Novel insights into ferroptosis: Implications for age-related diseases

Abstract

Rapid increase in aging populations is an urgent problem because older adults are more likely to suffer from disabilities and age-related diseases (ARDs), burdening healthcare systems and society in general. ARDs are characterized by the progressive deterioration of tissues and organs over time, eventually leading to tissue and organ failure. To date, there are no effective interventions to prevent the progression of ARDs. Hence, there is an urgent need for new treatment strategies. Ferroptosis, an iron-dependent cell death, is linked to normal development and homeostasis. Accumulating evidence, however, has highlighted crucial roles for ferroptosis in ARDs, including neurodegenerative and cardiovascular diseases. In this review, we a) summarize initiation, regulatory mechanisms, and molecular signaling pathways involved in ferroptosis, b) discuss the direct and indirect involvement of the activation and/or inhibition of ferroptosis in the pathogenesis of some important diseases, and c) highlight therapeutic targets relevant for ARDs.

Keywords: age-related diseases; ferroptosis; iron; lipid peroxidation; reactive oxygen species.

Figure 1

Changes in the morphological and bioenergy characteristics during ferroptosis, including mitochondrial shrinkage, membrane rupture, excess ROS, iron overload, and intracellular GSH depletion. Features of this figure were adapted from Servier Medical Art (http://smart.servier.com/) licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 2

Ferroptosis-related signaling molecules and signaling pathways. (A) Glutamate exchanges for cystine in a 1:1 ratio through the cystine/glutamate antiporter system Xc-, and inhibition of system Xc- by its core part SLC7A11 induces ferroptosis. (B) Ferric iron (Fe³⁺) bound to transferrin enters cells via membrane protein transferrin receptor 1 (TFR1) and localizes in endosomes, wherein the ferrireductase activity of STEAP3 reduces Fe³⁺ to redox-active iron (Fe²⁺). Finally, divalent metal transporter 1 (DMT1) releases Fe²⁺ from endosomes into a labile iron pool in the cytoplasm. In general, excess iron is stored in ferritin with ferritin heavy chain 1 (FtH1) and ferritin light chain 1 (FtL1). Under the action of H₂O₂, Fe²⁺ catalyzes the production of hydroxyl radical (HO∙) by Fenton reaction, triggering a chain reaction of radical lipid peroxidation and eventually leads to ferroptosis. (C) Ferroptosis is trigged by peroxidation (-OOH) of polyunsaturated fatty acids (PUFAs) and aberrant accumulation of lipid reactive oxygen species (ROS), resulting in membrane destabilization and rupture. Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) are necessary for ferroptosis to produce the target lipid pool containing arachidonic acid. GPX4 can hydrolyze lipid peroxides into non-toxic lipid alcohols (-OH). (D) Intracellular glutathione exists as oxidized glutathione (GSSG) and reduced glutathione (GSH); GPX4 requires GSH as a cofactor and reduces GSSG to GSH via glutathione reductase (GR). GPX4 inhibits the formation of Fe²⁺-dependent ROS by converting lipid hydroperoxides into lipid alcohols, and thus inhibits ferroptosis.