Next Article in Journal
Natural IgG against S-Protein and RBD of SARS-CoV-2 Do Not Bind and Hydrolyze DNA and Are Not Autoimmune
Next Article in Special Issue
The Role of ER Stress in Diabetes: Exploring Pathological Mechanisms Using Wolfram Syndrome
Previous Article in Journal
Iron- and Neuromelanin-Weighted Neuroimaging to Study Mitochondrial Dysfunction in Patients with Parkinson’s Disease
Previous Article in Special Issue
Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 23
Issue 22
10.3390/ijms232213679
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Ferroptosis Signaling in Pancreatic β-Cells: Novel Insights & Therapeutic Targeting

by
Suma Elumalai
1,
Udayakumar Karunakaran
1,
Jun-Sung Moon
1,2,* and
Kyu-Chang Won
1,2,*
1
Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea
2
Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Korea
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(22), 13679; https://doi.org/10.3390/ijms232213679
Submission received: 29 September 2022 / Revised: 2 November 2022 / Accepted: 5 November 2022 / Published: 8 November 2022
(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)
Browse Figures
Versions Notes

Abstract

:
Metabolic stress impairs pancreatic β-cell survival and function in diabetes. Although the pathophysiology of metabolic stress is complex, aberrant tissue damage and β-cell death are brought on by an imbalance in redox equilibrium due to insufficient levels of endogenous antioxidant expression in β-cells. The vulnerability of β-cells to oxidative damage caused by iron accumulation has been linked to contributory β-cell ferroptotic-like malfunction under diabetogenic settings. Here, we take into account recent findings on how iron metabolism contributes to the deregulation of the redox response in diabetic conditions as well as the ferroptotic-like malfunction in the pancreatic β-cells, which may offer insights for deciphering the pathomechanisms and formulating plans for the treatment or prevention of metabolic stress brought on by β-cell failure.

1. Introduction

Despite considerable advances in treatment, the prevalence of diabetes mellitus (DM) is increasing worldwide, endangering human health and placing an economic burden on society. Diabetes mellitus is a diverse condition caused by progressively impaired insulin production from β-cells and insulin resistance in target tissues. There are several types of diabetes, of which type I and type II are the most common. The dysfunction and destruction of pancreatic β-cells in type 1 diabetes (T1D) are caused by cytotoxic T cells and pro-inflammatory cytokines. Obesity, hyperglycemia, peripheral insulin resistance, and cytokine levels are the main features of type 2 diabetes (T2D), a complicated metabolic condition that results in a relative lack of insulin and β-cell failure. Apoptosis is the endpoint of β-cell death in both forms of disease [1,2,3,4]. Knowledge of the pathophysiology of this disease has now entered a new era based on an understanding of the biology and critical reappraisal of the pathobiology of β-cell failure. Increasing evidence suggests that iron accumulation is linked to an elevated risk of both type 1 and type 2 diabetes and is proposed to be involved in the pathophysiological mechanisms of β-cell failure [5,6,7,8]. This suggests that ferroptosis, an iron-dependent and non-apoptotic cell death, is one of the triggering events in β-cell pathophysiology and is characterized by the accumulation of toxic lipid reactive oxygen species (ROS). The key initiating step of ferroptosis is the inhibition of cystine uptake into cells, which can be prevented by iron chelation [9]. Many physiological and pathological factors perturb iron function and induce metabolic diseases, depending on the duration and degree of metabolic stress. In this review, we describe the critical events involved in ferroptosis with respect to their relevance to β-cell failure in diabetes.

2. Involvement of Iron and β-Cell Function: An Overview

The second-most prevalent metal in the Earth’s crust is iron, which is also a vital micronutrient for life. Its biological significance is demonstrated by the high prevalence of human diseases caused by disturbances in iron homeostasis. Iron is a transition metal that can adopt various oxidation states. The ferrous (Fe2+) and ferric (Fe3+) forms are the most prevalent, and this transition is largely responsible for the biological significance of iron. Iron is a crucial cofactor for electron transfer because of its propensity to receive and provide electrons, and its adaptable coordination chemistry is crucial for its versatility in binding to biological ligands [10]. Because of its chemical makeup and potential for harm, cells have created a sophisticated system for handling iron to maintain it at adequate and safe levels. Carriers and receptors bind and transport ions across membranes, and enzymes and buffering proteins regulate their redox state and free level. Buffering proteins also act as protective buffers. Iron-binding protein expression is regulated by iron regulatory proteins, according to ion density. Several of these proteins are present in pancreatic β-cells, such as the transferrin receptor (TrfR), the mitochondrial iron-storage protein frataxin, the cytosolic iron-storage proteins ferritin H and L chains, the iron-export regulatory hormone hepcidin (which is found in the insulin granules), the iron chaperone lipocalin 2, and the v-ATPase, supporting the hypothesis that β-cells have a classical iron metabolism [11,12,13,14,15,16]. After binding to TrfR, transferrin-bound iron is taken up in the blood. After that, the metalloreductase six transmembrane epithelial antigen of prostate family member 3 and DMT1 endocytose the transferrin-TrfR complex (STEAP 3). Iron is liberated from transferrin inside the endosome and reduced via a drop in pH by metalloreductase STEAP 3 and proton pump v-ATPase. Subsequently, the iron is delivered to the cytoplasmic labile iron pool (LIP) via DMT1 over a v-ATPase-provided proton gradient. Cytosolic LIP receives iron in the form of ferrous iron, which is then transported to ferritin for storage or to the nucleus, ER, mitochondria, and Fe-S proteins for functional use by iron chaperones such as lipocalin 2 and poly (rC) binding protein (PCBP) 1 and 2 [17]. Ferritin-bound iron is stored in insulin granules or adjacent to the plasma membrane in β-cells, and iron is exported from β-cells through ferroportin, the activity of which is suppressed by paracrine or autocrine effects of the small peptide hormone hepcidin [11,14,18]. Hepcidin binding to FPN induces its internalization and lysosomal degradation, thus directly inhibiting iron release into circulation from the sites of iron absorption, recycling, and storage. Furthermore, β-cells release hepcidin in response to glucose stimulation, indicating that ferroportin binding inhibits iron export as a positive feedback mechanism in iron management during glucose-stimulated insulin production [14]. Hence, due to its dual nature, iron levels must be maintained within a tight physiological range to avoid the detrimental consequences of both iron deficiency and excess iron.
Although iron has been detected in almost all intracellular organelles, given the significance of the mitochondria and ER in β-cell function and dysfunction as well as the therapeutic implications that follow, understanding the metabolism of iron in β-cell mitochondria and ER is of special interest. Most of the labile iron pool, in contrast, is transported to the mitochondria, where it combines with heme and Fe-S clusters. Iron is exported from endosomes by DMT1; however, it is unclear how iron travels from the cytosol to the inner mitochondrial membrane. A wide body of evidence suggests a possible role of frataxin, an iron chaperone located in the mitochondrial matrix that was observed to interact with the Fe-S-cluster assembly and presumably appears to be a key activator of mitochondrial energy flux by oxidative phosphorylation [19,20,21]. In this way, frataxin acts as a coordinator of the electron transport chain, leading to increased mitochondrial membrane potential Δψm and elevated cellular ATP content. However, disruption of the frataxin gene, specifically in pancreatic β-cells, leads to a reduction in insulin-secretory capacity and impaired glucose tolerance, resulting in overt DM due to a loss of β-cell mass. Furthermore, disruption of frataxin leads to increased levels of ROS within pancreatic islets, which in turn are associated with increased apoptosis and decreased proliferation [22]. This finding can be interpreted in two ways: first, it is necessary for complex II to properly utilize electrons. Ubiquinone (Q) is not entirely reduced to ubiquinol (QH2), and an excess of the intermediate semiquinone form results from improper electron incorporation into the respiratory chain. By interacting with molecular oxygen to produce superoxide radicals and induce oxidative stress in the mitochondria, the formation of this radical semiquinone has been linked to a pro-oxidizer impact. Second, frataxin disruption may decrease mitochondrial ATP production, which leads to reduced insulin exocytosis and secretion. In addition, frataxin deficiency can exacerbate ER stress in β-cells [23]. Therefore, it is of great interest to understand how the disruption of frataxin contributes to β-cell death and warrants further study (Figure 1).

3. Role of Iron Accumulation and β-Cell Dysfunction

Hereditary hemochromatosis is a common genetic disorder of iron metabolism where iron accumulates specifically in the endocrine pancreas resulting in decreased insulin secretion and increased protein oxidation and beta cell apoptosis [6,24]. Furthermore, experimental studies have indicated that patients with transfusional iron overload have increased iron deposition in β-cells, which may result in hyperglycemia and DM [25,26]. Paradoxically, iron is also deposited in the muscles and livers of patients with hemochromatosis, causing decreased glucose uptake and insulin resistance. In addition, the exact mechanisms by which iron deposition occurs are not known.
Consistent with the ability of iron to readily accept and donate electrons, iron is an essential cofactor for electron transfer, and its flexible coordination chemistry is key to its versatility in binding to biological ligands. Paradoxically, the same chemical properties that render iron biologically essential also underlie the toxicity of excess iron. In eukaryotic cells, small concentrations of labile Fe2+ are found in the cytosol and mitochondrial matrix; the lysosome also has redox-active iron derived from extracellular sources, and these cells also have the ability to break down ferritin and iron-rich intracellular organelles, such as mitochondria [27,28]. These redox-active iron pools can directly catalyze the creation of harmful free radicals using Fenton chemistry [29]. Both iron-dependent ROS-producing enzymes and labile iron are thought to contribute to ROS-dependent cell damage and cell death. Because of the difficulties in defining the targets and effects of ROS that are significant to mortality as well as the consequences of iron accumulation on cell function, this phenomenon is currently the subject of active research.

