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).

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

“…It has become appreciated recently that necrotic cell death is not always accidental and can instead occur downstream of regulated signaling events. Such types of regulated necrosis are lytic forms of cell death that can drive inflammation and immune responses following plasma membrane rupture and the release of cellular cargo into the extracellular Ferroptosis is a form of regulated necrosis that is iron-dependent and characterized by lipid peroxidation that occurs due to insufficient redox enzyme activity, particularly glutathione peroxidase 4 (GPX4) [260,262]. A recent study revealed that the treatment of human islets with the ferroptosis-inducing agent erastin leads to a reduction of islet cell viability, and that this could be prevented by cotreatment with an iron chelator [259].…”

Ferroptosis: New Dawn for Overcoming the Cardio-Cerebrovascular Diseases

“…Mitochondria are the most abundant organelles in cardiomyocytes, which are mainly responsible for energy metabolism ( Li N. et al, 2020 ); meanwhile, cardiomyocyte as an important source of energy, if its mitochondrial function deteriorates, it would lead to myocardial I/R injury. The double membranes structure of mitochondria provides an ideal location for ferroptosis, and some researchers have observed mitochondrial impairment in patients with ferroptosis ( Sha et al, 2021 ). After ferroptosis, excess intracellular free iron can enter the mitochondria, resulting in smaller myocardial mitochondria, increased mitochondrial membrane density, decreased mitochondrial respiration, and mitochondrial membrane potential depolarization ( Abdalkader et al, 2018 ; Sumneang et al, 2020 ), thus inducing CD and a series of Cardiac Diseases such as arrhythmia ( Hu et al, 2021 ).…”

Ferroptosis and Its Potential Role in Lung Cancer: Updated Evidence from Pathogenesis to Therapy

“…So far, many factors participate in the production of lipid peroxides such as Acyl-CoA synthetase long-chain family 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and lipoxygenases (LOXs). 43 ACSL4 is a member of the long-chain acyl coenzyme A synthase family (ACSLs), which is a class of essential enzymes involved in fatty acid metabolism. 44 LPCAT3 is a protein that catalyzes the reacylation of lysophospholipids to phospholipids.…”