431},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.
AU - Sara Anjum Niinuma
AU - Ashleigh Suzu-Nishio Takemoto
AU - William Junior Khalil
AU - Alexandra E Butler
AU - Abu Saleh Md Moin
PY - 2026
DA - 2026/09/23
JO - Cells
DO - 10.3390/cells15191733
UR - https://europepmc.org/article/MED/42882431
AB - Pancreatic β-cell failure is central to the pathogenesis of type 2 diabetes (T2D), developing when chronic metabolic stress overwhelms the adaptive capacity of these cells. Because insulin biosynthesis and glucose-stimulated secretion depend on tightly coordinated organelle function, crosstalk between the endoplasmic reticulum (ER) and mitochondria strongly influences β-cell fate. The two organelles are physically coupled at mitochondria-associated membranes (MAMs), contact sites that synchronize ER Ca²⁺ release with mitochondrial Ca²⁺ uptake and adenosine triphosphate (ATP) production, and that help regulate redox balance, autophagy, mitophagy and the unfolded protein response. This review draws together evidence on three questions. First, which stresses converge on the β-cell: ER stress, oxidative stress and dysregulated autophagy and mitophagy. Second, how ER-mitochondria crosstalk sustains β-cell health through Ca²⁺ handling and the proteins that maintain MAM integrity, including inositol 1,4,5-trisphosphate (IP₃) receptors, voltage-dependent anion channel 1 (VDAC1), mitofusin 2 (Mfn2) and the ER stress sensors IRE1α and PERK. Third, how glucolipotoxic and inflammatory stress remodels these contacts and pushes communication towards a maladaptive state marked by mitochondrial Ca²⁺ overload, ROS accumulation, defective organelle quality control, cellular senescence and apoptosis. We contrast rodent and human data, where MAM composition and glucotoxic responses diverge, and consider therapeutic strategies, such as incretin-based agents and the mitochondrial-derived peptide MOTS-c, that target this interface to preserve β-cell function in diabetes.
SN - 2073-4409
ER -