4. Is Ferroptosis the Result of Iron Accumulation and β-Cell Dysfunction?

Pancreatic β-cells are characterized by a relatively high iron content and a dependence on mitochondrial respiration for insulin secretion, which has long been considered an argument that oxidative stress is highly relevant in pancreatic β-cell dysfunction. Moreover, iron has long been recognized as a signaling molecule in the inflammatory response to the induction of insulin resistance, both in vitro and in vivo [30,31]. Signaling pathways that affect iron metabolism have also been shown to modulate ferroptosis. Thus, iron-dependent cell death may be especially important in DM. Metabolic dysfunction has been explained by several theories, including mitochondrial dysfunction, oxidative stress, ER stress, hyperglycemia (glucotoxicity), dyslipidemia, and the concomitant presence of both hyperglycemia and dyslipidemia (glucolipotoxicity) [32]. Another mechanism by which this environment is conducive to the development and/or progression of diabetes is the activation of chronic inflammation.

4.1. The Role of DMT1 in Ferroptotic Signaling

Indeed, experimental evidence has shown that the pro-inflammatory cytokine IL-1β induces divalent metal transporter 1 (DMT1) expression, which correlates with increased β-cell iron content and ROS production via an increased intracellular LIP. This was associated with elevated levels of the iron import mediators lipocalin-2 (Lcn2) and TrfR and decreased levels of ferroportin, an iron exporter. Iron chelation or genetic knockdown of DMT1 reduced cytokine-induced ROS formation and cell death. Interestingly, glucose-stimulated insulin secretion in the absence of cytokines in DMT1 knockout islets was defective, highlighting the physiological role of iron and ROS in the regulation of insulin secretion [33]. Furthermore, there is considerable evidence suggesting that the expression of DMT1 and LCN2 is induced by pro-inflammatory cytokines in pancreatic β-cells [34,35]. Whether this increase in LCN2 levels is a cause or result of metabolic dysregulation and whether it has an impact on disease progression have not been examined. Moreover, LCN2 is a neutrophil gelatinase-associated protein that influences iron homeostasis by forming a ternary complex with a siderophore as its cofactor, and it serves as a defense mechanism of the innate immune response system [36,37]. In addition to restricting iron availability, LCN2 also exerts a cytoprotective effect against STZ in a short-term HFD mouse model of diabetes by improving β-cell mass and promoting β-cell proliferation [38]. However, this also suggests that future studies are needed to understand the possible interference of LCN2 in the pathophysiology of pancreatic β-cell iron dysregulation. It has also been shown that by increasing NF-kB transcriptional activity, abnormal cytokine-dependent increases in cellular iron import via DMT1 primes β-cells for ROS-mediated inflammatory damage [33]. There is evidence that NF-kB controls the promoter activity of a number of genes whose expression has changed as a result of cytokine exposure, which is implicated in the deleterious effects of β-cells [39,40,41,42]. Indeed, it has been observed that pro-inflammatory cytokines upregulate the activation of inducible nitric oxide synthase (iNOS) gene expression and the subsequent formation of NO, which, in part, leads to the loss of function and activation of oxidative stress linked to β-cell failure [43,44,45]. Importantly, peroxynitrite, a novel and reactive peroxide resulting from the rapid interaction of superoxide radicals with NO, mediates cytokine-induced damage [46,47]. Furthermore, evidence supports a key role of peroxynitrite in the Fe-S cluster of IRP1 destabilization, resulting in the inactivation of aconitase activity and inhibition of the Fe-S cluster assembly [48,49,50]. These data suggest that the dysregulation of iron may cause ferroptotic cell death, which warrants further study. Notably, the inhibition of peroxynitrite formation by iNOS inhibitors or superoxide scavengers prevents β-cell destruction and diabetes development in non-obese diabetic NOD mice [51,52].

4.2. The Role of NADPH Oxidase in Ferroptotic Signaling

To learn more about the characteristics of the effector that mediates iron-induced cell damage, the effects of the NADPH oxidase enzyme system are emphasized below. Emerging evidence suggests that NADPH oxidase (NOX) is a major source of extra-mitochondrial superoxide radicals in β-cells [53,54,55,56,57]. The enzyme NADPH oxidase is a multi-subunit enzyme, and the assembly of the active enzyme complex is described in Ref. [57]. Broniowska et al. demonstrated that peroxynitrite formation by cytokines was reduced in the absence of superoxide, which suggests that NOX is involved in iron-mediated pancreatic β-cell damage [58]. Moreover, it should be noted that the activation of mitochondrial H202 and hydroxyl radical formation contribute to cytokine-induced pancreatic β-cell cytotoxicity [59]. However, evidence suggests that iron-induced NF-kB mediated NOX expression exerts inflammatory effects in atherosclerosis [60]. The precise connection between NOX and iron-induced β-cell inflammation is yet to be fully understood. In addition, activation of JNK signaling occurs downstream of iron- and NOX-induced β-cell apoptosis [33,61]. Even though JNK has many downstream targets, p66Shc, a 66 kDa Src collagen homolog (Shc) adaptor protein, was found to link mitochondrial ROS production in pancreatic β-cells in response to JNK activation under lipotoxic conditions [62,63,64,65]. Phosphorylation of p66Shc at Ser36 triggers its mitochondrial localization, where it generates H2O2 via its oxidoreductase activity [66,67,68]. Additionally, under glucolipotoxic conditions, elevated levels of LIPs by DMT1 mediate mitochondrial dysfunction and β-cell destruction [69], suggesting the possibility of p66Shc activation. However, further studies are required. In contrast, angiotensin II- (ANG-II)-induced NOX activation increased the LIP and iron-dependent oxidative stress by JNK-p66Shc mediated ferritin degradation in human umbilical vein endothelial cells and HT22 neuronal cells [70]. Interestingly, chronic hyperglycemia and ANG-II type 1 receptor-induced pro-inflammatory cytokine secretion in human islets cause superoxide production and p47phox and p22phox expression, which impairs insulin secretion and inflammation. However, inhibition of the ANG-II II type 1 receptor downregulates NADPH oxidase, which in turn suppresses oxidative stress, thus improving β-cell insulin secretion and decreasing β-cell inflammation [71,72,73]. These findings also provide a potential mechanism for how NOX-dependent H2O2 production is a likely cause of glucose and ANG-II working together to induce LIP and impairment in insulin secretion and the induction of β-cell dysfunction. Therefore, further research into this connection should provide insightful information regarding β-cell dysfunction during diabetes.
Indeed, Weaver et al. demonstrated that the pro-inflammatory cytokines induced 12-lipoxygenase expression and increased the flux of hydroxyeicosatetraenoic acid (12-HETE) from arachidonic acid (AA), impairing β-cell function by NOX-1 induction [74,75]. The lipoxygenases (LOXs) are non-heme iron-containing dioxygenases that catalyze the formation of a complex array of bioactive LOOHs that regulate cell signaling. Moreover, children newly diagnosed with type 1 diabetes have very high LOX-induced HETE plasma concentrations [76]. However, it is unknown how and to what extent HETE contributes to the pathophysiology of pancreatic β-cells in diabetes. The ability of LOX-overexpressing cells to undergo ferroptosis may be attributed to an initial increase in the concentration of a particular LOOH, which can later break down to produce alkoxyl and/or hydroxyl radicals via the Fenton reaction for nonenzymatic lipid peroxidation [77,78,79]. Moreover, to specifically initiate the production of the ferroptotic hydroperoxy-phospholipid hydroperoxyeicosaetetranoic acid, LOX induces circumstances in which PEBP1, a Raf-1 kinase inhibitory protein, eagerly binds LOX, altering its catalytic competence from free AA to AA-PE [80,81]. Interestingly, PEBP1 expression is high in the pancreatic islets, and the deletion of PEBP1 significantly suppressed streptozotocin-induced activation of β-cell destruction and increased β-cell mass [82]. Hence, it is tempting to speculate that PEBP1 is involved in ferroptosis signaling-induced β-cell dysfunction, which warrants further investigation.

4.3. ACSL4 in β-Cell Ferroptosis

Moreover, lipid peroxidation in ferroptosis is supported by acyl-CoA synthetase long-chain family member 4 (ACSL4), an acyl CoA synthetase enzyme that acylates PUFA and generates fatty acyl-CoA esters, which are transesterified into phospholipids [83]. Notably, ACSL4 is present in insulin-secretory granules and is involved in insulin secretion [84]. In addition, ACSL4 is essential for the induction of lipid oxidation during ferroptosis [85]. However, the relevance of ACSL4 in β-cell ferroptosis remains unexplored and enigmatic. Together, these findings suggest that the dysregulation of iron handling and lipid peroxidation disrupts the cellular redox balance in organelles that orchestrate ferroptotic death signals.

