The role of mitochondrial apoptotic pathway in islet amyloid-induced β-cell death

Wong, Helen Y.; Hui, Queenie; Zhou, Hao; Warnock, Garth L.; Woo, Minna; Luciani, Dan S.; Marzban, Lucy

doi:10.1016/j.mce.2021.111424

Cited by 7 publications

(4 citation statements)

References 53 publications

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“…However, we did not find altered p-eIF2α levels and significant altered expression pattern of ISR genes in scRNA seq between WT versus Npc1 -/or mature versus immature β cells. On the other hand, lysosome leakage induced by the accumulated autophagsome/lysosome can prompt cell apoptosis [54], and lysosome relating signals have been known pivotal for cell fate decision [55][56][57]. Therefore, future studies should be conducted to investigate other signals mediating NPC1 related mitophagy, from both mitochondria and lysosome to the expression of key pancreatic transcription genes, such as Pdx1, MafA, Nkx6.1, etc.…”

Section: Discussionmentioning

confidence: 99%

NPC1 is required for postnatal islet β cell differentiation by maintaining mitochondria turnover

Liu,

Hua,

Shen

et al. 2024

Theranostics

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Rationale: NPC1 is a protein localized on the lysosome membrane regulating intracellular cholesterol transportation and maintaining normal lysosome function. GWAS studies have found that NPC1 variants in T2D was a pancreatic islet expression quantitative trait locus, suggesting a potential role of NPC1 in T2D islet pathophysiology. Methods: Two-week-old Npc1 -/- mice and wild type littermates were employed to examine pancreatic β cell morphology and functional changes induced by loss of Npc1 . Single cell RNA sequencing was conducted on primary islets. Npc1 -/- Min6 cell line was generated using CRISPR/Cas9 gene editing. Seahorse XF24 was used to analyze primary islet and Min6 cell mitochondria respiration. Ultra-high-resolution cell imaging with Lattice SIM 2 and electron microscope imaging were used to observe mitochondria and lysosome in primary islet β and Min6 cells. Mitophagy Dye and mt-Keima were used to measure β cell mitophagy. Results: In Npc1 -/- mice, we found that β cell survival and pancreatic β cell mass expansion as well as islet glucose induced insulin secretion in 2-week-old mice were reduced. Npc1 loss retarded postnatal β cell differentiation and growth as well as impaired mitochondria oxidative phosphorylation (OXPHOS) function to increase mitochondrial superoxide production, which might be attributed to impaired autophagy flux particularly mitochondria autophagy (mitophagy) induced by dysfunctional lysosome in Npc1 null β cells. Conclusion: Our study revealed that NPC1 played an important role in maintaining normal lysosome function and mitochondria turnover, which ensured establishment of sufficient mitochondria OXPHOS for islet β cells differentiation and maturation.

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Section: Discussionmentioning

confidence: 99%

NPC1 is required for postnatal islet β cell differentiation by maintaining mitochondria turnover

Liu,

Hua,

Shen

et al. 2024

Theranostics

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“…Studies have reported that the death receptor pathway is triggered mainly by the binding of specific members of the tumor necrosis factor (TNF) superfamily to members of the cell surface TNF receptor family (TNF-R) ( 40 , 42 ). The mitochondrial apoptosis of cells is mediated by the interaction between the anti-apoptotic and pro-apoptotic components of the B cell lymphoma 2 (Bcl-2) family ( 43 ). Downregulation of Bcl-2 and upregulation of Bcl-2-associated X protein (Bax) and Bcl-2 antagonist killer (Bak) can result in the mitochondrial membrane permeability transition, which consequently augments the release of cytochrome c, leading to the activation of caspase-3 and the initiation of cellular apoptosis ( 40 , 44 , 45 ).…”

Section: Discussionmentioning

confidence: 99%

Activin A induces apoptosis of human lung adenocarcinoma A549 cells through endoplasmic reticulum stress pathway

