FXR-regulated COX6A2 triggers mitochondrial apoptosis of pancreatic β-cell in type 2 diabetes.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-12-20 DOI:10.1038/s41419-024-07302-4
Lianqi Shao, Xiangchen Kong, Simian Lv, Xingsheng Shu, Xiaosong Ma, Xiaojiao Ai, Dan Yan, Ying Ying
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Abstract

Pancreatic β-cell apoptosis plays a crucial role in the development of type 2 diabetes. Cytochrome c oxidase subunit 6A2 (COX6A2) and Farnesoid X Receptor (FXR) have been identified in pancreatic β-cells, however, whether they are involved in β-cell apoptosis is unclear. Here, we sought to investigate the role of FXR-regulated COX6A2 in diabetic β-cell apoptosis. We found that COX6A2 expression was increased in islets from diabetic animals, whereas FXR expression was suppressed. Notably, overexpression of COX6A2 facilitated β-cell apoptosis, whereas its deficiency attenuated this process and ameliorates type 2 diabetes, suggesting a pro-apoptotic role of COX6A2 in β-cells. Mechanistically, increased COX6A2 interacted with and enhanced the expression of voltage-dependent anion channel 1 (VDAC1), thereby promoting the mitochondrial translocation of Bax, leading to the release of cytochrome c from the mitochondria to the cytoplasm and ultimately causing β-cell apoptosis. Moreover, FXR negatively regulated COX6A2 expression through the inhibition of histone acetyltransferase p300 occupancy, diminishing histone H3 acetylation at lysine 27 on the Cox6a2 promoter. Furthermore, the deficiency of FXR intensified β-cell apoptosis under diabetic situations. Thus, it is probable that in diabetogenic environments, reduced FXR expression contributes to enhanced COX6A2 expression, culminating in β-cell apoptosis. These findings emphasize the essential involvement of the FXR/p300 pathway-controlled COX6A2 in β-cell apoptosis, revealing a previously undiscovered mechanism underlying diabetic β-cell apoptosis.

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FXR调控的COX6A2引发2型糖尿病患者胰腺β细胞线粒体凋亡。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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