4.4. Glutathione System in β-Cell Ferroptosis

To control the intracellular redox balance, cells have evolved a network of antioxidant systems to scavenge ROS, among which the glutathione (GSH)-dependent system may be particularly important. However, due to low levels of protective antioxidant enzymes compared with that in other tissues, redox imbalance is apparently a significant hallmark of pancreatic β-cell malfunction and death [86]. It is plausible that the ferroptotic effects of the diabetic milieu (glucose, cytokines, and fatty acids) may be mediated, in part, through the inhibition of the GSH system and subsequent activation of ROS production. However, under conditions of oxidative stress, the redox status of cells results in the loss of GSH, which lowers their reducing ability and can only be restored by producing fresh GSH [87]. Therefore, the GSH/GSSG ratio can be used as a sign of the redox environment inside the cell. Glutathione peroxidase 4 (GPX4) is the only enzyme that lowers lipid hydroperoxides to match alcohols or water by reducing free hydrogen peroxide [88]. Mechanistically, GSH synthesis is required for GPX4 activity, which offers reducing equivalents to eliminate oxidative species, supported by the fact that mice lacking the GSH-synthesizing enzyme glutamylcysteine synthetase and GPX4 die at the same developmental stage [89,90]. Moreover, GSH synthesis is manipulated by the availability of cysteine, and its uptake relies on the glutamate/cysteine antiporter (system xCT), which is composed of the transmembrane protein transporter SLC7A11 and the transmembrane regulatory protein SLC3A2 [91,92,93,94]. However, new experimental evidence demonstrates that the pharmacological inhibition of system xCT by erastin or GPX4 inactivation by RSL3 induces ferroptotic cell death in human islets. In addition, ferrostatin-1 (a ferroptosis inhibitor) or desferrioxamine, an iron chelator, prevents ferroptotic death and improves the function of human islets [95]. Further studies have shown that GPX4 overexpression prevents the accumulation of phospholipid hydroperoxides that make pancreatic β-cells susceptible to ferroptotic-like cell death by free fatty acids [96]. Supporting this, Krümmel et al. found that the overexpression of GPX4 efficiently prevents tert-butyl hydroperoxide and pro-inflammatory cytokine-induced lipid peroxidation and ferroptotic β-cell death [97]. Importantly, it has been shown that the availability of reduced GSH is regulated by NADPH supply, which is utilized by GSH reductase [98]. The major sources of NADPH are glucose-6-phosphate dehydrogenase and 6-phosphoglucanate dehydrogenase of the pentose phosphate pathway enzymes [99,100,101]. Importantly, glucose-6-phosphate dehydrogenase expression and activity are decreased by hyperglycemia, with a reduction in GSH reductase activity, rendering pancreatic β-cells susceptible to oxidative damage via the GSH/GSSH ratio [102,103]. Additionally, glutamine provides precursors for GSH production, resulting in a decrease in the steady-state level of lipid oxidation products, a crucial component of cell viability [104,105]. In this context, glutamine availability is sensed by Glutaminase 1 (GLS1), which converts glutamine into glutamate for GSH synthesis and plays an important role in insulin secretion [106,107,108,109]. Notably, we discovered that endogenous GLS1 mRNA and protein expression were suppressed upon exposure to diabetic milieu conditions (hyperglycemia, streptozotocin, and H2O2), leading to a reduction in GSH synthesis. This correlates with a significant decline in the GSH/GSSG ratio associated with the accelerated degradation of xCT and GPX4. In particular, a drop in GPX4 levels may cause phospholipid hydroperoxides to accumulate, which makes pancreatic cells more prone to cell death that resembles ferroptosis [110,111]. These results contribute to the integration of intracellular processes with an increase in ROS levels caused by diabetic milieu conditions (hyperglycemia, streptozotocin, and H2O2), resulting in the onset of islet dysfunction and diabetes. Further investigation is required to interpret these findings.

5. Therapeutic Agents Targeting Inhibition of Ferroptotic-Death

Notably, evidence indicates that iron accumulation and lipid peroxidation are associated with ferroptotic cell dysfunction. Therefore, medications that lower iron accumulation or lipid peroxidation inhibitors are helpful in treating diabetes, obesity, and peripheral insulin resistance. Iron-chelating substances are frequently used in the clinical context because they can easily limit and redistribute systemic iron. A growing body of evidence suggests that the chelators deferoxamine and deferiprone ameliorate experimental diabetes and preserve β-cell mass, protecting β-cells from apoptosis [33,112,113,114,115,116,117]. In contrast, the metabolic response to iron overload is tightly regulated by DMT1, and inhibition of DMT1 or iron restriction improved the glucose tolerance and circulating insulin levels in high-fat diet-induced diabetes and multiple low-dose streptozotocin-induced islet inflammation [7,17,33,69,118]. However, a number of small-molecule DMT1-mediated iron transport inhibitors have been studied. For example, ferristatin II (NSC306711) attenuates DMT1-mediated iron uptake and induces transferrin receptor degradation, which inversely correlates with the expression of lipid peroxidative genes and proteins to restrain ferroptosis [119,120,121,122]. To date, the beneficial activities of ferristatin II have not been studied in iron-related metabolic diseases and require further investigation. The antioxidant activity of the selenium-containing drug ebselen potently suppresses DMT1-mediated iron absorption and reduces iron-induced ROS production in Alzheimer’s disease [123,124]. Further studies suggest that ebselen ameliorates lipotoxic dysfunction by inhibiting oxidative stress and preserving insulin secretion and β-cell mass in Zucker diabetic models, as well as in other experimental diabetes models [125,126,127]. Additionally, pioglitazone, a member of the thiazolidinedione class of anti-diabetic medications, binds to and stabilizes mitoNEET, an inhibitor of the mitochondrial iron uptake protein, thereby inhibiting mitochondrial labile iron accumulation and reducing iron-mediated ROS formation [128,129,130,131,132]. Additionally, we showed that pioglitazone treatment reduces hyperglycemia-induced β-cell oxidative stress by boosting GLS1 stability and activity. Further research demonstrated that pioglitazone treatment restores both the GSH/GSSG ratio and GPX4 protein levels under hyperglycemic conditions, demonstrating that the protective effect of pioglitazone on β-cell apoptosis is dependent on antioxidants and inhibitors of ferroptosis [110]. Additionally, pioglitazone inhibits the expression of COX-2, which is stimulated by traumatic brain injury, most likely by interfering with the process of reducing ROS formation by blocking neuronal ferroptosis [133]. Additionally, pioglitazone has been shown to inhibit ACSL4, which is required for the execution of ferroptosis, and hence decreases mouse embryonic fibroblast ferroptosis [85]. The fundamental processes that initiate this paradoxical occurrence of ACSL4 inhibition and suppression of ferroptosis to enhance metabolic health are not entirely understood. Additionally, coenzyme Q, vitamin E, and di/tetrahydrobiopterin have shown promise as new therapeutic approaches to disease in investigations of the function of these endogenous antioxidants in ferroptosis inhibition [134,135,136,137]. Interestingly, c-Abl, which is elevated by metabolic stress in β-cells, accelerates lipid peroxidation and ferroptosis induced by GPX4 degradation by GLS1 inhibition. Additionally, the blockage of c-Abl by GNF2 allows cells to use glutamine metabolism (glutaminolysis) to produce GSH for β-cell survival and growth [111]. However, it is widely known that LOX inhibitors may inhibit the majority of ferroptotic cell deaths by preventing mitochondrial malfunction [138,139,140,141,142]. Furthermore, GLP-1 receptor agonist (GLP-1-RA) therapy and/or iron chelation enhances mitochondrial performance and restores β-cell function. In Wolfram syndrome and other types of diabetes linked to iron dysregulation, treatment with GLP-1-RA, likely enhanced by iron chelation, should be considered [143,144]. In general, it has become obvious that targeting iron metabolism and ferroptosis offers a compelling new therapeutic strategy for many disorders because of the significant gains in our understanding of the role of iron and ferroptotic damage in a variety of diseases (Figure 2).

6. Conclusions

According to experimental data, iron metabolism plays a role in the malfunction of pancreatic β-cells during the development of diabetes. The management of β-cell failure and T2D may be greatly affected by an understanding of this complex scenario and the role of iron-activated ferroptosis redox-regulated pathways. It is almost certain that these efforts will be helpful in the search for novel and efficient treatments for diseases associated with abnormal iron metabolism, even though more research is still required to thoroughly examine the illnesses linked to abnormal iron metabolism in pancreatic β-cells.

