Author
Yuki Sakakura
Other affiliations: Ibaraki Prefectural University of Health Sciences
Bio: Yuki Sakakura is an academic researcher from University of Tsukuba. The author has contributed to research in topics: Glutathione & Sterol Regulatory Element Binding Protein 1. The author has an hindex of 5, co-authored 5 publications receiving 635 citations. Previous affiliations of Yuki Sakakura include Ibaraki Prefectural University of Health Sciences.
Papers
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TL;DR: It is demonstrated that system x–c contributes to maintaining the plasma redox balance in vivo but is dispensable in mammalian development, although it is vitally important to cells in vitro.
346 citations
TL;DR: It is demonstrated that SREBPs activate every step of cholesterol synthetic pathway, contributing to an efficient cholesterol synthesis.
219 citations
TL;DR: It is demonstrated that ACAS is a novel hepatic lipogenic enzyme, providing further evidence that SREBP-1 and insulin control the supply of acetyl-CoA directly from cellular acetate for lipogenesis and suggesting that this enzyme might also play an important role in basic cellular energy metabolism.
Abstract: DNA microarray analysis on upregulated genes in the livers from transgenic mice overexpressing nuclear sterol regulatory element-binding protein (SREBP)-1a, identified an espressed sequence tag (ES...
83 citations
TL;DR: The results suggest that system xc– plays an important role in neutrophils when they are activated, and their GSH consumption is accelerated.
Abstract: Reactive oxygen species (ROS) produced by neutrophils are essential in the host defense against infections but may be harmful to neutrophils themselves. Glutathione (GSH) plays a pivotal role in protecting cells against ROS-mediated oxidant injury. Cystine/glutamate transporter, designated as system x c - and consisting of two proteins, xCT and 4F2hc, is important to maintain GSH levels in mammalian-cultured cells. In the present paper, we have investigated system x c - in neutrophils. In human peripheral blood neutrophils, neither the activity of system x c - nor xCT mRNA was detected. The activity was induced, and xCT mRNA was expressed when they were cultured in vitro. The mRNA expression was much enhanced in the presence of opsonized zymosan or PMA. In contrast, mouse peritoneal exudate neutrophils, immediately after preparation, exhibited system x c - activity and expressed xCT mRNA. The activity and the expression were heightened further when they were cultured. Peritoneal exudate cells (mostly neutrophils) from xCT-deficient (XCT -/- ) mice had lower cysteine content than those from the wild-type mice. GSH levels in the XCT -/- cells decreased rapidly when they were cultured, whereas those in the wild-type cells were maintained during the culture. Apoptosis induced in culture was enhanced in the XCT -/- cells compared with the wild-type cells. These results suggest that system x c - plays an important role in neutrophils when they are activated, and their GSH consumption is accelerated.
49 citations
TL;DR: The results suggest that neurons separated from the other types of cells cannot survive due to the oxidative stress, which may otherwise be neutralized by a mechanism involving glutathione, and that antioxidants including serotonin has a beneficial effect on these purified neurons.
7 citations
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TL;DR: The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice and form the subject of this review.
Abstract: Lipid homeostasis in vertebrate cells is regulated by a family of membrane-bound transcription factors designated sterol regulatory element–binding proteins (SREBPs). SREBPs directly activate the expression of more than 30 genes dedicated to the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids, as well as the NADPH cofactor required to synthesize these molecules (1–4). In the liver, three SREBPs regulate the production of lipids for export into the plasma as lipoproteins and into the bile as micelles. The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice. These studies form the subject of this review.
4,406 citations
Columbia University1, University of Pittsburgh2, Florey Institute of Neuroscience and Mental Health3, Stanford University4, German Cancer Research Center5, Ludwig Maximilian University of Munich6, Yale University7, Memorial Sloan Kettering Cancer Center8, Dresden University of Technology9, Wistar Institute10, National University of Mar del Plata11, University of Texas Health Science Center at San Antonio12, Guangzhou Medical University13, University of Connecticut Health Center14, Nagoya University15, New York University16, University of Arizona17
TL;DR: The mechanisms underlying ferroptosis are reviewed, connections to other areas of biology and medicine are highlighted, and tools and guidelines for studying this emerging form of regulated cell death are recommended.
3,356 citations
TL;DR: The discovery of ferroptosis, the mechanism of ferraptosis regulation, and its increasingly appreciated relevance to both normal and pathological physiology are summarized.
1,562 citations
TL;DR: From a mechanistic standpoint, oxidative stress may be better defined as a disruption of redox signaling and control and adoption of such a definition could redirect research to identify key perturbations of red Oxidative stress-related disease processes and lead to new treatments for oxidative stressed disease processes.
Abstract: Oxidative stress is often defined as an imbalance of pro-oxidants and antioxidants, which can be quantified in humans as the redox state of plasma GSH/GSSG. Plasma GSH redox in humans becomes oxidized with age, in response to oxidative stress (chemotherapy, smoking), and in common diseases (type 2 diabetes, cardiovascular disease). However, data also show that redox of plasma GSH/GSSG is not equilibrated with the larger plasma cysteine/cystine (Cys/CySS) pool, indicating that the "balance" of pro-oxidants and antioxidants cannot be defined by a single entity. The major cellular thiol/disulfide systems, including GSH/GSSG, thioredoxin- 1 (-SH2/-SS-), and Cys/CySS, are not in redox equilibrium and respond differently to chemical toxicants and physiologic stimuli. Individual signaling and control events occur through discrete redox pathways rather than through mechanisms that are directly responsive to a global thiol/disulfide balance such as that conceptualized in the common definition of oxidative stress. ...
1,438 citations
TL;DR: In this paper, the authors provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of the potential therapeutic roles, and its pathological roles, together with a potential for therapeutic targeting.
Abstract: The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.
1,243 citations