Zhang,

Qi,

et al. 2023

Oncol Rep

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Activin A, a member of the transforming growth factor-β (TGF-β) superfamily, has been implicated in the tumorigenesis and progression of various cancers. However, it remains unclear whether activin A induces apoptosis in human lung adenocarcinoma cells through the endoplasmic reticulum (ER) stress pathway. In the present study, BrdU, flow cytometry and western blotting were used to examine cell proliferation, apoptosis and protein expression, respectively. The present study revealed that activin A inhibited human lung adenocarcinoma A549 cell proliferation, induced apoptosis, and upregulated the protein levels of C/EBP homologous protein (CHOP), growth arrest and DNA damage-inducible protein 34 (GADD34), cleaved-caspase-3 and caspase-12. Furthermore, the administration of activin A did not alter the levels of suppressor of mothers against decapentaplegic 3 (Smad3) or phosphorylated (p)-Smad3 proteins, whereas, it significantly elevated the levels of ActRIIA and p-extracellular signal regulated kinase proteins 1 and 2 (ERK1/2) proteins in A549 cells. The apoptotic effects of activin A on A549 cells were attenuated by the ERK inhibitor FR180204, which also downregulated CHOP and caspase-12 protein levels. Additionally, activin A increased intracellular calcium flux in A549 cells, and the calcium ion chelator BAPTA acetoxymethyl ester (BAPTA-AM) inhibited activin A-induced A549 cell apoptosis, whereas the calcium agonist ionomycin significantly increased apoptosis of A549 cells induced by activin A. These findings indicated that the activation of the ER stress pathway resulting in apoptosis of A549 cells triggered by activin A is facilitated by the ActRIIA-ERK1/2 signaling and calcium signaling. The present findings suggest that the agonists of ERK and calcium signaling exhibit promising clinical therapeutic potential for the induction of apoptosis in lung adenocarcinoma.

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“…Wong et al [ 19 ] demonstrated that overexpression of hIAPP in INS-1 cells formed three oligomers between 4 and 8 kDa in size. Kim et al [ 20 ] showed that hIAPP-transfected INS-1 cells expressed three oligomers of less than 17 kDa size under autophagy inhibition conditions, including inhibition by 3-methyladenine and bafilomycin.…”

Section: Discussionmentioning

confidence: 99%

“…That is, suppression of HIF1α activation enhances hIAPP-induced β-cytotoxicity. Wong et al [ 19 ] showed that hIAPP aggregation in adenoviral hIAPP transduced INS-1E cells and human islet β-cells triggers mitochondrial apoptosis and blocks the release of cytochrome c or pro-apoptotic proteins Bax and Bak. The hIAPP aggregates were demonstrated to enhance the survival of β cells.…”

Section: Discussionmentioning

confidence: 99%

Human Islet Amyloid Polypeptide Overexpression in INS-1E Cells Influences Amylin Oligomerization under ER Stress and Oxidative Stress

Yoo

Joo

2021

IJMS

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Human amylin or islet amyloid polypeptide (hIAPP) is synthesized in the pancreatic β-cells and has been shown to contribute to the pathogenesis of type 2 diabetes (T2D) in vitro and in vivo. This study compared amylin oligomerization/expression and signal transduction under endoplasmic reticulum (ER) stress and oxidative stress. pCMV-hIAPP-overexpressing INS-1E cells presented different patterns of amylin oligomerization/expression under ER stress and oxidative stress. Amylin oligomerization/expression under ER stress showed three amylin oligomers of less than 15 kDa size in pCMV-hIAPP-overexpressing cells, while one band was detected under oxidative stress. Under ER stress conditions, HIF1α, p-ERK, CHOP, Cu/Zn-SOD, and Bax were significantly increased in pCMV-hIAPP-overexpressing cells compared to the pCMV-Entry-expressing cells (control), whereas p-Akt, p-mTOR, Mn-SOD, catalase, and Bcl-2 were significantly decreased. Under oxidative stress conditions, HIF1α, p-ERK, CHOP, Mn-SOD, catalase, and Bcl-2 were significantly reduced in pCMV-hIAPP-overexpressing cells compared to the control, whereas p-mTOR, Cu/Zn-SOD, and Bax were significantly increased. In mitochondrial oxidative phosphorylation (OXPHOS), the mitochondrial complex I and complex IV were significantly decreased under ER stress conditions and significantly increased under oxidative stress conditions in pCMV-hIAPP-overexpressing cells compared to the control. The present study results demonstrate that amylin undergoes oligomerization under ER stress in pCMV-hIAPP-overexpressing cells. In addition, human amylin overexpression under ER stress in the pancreatic β cells may enhance amylin protein aggregation, resulting in β-cell dysfunction.

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The role of mitochondrial apoptotic pathway in islet amyloid-induced β-cell death

Cited by 7 publications

References 53 publications

NPC1 is required for postnatal islet β cell differentiation by maintaining mitochondria turnover

NPC1 is required for postnatal islet β cell differentiation by maintaining mitochondria turnover

Activin A induces apoptosis of human lung adenocarcinoma A549 cells through endoplasmic reticulum stress pathway

Human Islet Amyloid Polypeptide Overexpression in INS-1E Cells Influences Amylin Oligomerization under ER Stress and Oxidative Stress

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