Author Contributions

Conceptualization, S.E. and U.K.; resources, S.E., U.K. and J.-S.M.; data curation, S.E. and U.K.; writing-original draft preparation, S.E. and U.K.; writing-review and editing, U.K., S.E., J.-S.M. and K.-C.W.; visualization, S.E.; supervision, K.-C.W.; funding acquisition, J.-S.M. and K.-C.W. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government, grant number NRF-2020R1A2C1003649 to K.-C.W. and NRF-2020R1A2C4002626 to J.-S.M.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

DMT1Divalent metal transporter 1
FPNFerroportin
TrfRTransferrin receptor
STZStreptozotocin
c-Ablc-Abelson tyrosine kinase
LOXLipoxygenase
LCN2Lipocalin-2
ACSL4Acyl-CoA Synthetase Long Chain Family Member 4
HFDHigh fat diet; NO—Nitric oxide; GLS1—Glutaminase 1

References

  1. Zimmet, P.; Alberti, K.G.; Shaw, J. Global and societal implications of the diabetes epidemic. Nature 2001, 414, 782–787. [Google Scholar] [CrossRef] [PubMed]
  2. Robertson, R.P. Beta-cell deterioration during diabetes: What’s in the gun? Trends Endocrinol. Metab. 2009, 20, 20388–20393. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Wilcox, N.S.; Rui, J.; Hebrok, M.; Herold, K.C. Life and death of β cells in Type 1 diabetes: A comprehensive review. J. Autoimmun. 2016, 71, 51–58. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Lebastchi, J.; Deng, S.; Lebastchi, A.H.; Beshar, I.; Gitelman, S.; Willi, S.; Gottlieb, P.; Akirav, E.M.; Bluestone, J.A.; Herold, K.C. Immune therapy and β-cell death in type 1 diabetes. Diabetes 2013, 62, 1676–1680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Masuda, Y.; Ichii, H.; Vaziri, D.N. At pharmacologically relevant concentrations intravenous iron preparations cause pancreatic beta cell death. Am. J. Transl. Res. 2013, 6, 64–70. [Google Scholar]
  6. Huang, J.; Jones, D.; Luo, B.; Sanderson, M.; Soto, J.; Abel, E.D.; Cooksey, R.C.; McClain, D.A. Iron overload and diabetes risk: A shift from glucose to Fatty Acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis. Diabetes 2011, 60, 80–87. [Google Scholar] [CrossRef] [Green Version]
  7. Cooksey, R.C.; Jones, D.; Gabrielsen, S.; Huang, J.; Simcox, J.A.; Luo, B.; Soesanto, Y.; Rienhoff, H.; Abel, E.D.; McClain, D.A. Dietary iron restriction or iron chelation protects from diabetes and loss of beta-cell function in the obese (ob/ob lep-/-) mouse. Am. J. Physiol. Endocrinol. Metab. 2010, 298, E1236–E1243. [Google Scholar] [CrossRef] [Green Version]
  8. Simcox, J.A.; McClain, D.A. Iron and diabetes risk. Cell Metab. 2013, 17, 329–341. [Google Scholar] [CrossRef] [Green Version]
  9. Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012, 149, 1060–1072. [Google Scholar] [CrossRef] [Green Version]
  10. Papanikolaou, G.; Pantopoulos, K. Iron metabolism and toxicity. Toxicol. Appl. Pharmacol. 2005, 202, 199–211. [Google Scholar] [CrossRef]
  11. Aigner, E.; Felder, T.K.; Oberkofler, H.; Hahne, P.; Auer, S.; Soyal, S.; Stadlmayr, A.; Schwenoha, K.; Pirich, C.; Hengster, P.; et al. Glucose acts as a regulator of serum iron by increasing serum hepcidin concentrations. J. Nutr. Biochem. 2013, 24, 112–117. [Google Scholar] [CrossRef]
  12. Chang, S.Y.; Kim, D.B.; Ko, S.H.; Jo, Y.H.; Kim, M.J. Induction mechanism of lipocalin-2 expression by co-stimulation with interleukin-1β and interferon-γ in RINm5F beta-cells. Biochem. Biophys. Res. Commun. 2013, 434, 577–583. [Google Scholar] [CrossRef] [PubMed]
  13. Del Guerra, S.; D’Aleo, V.; Gualtierotti, G.; Pandolfi, R.; Boggi, U.; Vistoli, F.; Barnini, S.; Filipponi, F.; Del Prato, S.; Lupi, R. Evidence for a role of frataxin in pancreatic islets isolated from multi-organ donors with and without type 2 diabetes mellitus. Horm. Metab. Res. 2012, 44, 471–475. [Google Scholar] [CrossRef] [PubMed]
  14. Kulaksiz, H.; Fein, E.; Redecker, P.; Stremmel, W.; Adler, G.; Cetin, Y. Pancreatic beta-cells express hepcidin, an iron-uptake regulatory peptide. J. Endocrinol. 2008, 197, 241–249. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Lu, J.P.; Hayashi, K.; Awai, M. Transferrin receptor expression in normal, iron-deficient and iron-overloaded rats. Acta Pathol. Jpn. 1989, 39, 759–764. [Google Scholar] [CrossRef] [PubMed]
  16. Ohta, T.; Yamamoto, M.; Numata, M.; Iseki, S.; Kitagawa, H.; Kayahara, M.; Nagakawa, T.; Miwa, K.; Nakagawa, A.; Morise, T.; et al. Differential expression of vacuolar-type H+-ATPase between normal human pancreatic islet B-cells and insulinoma cells. Int. J. Oncol. 1997, 11, 597–601. [Google Scholar] [CrossRef] [PubMed]
  17. Hansen, J.B.; Moen, I.W.; Mandrup-Poulsen, T. Iron: The hard player in diabetes pathophysiology. Acta Physiol. 2014, 210, 717–732. [Google Scholar] [CrossRef]
  18. Qiao, B.; Sugianto, P.; Fung, E.; Del-Castillo-Rueda, A.; Moran-Jimenez, M.J.; Ganz, T.; Nemeth, E. Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab. 2012, 15, 918–924. [Google Scholar] [CrossRef] [Green Version]
  19. Yoon, T.; Cowan, J.A. Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins. J. Am. Chem. Soc. 2003, 125, 6078–6084. [Google Scholar] [CrossRef]
  20. Ristow, M.; Pfister, M.F.; Yee, A.J.; Schubert, M.; Michael, L.; Zhang, C.Y.; Ueki, K.; Michael, M.D., 2nd; Lowell, B.B.; Kahn, C.R. Frataxin activates mitochondrial energy conversion and oxidative phosphorylation. Proc. Natl. Acad. Sci. USA 2000, 97, 12239–12243. [Google Scholar] [CrossRef] [Green Version]
  21. González-Cabo, P.; Vázquez-Manrique, R.P.; García-Gimeno, M.A.; Sanz, P.; Palau, F. Frataxin interacts functionally with mitochondrial electron transport chain proteins. Hum. Mol. Genet. 2005, 4, 2091–2098. [Google Scholar] [CrossRef] [PubMed]
  22. Ristow, M.; Mulder, H.; Pomplun, D.; Schulz, T.J.; Müller-Schmehl, K.; Krause, A.; Fex, M.; Puccio, H.; Müller, J.; Isken, F.; et al. Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass. J. Clin. Investig. 2003, 112, 527–534. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Cnop, M.; Igoillo-Esteve, M.; Rai, M.; Begu, A.; Serroukh, Y.; Depondt, C.; Musuaya, A.E.; Marhfour, I.; Ladrière, L.; Moles Lopez, X.; et al. Central role and mechanisms of β-cell dysfunction and death in friedreich ataxia-associated diabetes. Ann. Neurol. 2012, 72, 971–982. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Cooksey, R.C.; Jouihan, H.A.; Ajioka, R.S.; Hazel, M.W.; Jones, D.L.; Kushner, J.P.; McClain, D.A. Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. Endocrinology 2004, 145, 5305–5312. [Google Scholar] [CrossRef]
  25. Lu, J.; Hayashi, K. Selective iron deposition in pancreatic islet B cells of transfusional iron-overloaded autopsy cases. Pathol. Int. 1994, 44, 194–199. [Google Scholar] [CrossRef]
  26. Kishimoto, M.; Endo, H.; Hagiwara, S.; Miwa, A.; Noda, M. Immunohistochemical findings in the pancreatic islets of a patient with transfusional iron overload and diabetes: Case report. J. Med. Investig. 2010, 57, 345–349. [Google Scholar] [CrossRef] [Green Version]
  27. Mühlenhoff, U.; Hoffmann, B.; Richter, N.; Rietzschel, N.; Spantgar, F.; Stehling, O.; Uzarska, M.A.; Lill, R. Compartmentalization of iron between mitochondria and the cytosol and its regulation. Eur. J. Cell Biol. 2015, 94, 292–308. [Google Scholar] [CrossRef]
  28. Kurz, T.; Eaton, J.W.; Brunk, U.T. The role of lysosomes in iron metabolism and recycling. Int. J. Biochem. Cell Biol. 2011, 43, 1686–1697. [Google Scholar] [CrossRef] [Green Version]
  29. Winterbourn, C.C. Toxicity of iron and hydrogen peroxide: The Fenton reaction. Toxicol. Lett. 1995, 82, 969–974. [Google Scholar] [CrossRef]
