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Multiple inducers and inhibitors of ferroptosis have been identified to affect accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism ( Table 2). 1 According to their original study, ferroptosis is remarkably distinct from other types of RCD such as apoptosis, necroptosis, and autophagic cell death at morphological, biochemical, and genetic levels ( Table 1). What is the specific role of ferroptosis in human disease?įerroptosis is the term for a form of RCD that was recently coined in 2012 by the lab of Dr. How do mitochondrial dynamics and endoplasmic reticulum (ER) stressors affect ferroptosis? What explains the cross-regulation between ferroptosis and other types of RCD? ![]() What controls the network of ferroptosis-signaling pathways? How does the downstream signaling or executor of iron-dependent ROS metabolism identify and distinguish ferroptosis from other types of RCD? In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). ![]() It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. Ferroptosis is a recently recognized form of regulated cell death.
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