Department of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, Hebei, China.
J Diabetes Investig. 2024 May;15(5):559-571. doi: 10.1111/jdi.14147. Epub 2024 Jan 23.
AIMS/INTRODUCTION: Mitochondrial damage caused by oxidative stress is a main driver of pancreatic β-cell dysfunction in the pathogenesis of type 2 diabetes mellitus. Prohibitin2 (PHB2) is a vital inner mitochondrial membrane protein that participates in mitophagy to remove the damaged mitochondria. This study aimed to investigate the role and mechanisms of PHB2-mediated mitophagy in oxidative stress-induced pancreatic β-cell dysfunction.
PHB2 and mitophagy-related protein expression were analyzed by real-time polymerase chain reaction and western blotting in RINm5F cells treated with HO and islets of diabetic rats. Mitophagy was observed by mitochondrial and lysosome colocalization. RINm5F cells were transfected by phb2 siRNA or overexpression plasmid to explore the role of PHB2 in mitophagy of RINm5F cells. The mechanism of Nrf2 regulating PHB2 was explored by Nrf2 inhibitor and agonist.
The expression of PHB2, mitophagy related protein PINK1, and Parkin were decreased in RINm5F cells incubated with HO and in islets of diabetic rats. Overexpression of PHB2 protected β-cells from oxidative stress by promoting mitophagy and inhibiting cell apoptosis, whereas transfection with PHB2 siRNA suppressed mitophagy. Furthermore, PHB2-mediated mitophagy induced by oxidative stress was through the Nrf2/PHB2 pathway in β-cells. Antioxidant NAC alleviated oxidative stress injury by promoting PHB2-mediated mitophagy.
Our study suggested that PHB2-mediated mitophagy can protect β-cells from apoptosis via the Nrf2/PHB2 pathway under oxidative stress. Antioxidants may protect β-cell from oxidative stress by prompting PHB2-mediated mitophagy. PHB2-mediated mitophagy as a potential mechanism takes part in the oxidative stress induced β-cell injury.
目的/引言：氧化应激引起的线粒体损伤是 2 型糖尿病发病机制中胰腺β 细胞功能障碍的主要驱动因素。抑制素 2（PHB2）是一种重要的线粒体内部膜蛋白，参与线粒体自噬以清除受损的线粒体。本研究旨在探讨 PHB2 介导的线粒体自噬在氧化应激诱导的胰腺β 细胞功能障碍中的作用和机制。
通过实时聚合酶链反应和蛋白质印迹分析 HO 处理的 RINm5F 细胞和糖尿病大鼠胰岛中 PHB2 和线粒体自噬相关蛋白的表达。通过线粒体和溶酶体共定位观察线粒体自噬。用 phb2 siRNA 或过表达质粒转染 RINm5F 细胞，探讨 PHB2 在 RINm5F 细胞线粒体自噬中的作用。用 Nrf2 抑制剂和激动剂探讨 Nrf2 调节 PHB2 的机制。
HO 孵育的 RINm5F 细胞和糖尿病大鼠胰岛中 PHB2、线粒体自噬相关蛋白 PINK1 和 Parkin 的表达降低。PHB2 的过表达通过促进线粒体自噬和抑制细胞凋亡来保护β细胞免受氧化应激，而过表达 PHB2 siRNA 则抑制线粒体自噬。此外，β 细胞中氧化应激诱导的 PHB2 介导的线粒体自噬是通过 Nrf2/PHB2 通路发生的。抗氧化剂 NAC 通过促进 PHB2 介导的线粒体自噬来减轻氧化应激损伤。
本研究表明，在氧化应激下，PHB2 介导的线粒体自噬可以通过 Nrf2/PHB2 通路保护β 细胞免于凋亡。抗氧化剂可能通过促使 PHB2 介导的线粒体自噬来保护β 细胞免受氧化应激。PHB2 介导的线粒体自噬作为一种潜在的机制，参与了氧化应激诱导的β 细胞损伤。