  30. Gabrielsen, J.S.; Gao, Y.; Simcox, J.A.; Huang, J.; Thorup, D.; Jones, D.; Cooksey, R.C.; Gabrielsen, D.; Adams, T.D.; Hunt, S.C.; et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J. Clin. Investig. 2012, 122, 3529–3540. [Google Scholar] [CrossRef] [Green Version]
  31. Hubler, M.J.; Peterson, K.R.; Hasty, A.H. Iron homeostasis: A new job for macrophages in adipose tissue. Trends Endocrinol. Metab. 2015, 26, 101–109. [Google Scholar] [CrossRef] [PubMed]
  32. Eizirik, D.L.; Pasquali, L.; Cnop, M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: Different pathways to failure. Nat. Rev. Endocrinol. 2020, 16, 349–362. [Google Scholar] [CrossRef] [PubMed]
  33. Hansen, J.B.; Tonnesen, M.F.; Madsen, A.N.; Hagedorn, P.H.; Friberg, J.; Grunnet, L.G.; Heller, R.S.; Nielsen, A.Ø.; Størling, J.; Baeyens, L.; et al. Divalent Metal Transporter 1 Regulates Iron-Mediated ROS and Pancreatic β Cell Fate in Response to Cytokines. Cell Metab. 2012, 16, 449–461. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Lortz, S.; Schröter, S.; Stückemann, V.; Mehmeti, I.; Lenzen, S. Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells. J. Mol. Endocrinol. 2014, 52, 301–310. [Google Scholar] [CrossRef] [Green Version]
  35. Hekerman, P.; Zeidler, J.; Korfmacher, S.; Bamberg-Lemper, S.; Knobelspies, H.; Zabeau, L.; Tavernier, J.; Becker, W. Leptin induces inflammation-related genes in RINm5F insulinoma cells. BMC Mol. Biol. 2007, 8, 41. [Google Scholar] [CrossRef] [Green Version]
  36. Flo, T.H.; Smith, K.D.; Sato, S.; Rodriguez, D.J.; Holmes, M.A.; Strong, R.K.; Akira, S.; Aderem, A. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004, 432, 917–921. [Google Scholar] [CrossRef]
  37. Xiao, X.; Yeoh, B.S.; Vijay-Kumar, M. Lipocalin 2: An Emerging Player in Iron Homeostasis and Inflammation. Annu. Rev. Nutr. 2017, 37, 103–130. [Google Scholar] [CrossRef]
  38. Mosialou, I.; Shikhel, S.; Luo, N.; Petropoulou, P.I.; Panitsas, K.; Bisikirska, B.; Rothman, N.J.; Tenta, R.; Cariou, B.; Wargny, M.; et al. Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes. J. Exp. Med. 2020, 217, e20191261. [Google Scholar] [CrossRef]
  39. Darville, M.I.; Eizirik, D.L. Regulation by cytokines of the inducible nitric oxide synthase promoter in insulin-producing cells. Diabetologia 1998, 41, 1101–1108. [Google Scholar] [CrossRef] [Green Version]
  40. Kutlu, B.; Naamane, N.; Berthou, L.; Eizirik, D.L. New approaches for in silico identification of cytokine-modified beta cell gene networks. Ann. NY Acad. Sci. 2004, 1037, 103741–103758. [Google Scholar] [CrossRef]
  41. Naamane, N.; van Helden, J.; Eizirik, D.L. In silico identification of NF-kappaB-regulated genes in pancreatic beta-cells. BMC Bioinform. 2007, 8, 55. [Google Scholar] [CrossRef] [PubMed]
  42. Ortis, F.; Cardozo, A.K.; Crispim, D.; Störling, J.; Mandrup-Poulsen, T.; Eizirik, D.L. Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-kappaB activation. Mol. Endocrinol. 2006, 20, 1867–1879. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Tong, X.; Kono, T.; Evans-Molina, C. Nitric oxide stress and activation of AMP-activated protein kinase impair β-cell sarcoendoplasmic reticulum calcium ATPase 2b activity and protein stability. Cell Death Dis. 2015, 6, e1790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Steer, S.A.; Scarim, A.L.; Chambers, K.T.; Corbett, J.A. Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1. PLoS Med. 2006, 3, e17. [Google Scholar]
  45. Chambers, K.T.; Unverferth, J.A.; Weber, S.M.; Wek, R.C.; Urano, F.; Corbett, J.A. The role of nitric oxide and the unfolded protein response in cytokine-induced beta-cell death. Diabetes 2008, 57, 124–132. [Google Scholar] [CrossRef] [Green Version]
  46. Lakey, J.R.; Suarez-Pinzon, W.L.; Strynadka, K.; Korbutt, G.S.; Rajotte, R.V.; Mabley, J.G.; Szabó, C.; Rabinovitch, A. Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells. Lab. Investig. 2001, 81, 1683–1692. [Google Scholar] [CrossRef] [Green Version]
  47. Suarez-Pinzon, W.L.; Mabley, J.G.; Strynadka, K.; Power, R.F.; Szabó, C.; Rabinovitch, A. An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice. J. Autoimmun. 2001, 16, 449–455. [Google Scholar] [CrossRef]
  48. Soum, E.; Drapier, J.C. Nitric oxide and peroxynitrite promote complete disruption of the [4Fe-4S] cluster of recombinant human iron regulatory protein 1. J. Biol. Inorg. Chem. 2003, 8, 226–232. [Google Scholar] [CrossRef]
  49. Soum, E.; Brazzolotto, X.; Goussias, C.; Bouton, C.; Moulis, J.-M.; Mattioli, T.A.; Drapier, J.-C. Peroxynitrite and Nitric Oxide Differently Target the Iron−Sulfur Cluster and Amino Acid Residues of Human Iron Regulatory Protein 1. Biochemistry 2003, 42, 7648–7654. [Google Scholar] [CrossRef]
  50. Condeles, A.L.; Toledo, J.C., Jr. The Labile Iron Pool Reacts Rapidly and Catalytically with Peroxynitrite. Biomolecules 2021, 11, 1331. [Google Scholar] [CrossRef]
  51. Kowluru, A. Oxidative Stress in Cytokine-Induced Dysfunction of the Pancreatic Beta Cell: Known Knowns and Known Unknowns. Metabolites 2020, 10, 480. [Google Scholar] [CrossRef] [PubMed]
  52. Mabley, J.G.; Southan, G.J.; Salzman, A.L.; Szabó, C. The combined inducible nitric oxide synthase inhibitor and free radical scavenger guanidinoethyldisulfide prevents multiple low-dose streptozotocin-induced diabetes in vivo and interleukin-1beta-induced suppression of islet insulin secretion in vitro. Pancreas 2004, 28, E39–E44. [Google Scholar] [CrossRef] [PubMed]
  53. Morgan, D.; Oliveira-Emilio, H.R.; Keane, D.; Hirata, A.E.; Da Rocha, M.S.; Bordin, S.; Curi, R.; Newsholme, P.; Carpinelli, A.R. Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line. Diabetologia 2006, 50, 359–369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Oliveira, H.R.; Verlengia, R.; Carvalho, C.R.; Britto, L.R.; Curi, R.; Carpinelli, A.R. Pancreatic beta-cells express phagocyte-like NAD(P)H oxidase. Diabetes 2003, 52, 1457–1463. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Uchizono, Y.; Takeya, R.; Iwase, M.; Sasaki, N.; Oku, M.; Imoto, H.; Iida, M.; Sumimoto, H. Expression of isoforms of NADPH oxidase components in rat pancreatic islets. Life Sci. 2006, 80, 133–139. [Google Scholar] [CrossRef] [PubMed]
  56. Newsholme, P.; Morgan, D.; Rebelato, E.; Oliveira-Emilio, H.C.; Procopio, J.; Curi, R.; Carpinelli, A. Insights into the critical role of NADPH oxidase(s) in the normal and dysregulated pancreatic beta cell. Diabetologia 2009, 52, 2489–2498. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Elumalai, S.; Karunakaran, U.; Moon, J.S.; Won, K.C. NADPH Oxidase (NOX) Targeting in Diabetes: A Special Emphasis on Pancreatic β-Cell Dysfunction. Cells 2021, 10, 1573. [Google Scholar] [CrossRef] [PubMed]
  58. Broniowska, K.A.; Mathews, C.E.; Corbett, J.A. Do β-cells generate peroxynitrite in response to cytokine treatment? J. Biol. Chem. 2013, 288, 36567–36578. [Google Scholar] [CrossRef] [Green Version]
  59. Gurgul-Convey, E.; Mehmeti, I.; Lortz, S.; Lenzen, S. Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria. J. Mol. Med. 2011, 89, 785–798. [Google Scholar] [CrossRef]
  60. Li, L.; Frei, B. Iron chelation inhibits NF-kappaB-mediated adhesion molecule expression by inhibiting p22 (phox) protein expression and NADPH oxidase activity. Arterioscler. Thromb. Vasc. Biol. 2006, 26, 2638–2643. [Google Scholar] [CrossRef] [Green Version]
