Mechanism of Ferroptosis and Its Role in Type 2 Diabetes Mellitus

Abstract

Ferroptosis is a novel form of nonapoptotic regulated cell death (RCD). It features iron-dependent lipid peroxide accumulation accompanied by inadequate redox enzymes, especially glutathione peroxidase 4 (GPX4). RAS-selective lethal 3 (RSL3), erastin, and ferroptosis inducing 56 (FIN56) induce ferroptosis via different manners targeting GPX4 function. Acyl-CoA synthetase long-chain family 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and lipoxygenases (LOXs) participate in the production of lipid peroxides. Heat shock protein family B member 1 (HSPB1) and nuclear receptor coactivator 4 (NCOA4) regulate iron homeostasis preventing ferroptosis caused by the high concentration of intracellular iron. Ferroptosis is ubiquitous in our body as it exists in both physiologic and pathogenic processes. It is involved in glucose-stimulated insulin secretion (GSIS) impairment and arsenic-induced pancreatic damage in the pathogenesis of diabetes. Moreover, iron and the iron-sulfur (Fe-S) cluster influence each other, causing mitochondrial iron accumulation, more reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, failure in biosynthesis of insulin, and ferroptosis in β-cells. In addition, ferroptosis also engages in the pathogenesis of diabetic complications such as myocardial ischemia and diabetic cardiomyopathy (DCM). In this review, we summarize the mechanism of ferroptosis and especially its association with type 2 diabetes mellitus (T2DM).

Figure 1

The pathway of Fe-S cluster deficiency in T2DM. Fe-S cluster deficiency affects the modification and function of tRNA, resulting in mistranslated proinsulin. This mistranslation can lead to ER stress and impaired insulin synthesis and secretion. Also, iron accumulation and more ROS production due to Fe-S cluster deficiency in mitochondria promote lipid peroxidation, further inducing ferroptosis in β-cells. Additionally, ROS directly impairs insulin synthesis and secretion.

Figure 2

Selenoproteins, LOXs, and ACSL4 affect pathogenesis of DM in different ways. GPX1 and GPX4 are both selenoproteins. A decrease in GPX1 or GPX4 causes accumulation of ROS and lipid peroxides in β-cells. Excessive ROS and lipid peroxides in turn induce ferroptosis in β-cells. ROS also promotes glucose intake into skeletal muscles. An increase in LOXs or ACSL4 produces excessive lipid peroxides and then ferroptosis in β-cells as well. Although ACSL4 can promote insulin secretion in β-cells, it aggravates peripheral insulin resistance.