Zaher Amira, Stephens Samuel B
Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52246, USA.
Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA 52246, USA.
Cells. 2025 Mar 8;14(6):399. doi: 10.3390/cells14060399.
Pancreatic β-cells rely on a delicate balance between the endoplasmic reticulum (ER) and mitochondria to maintain sufficient insulin stores for the regulation of whole animal glucose homeostasis. The ER supports proinsulin maturation through oxidative protein folding, while mitochondria supply the energy and redox buffering that maintain ER proteostasis. In the development of Type 2 diabetes (T2D), the progressive decline of β-cell function is closely linked to disruptions in ER-mitochondrial communication. Mitochondrial dysfunction is a well-established driver of β-cell failure, whereas the downstream consequences for ER redox homeostasis have only recently emerged. This interdependence of ER-mitochondrial functions suggests that an imbalance is both a cause and consequence of metabolic dysfunction. In this review, we discuss the regulatory mechanisms of ER redox control and requirements for mitochondrial function. In addition, we describe how ER redox imbalances may trigger mitochondrial dysfunction in a vicious feed forward cycle that accelerates β-cell dysfunction and T2D onset.
胰腺β细胞依赖内质网（ER）和线粒体之间的微妙平衡来维持足够的胰岛素储备，以调节动物整体的葡萄糖稳态。内质网通过氧化蛋白折叠支持胰岛素原的成熟，而线粒体提供维持内质网蛋白质稳态所需的能量和氧化还原缓冲。在2型糖尿病（T2D）的发展过程中，β细胞功能的逐渐衰退与内质网-线粒体通讯的破坏密切相关。线粒体功能障碍是β细胞功能衰竭的一个公认驱动因素，而内质网氧化还原稳态的下游后果直到最近才被发现。内质网-线粒体功能的这种相互依赖性表明，失衡既是代谢功能障碍的原因，也是其后果。在这篇综述中，我们讨论了内质网氧化还原控制的调节机制以及线粒体功能的需求。此外，我们描述了内质网氧化还原失衡如何在一个恶性循环中触发线粒体功能障碍，加速β细胞功能障碍和T2D的发生。