  61. Syed, I.; Kyathanahalli, C.N.; Jayaram, B.; Govind, S.; Rhodes, C.J.; Kowluru, R.A.; Kowluru, A. Increased phagocyte-like NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets: Role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet. Diabetes 2011, 60, 2843–2852. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Natalicchio, A.; Tortosa, F.; Labarbuta, R.; Biondi, G.; Marrano, N.; Carchia, E.; Giorgino, F. The p66(Shc) redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells. Diabetologia 2015, 58, 2682. [Google Scholar] [CrossRef] [PubMed]
  63. Elumalai, S.; Karunakaran, U.; Moon, J.S.; Won, K.C. High glucose-induced PRDX3 acetylation contributes to glucotoxicity in pancreatic β-cells: Prevention by Teneligliptin. Free Radic. Biol. Med. 2020, 160, 618–629. [Google Scholar] [CrossRef] [PubMed]
  64. Karunakaran, U.; Lee, J.E.; Elumalai, S.; Moon, J.S.; Won, K.C. Myricetin prevents thapsigargin-induced CDK5-P66Shc signalosome mediated pancreatic β-cell dysfunction. Free Radic. Biol. Med. 2019, 141, 59–66. [Google Scholar] [CrossRef]
  65. Biondi, G.; Marrano, N.; Dipaola, L.; Borrelli, A.; Rella, M.; D’Oria, R.; Genchi, V.A.; Caccioppoli, C.; Porreca, I.; Cignarelli, A.; et al. The p66Shc Protein Mediates Insulin Resistance and Secretory Dysfunction in Pancreatic β-Cells under Lipotoxic Conditions. Diabetes 2022, 71, 1763–1771. [Google Scholar] [CrossRef]
  66. Giorgio, M.; Migliaccio, E.; Orsini, F.; Paolucci, D.; Moroni, M.; Contursi, C.; Pelliccia, G.; Luzi, L.; Minucci, S.; Marcaccio, M.; et al. Electron Transfer between Cytochrome c and p66Shc Generates Reactive Oxygen Species that Trigger Mitochondrial Apoptosis. Cell 2005, 122, 221–233. [Google Scholar] [CrossRef]
  67. Pinton, P.; Rimessi, A.; Marchi, S.; Orsini, F.; Migliaccio, E.; Giorgio, M.; Contursi, C.; Minucci, S.; Mantovani, F.; Wieckowski, M.R.; et al. Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science 2007, 315, 659–663. [Google Scholar] [CrossRef]
  68. Khalid, S.; Drasche, A.; Thurner, M.; Hermann, M.; Ashraf, M.I.; Fresser, F.; Baier, G.; Kremser, L.; Lindner, H.; Troppmair, J.; et al. cJun N-terminal kinase (JNK) phosphorylation of serine 36 is critical for p66Shc activation. Sci. Rep. 2016, 6, 2. [Google Scholar] [CrossRef] [Green Version]
  69. Hansen, J.B.; Dos Santos, L.R.B.; Liu, Y.; Prentice, K.J.; Teudt, F.; Tonnesen, M.; Jonas, J.C.; Wheeler, M.B.; Mandrup-Poulsen, T. Glucolipotoxic conditions induce β-cell iron import 0930 cytosolic ROS formation and apoptosis. J. Mol. Endocrinol. 2018, 61, 69–77. [Google Scholar] [CrossRef] [Green Version]
  70. Borkowska, A.; Popowska, U.; Spodnik, J.; Herman-Antosiewicz, A.; Woźniak, M.; Antosiewicz, J. JNK/p66Shc/ITCH Signaling Pathway Mediates Angiotensin II-induced Ferritin Degradation and Labile Iron Pool Increase. Nutrients 2020, 12, 668. [Google Scholar] [CrossRef] [Green Version]
  71. Sauter, N.S.; Thienel, C.; Plutino, Y.; Kampe, K.; Dror, E.; Traub, S.; Timper, K.; Bédat, B.; Pattou, F.; Kerr-Conte, J.; et al. Angiotensin II induces interleukin-1β-mediated islet inflammation and β-cell dysfunction independently of vasoconstrictive effects. Diabetes 2015, 64, 1273–1283. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Chu, K.Y.; Lau, T.; Carlsson, P.O.; Leung, P.S. Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. Diabetes 2006, 55, 367–374. [Google Scholar] [CrossRef] [PubMed]
  73. Chu, K.Y.; Leung, P.S. Angiotensin II Type 1 receptor antagonism mediates uncoupling protein 2-driven oxidative stress and ameliorates pancreatic islet beta-cell function in young Type 2 diabetic mice. Antioxid. Redox Signal 2007, 9, 869–878. [Google Scholar] [CrossRef] [PubMed]
  74. Weaver, J.R.; Holman, T.R.; Imai, Y.; Jadhav, A.; Kenyon, V.; Maloney, D.J.; Nadler, J.L.; Rai, G.; Simeonov, A.; Taylor-Fishwick, D.A. Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction. Mol. Cell Endocrinol. 2012, 358, 88–95. [Google Scholar] [CrossRef] [PubMed]
  75. Taylor-Fishwick, D.A.; Weaver, J.; Glenn, L.; Kuhn, N.; Rai, G.; Jadhav, A.; Simeonov, A.; Dudda, A.; Schmoll, D.; Holman, T.R.; et al. Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction. Diabetologia 2015, 58, 549–557. [Google Scholar] [CrossRef] [Green Version]
  76. Hennessy, E.; Tisdall, A.R.; Murphy, N.; Carroll, A.; O’Gorman, D.; Breen, L.; Clarke, C.; Clynes, M.; Dowling, P.; Sreenan, S. Elevated 12-hydroxyeicosatetraenoic acid (12-HETE) levels in serum of individuals with newly diagnosed Type 1 diabetes. Diabet. Med. 2016, 34, 292–294. [Google Scholar] [CrossRef]
  77. Kuhn, H.; Saam, J.; Eibach, S.; Holzhütter, H.G.; Ivanov, I.; Walther, M. Structural biology of mammalian lipoxygenases: Enzymatic consequences of targeted alterations of the protein structure. Biochem. Biophys. Res. Commun. 2005, 338, 93–101. [Google Scholar] [CrossRef]
  78. Yang, W.S.; Kim, K.J.; Gaschler, M.M.; Patel, M.; Shchepinov, M.S.; Stockwell, B.R. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl. Acad. Sci. USA 2016, 113, E4966–E4975. [Google Scholar] [CrossRef] [Green Version]
  79. Feng, H.; Stockwell, B.R. Unsolved mysteries: How does lipid peroxidation cause ferroptosis? PLoS Biol. 2018, 16, e2006203. [Google Scholar] [CrossRef]
  80. Yeung, K.; Seitz, T.; Li, S.; Janosch, P.; McFerran, B.; Kaiser, C.; Fee, F.; Katsanakis, K.D.; Rose, D.W.; Mischak, H.; et al. Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 1999, 401, 173–177. [Google Scholar] [CrossRef] [Green Version]
  81. Wenzel, S.E.; Tyurina, Y.Y.; Zhao, J.; Croix, C.M.S.; Dar, H.H.; Mao, G.; Tyurin, V.A.; Anthonymuthu, T.S.; Kapralov, A.A.; Amoscato, A.A.; et al. PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell 2017, 171, 628–641.e26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Pardo, F.N.; Altirriba, J.; Pradas-Juni, M.; García, A.; Ahlgren, U.; Barberà, A.; Slebe, J.C.; Yáñez, A.J.; Gomis, R.; Gasa, R. The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice. Diabetologia 2012, 55, 3331–3340. [Google Scholar] [CrossRef] [PubMed]
  83. Küch, E.M.; Vellaramkalayil, R.; Zhang, I.; Lehnen, D.; Brügger, B.; Stremmel, W.; Ehehalt, R.; Poppelreuther, M.; Füllekrug, J. Differentially localized acyl-CoA synthetase 4 isoenzymes mediate the metabolic channeling of fatty acids towards phosphatidylinositol. Biochim. Biophys. Acta 2014, 1841, 227–239. [Google Scholar] [CrossRef] [PubMed]
  84. Israr-ul, H.A.; Longacre, M.J.; Stoker, S.W.; Kendrick, M.A.; O’Neill, L.M.; Zitur, L.J.; Fernandez, L.A.; Ntambi, J.M.; MacDonald, M.J. Characterization of Acyl-CoA synthetase isoforms in pancreatic beta cells: Gene silencing shows participation of ACSL3 and ACSL4 in insulin secretion. Arch. Biochem. Biophys. 2017, 618, 32–43. [Google Scholar]
  85. Doll, S.; Proneth, B.; Tyurina, Y.Y.; Panzilius, E.; Kobayashi, S.; Ingold, I.; Irmler, M.; Beckers, J.; Aichler, M.; Walch, A.; et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 2017, 13, 91–98. [Google Scholar] [CrossRef]
  86. Lenzen, S.; Drinkgern, J.; Tiedge, M. Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic. Biol. Med. 1996, 20, 463–466. [Google Scholar] [CrossRef]
  87. Schafer, F.Q.; Buettner, G.R. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic. Biol. Med. 2001, 30, 1191–1212. [Google Scholar] [CrossRef]
  88. Roveri, A.; Maiorino, M.; Nisii, C.; Ursini, F. Purification and characterization of phospholipid hydroperoxide glutathione peroxidase from rat testis mitochondrial membranes. Biochim. Biophys. Acta 1994, 1208, 211–221. [Google Scholar] [CrossRef]
  89. Shi, Z.-Z.; Osei-Frimpong, J.; Kala, G.; Kala, S.V.; Barrios, R.J.; Habib, G.M.; Lukin, D.J.; Danney, C.M.; Matzuk, M.M.; Lieberman, M.W. Glutathione synthesis is essential for mouse development but not for cell growth in culture. Proc. Natl. Acad. Sci. USA 2000, 97, 5101–5106. [Google Scholar] [CrossRef] [Green Version]
