Iron Metabolism in Ferroptosis

Abstract

Ferroptosis is a form of regulated cell death that is characterized by iron-dependent oxidative damage and subsequent plasma membrane ruptures and the release of damage-associated molecular patterns. Due to the role of iron in mediating the production of reactive oxygen species and enzyme activity in lipid peroxidation, ferroptosis is strictly controlled by regulators involved in many aspects of iron metabolism, such as iron uptake, storage, utilization, and efflux. Translational and transcriptional regulation of iron homeostasis provide an integrated network to determine the sensitivity of ferroptosis. Impaired ferroptosis is implicated in various iron-related pathological conditions or diseases, such as cancer, neurodegenerative diseases, and ischemia-reperfusion injury. Understanding the molecular mechanisms underlying the regulation of iron metabolism during ferroptosis may provide effective strategies for the treatment of ferroptosis-associated diseases. Indeed, iron chelators effectively prevent the occurrence of ferroptosis, which may provide new approaches for the treatment of iron-related disorders. In this review, we summarize recent advances in the theoretical modeling of iron-dependent ferroptosis, and highlight the therapeutic implications of iron chelators in diseases.

Characteristics and Biomarkers of Ferroptosis

“…Since the initial study defined ferroptosis as an iron-dependent RCD, iron accumulation-mediated biochemical events (e.g., elevated Fenton reaction or activated iron-containing enzymes) seem to be a biochemical sign of ferroptosis ( Chen et al, 2020c ). Iron is an essential trace element, distributed in various subcellular organelles (e.g., mitochondria and lysosomes).…”

“…In contrast, iron chelators (e.g., deferoxamine) limit ferroptosis in vitro ( Dixon et al, 2012 ) or in vivo ( Lu et al, 2020 ). The level of iron in cells is controlled by a complex network that involves the absorption, storage, utilization, and outflow of iron ( Chen et al, 2020c ). As expected, certain molecular regulators related to iron homeostasis control ferroptosis sensitivity.…”

NUPR1 is a critical repressor of ferroptosis

“…Our studies reveal a role for NUPR1 in preventing intracellular iron accumulation in response to ferroptosis activators. Ferroptosis is generally recognized as an iron-dependent oxidative death, which can be suppressed by iron chelators, the depletion of the iron uptake receptor TFRC or the overexpression of the iron storage protein ferritin 8 . Given that depletion of NUPR1 increased iron accumulation induced by classical ferroptosis activators (erastin or RSL3), the expression levels of core iron metabolism-associated genes were measured in WT and Nupr1 − / − cells.…”

“…In recent years, an increasing level of interest has been manifested with regard to ferroptosis, a non-apoptotic-regulated cell death 3 , 4 , which plays a possible pathogenic role in cancer, neurodegeneration, and organ dysfunction 5 – 7 . The induction of ferroptosis has been shown to rely on iron accumulation, which facilitates oxidative damage through either the production of highly reactive hydroxyl free radicals in the Fenton reaction or the activation of iron-containing enzymes, such as lipoxygenase 8 . Ferroptotic cells exhibit a necrosis-like morphology and damage-associated molecular patterns (DAMPs) released from ferroptotic cells may function as extracellular inflammatory mediators to contribute to tissue injury 9 .…”

Insights into the Roles of the Sideroflexins/SLC56 Family in Iron Homeostasis and Iron-Sulfur Biogenesis

“…Growing evidence supports the key role of iron metabolism in ferroptosis, even if the exact mechanisms are not fully elucidated [ 87 ]. Ferroptosis is a physiological cell death contributing to tissue homeostasis and implicated in pathology (cancer, neurodegenerative disease and cardiac injury).…”