  90. Yant, L.J.; Ran, Q.; Rao, L.; Van Remmen, H.; Shibatani, T.; Belter, J.G.; Motta, L.; Richardson, A.; Prolla, T.A. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic. Biol. Med. 2003, 34, 496–502. [Google Scholar] [CrossRef]
  91. Bannai, S. Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J. Biol. Chem. 1986, 261, 2256–2263. [Google Scholar] [CrossRef]
  92. Bröer, S.; Wagner, C.A. Structure-function relationships of heterodimeric amino acid transporters. Cell Biochem. Biophys. 2002, 36, 155–168. [Google Scholar] [CrossRef]
  93. Lewerenz, J.; Maher, P.; Methner, A. Regulation of xCT expression and system x (c) (-) function in neuronal cells. Amino Acids 2012, 42, 171–179. [Google Scholar] [CrossRef] [PubMed]
  94. Mandal, P.K.; Seiler, A.; Perisic, T.; Kölle, P.; Canak, A.B.; Förster, H.; Weiss, N.; Kremmer, E.; Lieberman, M.W.; Bannai, S.; et al. System x(c)—And thioredoxin reductase 1 cooperatively rescue glutathione deficiency. J. Biol. Chem. 2010, 285, 22244–22253. [Google Scholar] [CrossRef] [Green Version]
  95. Bruni, A.; Pepper, A.R.; Pawlick, R.L.; Gala-Lopez, B.; Gamble, A.F.; Kin, T.; Seeberger, K.; Korbutt, G.S.; Bornstein, S.R.; Linkermann, A.; et al. Ferroptosis-inducing agents compromise in vitro human islet viability and function. Cell Death Dis. 2018, 9, 595. [Google Scholar] [CrossRef]
  96. Koulajian, K.; Ivovic, A.; Ye, K.; Desai, T.; Shah, A.; Fantus, I.G.; Ran, Q.; Giacca, A. Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo. Am. J. Physiol. Metab. 2013, 305, E254–E262. [Google Scholar] [CrossRef] [Green Version]
  97. Krümmel, B.; Plötz, T.; Jörns, A.; Lenzen, S.; Mehmeti, I. The central role of glutathione peroxidase 4 in the regulation of ferroptosis and its implications for pro-inflammatory cytokine-mediated beta-cell death. Biochim. Biophys. Acta Mol. Basis Dis. 2021, 1867, 16. [Google Scholar] [CrossRef]
  98. Xiao, W.; Wang, R.S.; Handy, D.E.; Loscalzo, J. NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism. Antioxid. Redox Signal. 2018, 28, 251–272. [Google Scholar] [CrossRef]
  99. Stanton, R.C. Glucose-6-phosphate dehydrogenase NADPH, and cell survival. IUBMB Life 2012, 64, 362–369. [Google Scholar] [CrossRef] [Green Version]
  100. Ferguson, G.D.; Bridge, W.J. The glutathione system and the related thiol network in Caenorhabditis elegans. Redox Biol. 2019, 24, 101171. [Google Scholar] [CrossRef]
  101. Ge, T.; Yang, J.; Zhou, S.; Wang, Y.; Li, Y.; Tong, X. The Role of the Pentose Phosphate Pathway in Diabetes and Cancer. Front. Endocrinol. 2020, 11, 365. [Google Scholar] [CrossRef] [PubMed]
  102. Díaz-Flores, M.; Ibáñez-Hernández, M.A.; Galván, R.E.; Gutiérrez, M.; Durán-Reyes, G.; Medina-Navarro, R.; Pascoe-Lira, D.; Ortega-Camarillo, C.; Vilar-Rojas, C.; Cruz, M.; et al. Glucose-6-phosphate dehydrogenase activity and NADPH/NADP+ ratio in liver and pancreas are dependent on the severity of hyperglycemia in rat. Life Sci. 2006, 78, 2601–2607. [Google Scholar] [CrossRef] [PubMed]
  103. Zhang, Z.; Liew, C.W.; Handy, D.E.; Zhang, Y.; Leopold, J.A.; Hu, J.; Guo, L.; Kulkarni, R.N.; Loscalzo, J.; Stanton, R.C. High glucose inhibits glucose-6-phosphate dehydrogenase leading to increased oxidative stress and beta-cell apoptosis. FASEB J. 2010, 24, 1497–1505. [Google Scholar] [CrossRef] [PubMed]
  104. Corless, M.; Kiely, A.; McClenaghan, N.H.; Flatt, P.R.; Newsholme, P. Glutamine regulates expression of key transcription factor signal transduction, metabolic gene, and protein expression in a clonal pancreatic beta-cell line. J. Endocrinol. 2006, 190, 719–727. [Google Scholar] [CrossRef] [PubMed]
  105. Jang, H.; Kwak, J.; Cho, E.; We, Y.; Lee, Y.; Kim, S.; Han, D. Glutamine Induces Heat-Shock Protein-70 and Glutathione Expression and Attenuates Ischemic Damage in Rat Islets. Transplant. Proc. 2008, 40, 2581–2584. [Google Scholar] [CrossRef]
  106. Littman, E.D.; Opara, E.C.; Akwari, O.E. Glutathione-mediated preservation and enhancement of isolated perifused islet function. J. Surg. Res. 1995, 59, 694–698. [Google Scholar] [CrossRef]
  107. Gao, Z.Y.; Li, G.; Najafi, H.; Wolf, B.A.; Matschinsky, F.M. Glucose regulation of glutaminolysis and its role in insulin secretion. Diabetes 1999, 48, 1535–1542. [Google Scholar] [CrossRef]
  108. Maechler, P.; Wollheim, C.B. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature 1999, 402, 685–689. [Google Scholar] [CrossRef] [Green Version]
  109. Han, G.; Takahashi, H.; Murao, N.; Gheni, G.; Yokoi, N.; Hamamoto, Y.; Asahara, S.; Seino, Y.; Kido, Y.; Seino, S. Glutamate is an essential mediator in glutamine-amplified insulin secretion. J. Diabetes Investig. 2021, 12, 920–930. [Google Scholar] [CrossRef]
  110. Karunakaran, U.; Elumalai, S.; Moon, J.S.; Won, K.C. Pioglitazone-induced AMPK-Glutaminase-1 prevents high glucose-induced pancreatic β-cell dysfunction by glutathione antioxidant system. Redox Biol. 2021, 45, 10. [Google Scholar] [CrossRef]
  111. Karunakaran, U.; Elumalai, S.; Moon, J.S.; Won, K.C. c-Abl tyrosine kinase inhibition attenuate oxidative stress-induced pancreatic β-Cell dysfunction via glutathione antioxidant system. Transl. Res. 2022, 249, 74–87. [Google Scholar] [CrossRef] [PubMed]
  112. Vaithilingam, V.; Oberholzer, J.; Guillemin, G.J.; Tuch, B.E. Beneficial effects of desferrioxamine on encapsulated human islets--in vitro and in vivo study. Am. J. Transplant. 2010, 10, 1961–1969. [Google Scholar] [CrossRef] [PubMed]
  113. Nomikos, I.N.; Prowse, S.J.; Carotenuto, P.; Lafferty, K.J. Combined treatment with nicotinamide and desferrioxamine prevents islet allograft destruction in NOD mice. Diabetes 1986, 35, 1302–1304. [Google Scholar] [CrossRef]
  114. Bradley B 1969 Prowse, S.J.; Bauling, P.; Lafferty, K.J. Desferrioxamine treatment prevents chronic islet allograft damage. Diabetes 1986, 35, 550–555. [Google Scholar] [CrossRef]
  115. Stokes, R.A.; Cheng, K.; Deters, N.; Lau, S.M.; Hawthorne, W.J.; O’connell, P.J.; Stolp, J.; Grey, S.; Loudovaris, T.; Kay, T.W.; et al. Hypoxia-inducible factor-1α (HIF-1α) potentiates β-cell survival after islet transplantation of human and mouse islets. Cell Transplant. 2013, 22, 253–266. [Google Scholar] [CrossRef] [PubMed]
  116. Danielpur, L.; Sohn, Y.-S.; Karmi, O.; Fogel, C.; Zinger, A.; Abu-Libdeh, A.; Israeli, T.; Riahi, Y.; Pappo, O.; Birk, R.; et al. GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves β-Cell Function in Type 2 Wolfram Syndrome. J. Clin. Endocrinol. Metab. 2016, 101, 3592–3599. [Google Scholar] [CrossRef] [PubMed]
  117. Murali, A.R.; Gupta, A.; Brown, K. Systematic review and meta-analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non-alcoholic fatty liver disease. Hepatol. Res. 2018, 48, E30–E41. [Google Scholar] [CrossRef] [Green Version]
  118. Minamiyama, Y.; Takemura, S.; Kodai, S.; Shinkawa, H.; Tsukioka, T.; Ichikawa, H.; Naito, Y.; Yoshikawa, T.; Okada, S. Iron restriction improves type 2 diabetes mellitus in Otsuka Long-Evans Tokushima fatty rats. Am. J. Physiol. Metab. 2010, 298, E1140–E1149. [Google Scholar] [CrossRef] [Green Version]
  119. Yanatori, I.; Yasui, Y.; Noguchi, Y.; Kishi, F. Inhibition of iron uptake by ferristatin II is exerted through internalization of DMT1 at the plasma membrane. Cell Biol. Int. 2014, 39, 427–434. [Google Scholar] [CrossRef]
  120. Horonchik, L.; Wessling-Resnick, M. The Small-Molecule Iron Transport Inhibitor Ferristatin/NSC306711 Promotes Degradation of the Transferrin Receptor. Chem. Biol. 2008, 15, 647–653. [Google Scholar] [CrossRef] [Green Version]
  121. Byrne, S.L.; Buckett, P.D.; Kim, J.; Luo, F.; Sanford, J.; Chen, J.; Enns, C.; Wessling-Resnick, M. Ferristatin II Promotes Degradation of Transferrin Receptor-1 In Vitro and In Vivo. PLoS ONE 2013, 8, e70199. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Cheng, Y.; Qu, W.; Li, J.; Jia, B.; Song, Y.; Wang, L.; Rui, T.; Li, Q.; Luo, C. Ferristatin II, an Iron Uptake Inhibitor, Exerts Neuroprotection against Traumatic Brain Injury via Suppressing Ferroptosis. ACS Chem. Neurosci. 2022, 13, 664–675. [Google Scholar] [CrossRef] [PubMed]
  123. Wetli, H.A.; Buckett, P.D.; Wessling-Resnick, M. Small-Molecule Screening Identifies the Selanazal Drug Ebselen as a Potent Inhibitor of DMT1-Mediated Iron Uptake. Chem. Biol. 2006, 13, 965–972. [Google Scholar] [CrossRef]
  124. Xie, L.; Zheng, W.; Xin, N.; Xie, J.-W.; Wang, T.; Wang, Z.-Y. Ebselen inhibits iron-induced tau phosphorylation by attenuating DMT1 up-regulation and cellular iron uptake. Neurochem. Int. 2012, 61, 334–340. [Google Scholar] [CrossRef]
  125. Mahadevan, J.; Parazzoli, S.; Oseid, E.; Hertzel, A.V.; Bernlohr, D.A.; Vallerie, S.N.; Liu, C.Q.; Lopez, M.; Harmon, J.S.; Robertson, R.P. Ebselen treatment prevents islet apoptosis, maintains intranuclear Pdx-1 and MafA levels, and preserves β-cell mass and function in ZDF rats. Diabetes 2013, 62, 3582–3588. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Wang, X.; Yun, J.W.; Lei, X.G. Glutathione peroxidase mimic ebselen improves glucose-stimulated insulin secretion in murine islets. Antioxid. Redox Signal. 2014, 20, 191–203. [Google Scholar] [CrossRef] [Green Version]
  127. De-Mello, M.A.; Flodström, M.; Eizirik, D.L. Ebselen and cytokine-induced nitric oxide synthase expression in insulin-producing cells. Biochem. Pharmacol. 1996, 52, 1703–1709. [Google Scholar] [CrossRef]
  128. Colca, J.R.; McDonald, W.G.; Waldon, D.J.; Leone, J.W.; Lull, J.M.; Bannow, C.A.; Lund, E.T.; Mathews, W.R. Identification of a novel mitochondrial protein (“mitoNEET”) cross-linked specifically by a thiazolidinedione photoprobe. Am. J. Physiol. Endocrinol. Metab. 2004, 286, E252–E260. [Google Scholar] [CrossRef] [Green Version]
  129. Landry, A.P.; Ding, H. Redox Control of Human Mitochondrial Outer Membrane Protein MitoNEET [2Fe-2S] Clusters by Biological Thiols and Hydrogen Peroxide. J. Biol. Chem. 2014, 289, 4307–4315. [Google Scholar] [CrossRef] [Green Version]
  130. Paddock, M.L.; Wiley, S.E.; Axelrod, H.L.; Cohen, A.E.; Roy, M.; Abresch, E.C.; Capraro, D.; Murphy, A.N.; Nechushtai, R.; Dixon, J.E.; et al. MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone. Proc. Natl. Acad. Sci. USA 2007, 104, 14342–14347. [Google Scholar] [CrossRef] [Green Version]
  131. Tamir, S.; Paddock, M.L.; Darash-Yahana-Baram, M.; Holt, S.H.; Sohn, Y.S.; Agranat, L.; Michaeli, D.; Stofleth, J.T.; Lipper, C.H.; Morcos, F.; et al. Structure–function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease. Biochim. Biophys. Acta 2015, 1853, 1294–1315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Ishida, H.; Takizawa, M.; Ozawa, S.; Nakamichi, Y.; Yamaguchi, S.; Katsuta, H.; Tanaka, T.; Maruyama, M.; Katahira, H.; Yoshimoto, K.; et al. Pioglitazone improves insulin secretory capacity and prevents the loss of beta-cell mass in obese diabetic db/db mice: Possible protection of beta cells from oxidative stress. Metabolism 2004, 53, 488–494. [Google Scholar] [CrossRef] [PubMed]
  133. Liang, H.; Tang, T.; Huang, H.; Li, T.; Gao, C.; Han, Y.; Yuan, B.; Gao, S.; Wang, H.; Zhou, M.-L. Peroxisome proliferator-activated receptor-γ ameliorates neuronal ferroptosis after traumatic brain injury in mice by inhibiting cyclooxygenase-2. Exp. Neurol. 2022, 354, 114100. [Google Scholar] [CrossRef]
  134. Mishima, E.; Conrad, M. Nutritional and Metabolic Control of Ferroptosis. Annu. Rev. Nutr. 2022, 42, 275–309. [Google Scholar] [CrossRef] [PubMed]
  135. Pallotti, F.; Bergamini, C.; Lamperti, C.; Fato, R. The Roles of Coenzyme Q in Disease: Direct and Indirect Involvement in Cellular Functions. Int. J. Mol. Sci. 2021, 23, 128. [Google Scholar] [CrossRef]
  136. Kraft, V.A.; Bezjian, C.T.; Pfeiffer, S.; Ringelstetter, L.; Müller, C.; Zandkarimi, F.; Merl-Pham, J.; Bao, X.; Anastasov, N.; Kössl, J.; et al. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Cent. Sci. 2020, 6, 41–53. [Google Scholar] [CrossRef] [Green Version]
  137. Bersuker, K.; Hendricks, J.M.; Li, Z.; Magtanong, L.; Ford, B.; Tang, P.H.; Roberts, M.A.; Tong, B.; Maimone, T.J.; Zoncu, R.; et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 2019, 575, 688–692. [Google Scholar] [CrossRef] [PubMed]
  138. Liu, Y.; Wang, W.; Li, Y.; Xiao, Y.; Cheng, J.; Jia, J. The 5-Lipoxygenase Inhibitor Zileuton Confers Neuroprotection against Glutamate Oxidative Damage by Inhibiting Ferroptosis. Biol. Pharm. Bull. 2015, 38, 1234–1239. [Google Scholar] [CrossRef] [Green Version]
  139. Zilka, O.; Shah, R.; Li, B.; Angeli, J.P.F.; Griesser, M.; Conrad, M.; Pratt, D.A. On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death. ACS Cent. Sci. 2017, 3, 232–243. [Google Scholar] [CrossRef]
  140. Shah, R.; Shchepinov, M.S.; Pratt, D.A. Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis. ACS Cent. Sci. 2018, 4, 387–396. [Google Scholar] [CrossRef]
  141. Hernandez-Perez, M.; Chopra, G.; Fine, J.; Conteh, A.M.; Anderson, R.M.; Linnemann, A.K.; Benjamin, C.; Nelson, J.B.; Benninger, K.S.; Nadler, J.L.; et al. Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes. Diabetes 2017, 66, 2875–2887. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Ma, K.; Xiao, A.; Park, S.H.; Glenn, L.; Jackson, L.; Barot, T.; Weaver, J.R.; Taylor-Fishwick, D.A.; Luci, D.K.; Maloney, D.J.; et al. 12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets. J. Clin. Endocrinol. Metab. 2017, 102, 2789–2797. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Kondo, M.; Tanabe, K.; Amo-Shiinoki, K.; Hatanaka, M.; Morii, T.; Takahashi, H.; Seino, S.; Yamada, Y.; Tanizawa, Y. Activation of GLP-1 receptor signalling alleviates cellular stresses and improves beta cell function in a mouse model of Wolfram syndrome. Diabetologia 2018, 61, 2189–2201. [Google Scholar] [CrossRef] [PubMed]
  144. Song, J.X.; An, J.R.; Chen, Q.; Yang, X.Y.; Jia, C.L.; Xu, S.; Zhao, Y.S.; Ji, E.S. Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice. Bioengineered 2022, 13, 8334–8348. [Google Scholar] [CrossRef]
Ijms 23 13679 g001 550
Figure 1. Role of iron in β-cell physiology.
Figure 1. Role of iron in β-cell physiology.
Ijms 23 13679 g001
Ijms 23 13679 g002 550
Figure 2. Role of iron in β-cell ferroptotic signaling and therapeutic agents targeting the inhibition of ferroptotic-death.
Figure 2. Role of iron in β-cell ferroptotic signaling and therapeutic agents targeting the inhibition of ferroptotic-death.
Ijms 23 13679 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Elumalai, S.; Karunakaran, U.; Moon, J.-S.; Won, K.-C. Ferroptosis Signaling in Pancreatic β-Cells: Novel Insights & Therapeutic Targeting. Int. J. Mol. Sci. 2022, 23, 13679. https://doi.org/10.3390/ijms232213679

AMA Style

Elumalai S, Karunakaran U, Moon J-S, Won K-C. Ferroptosis Signaling in Pancreatic β-Cells: Novel Insights & Therapeutic Targeting. International Journal of Molecular Sciences. 2022; 23(22):13679. https://doi.org/10.3390/ijms232213679

Chicago/Turabian Style

Elumalai, Suma, Udayakumar Karunakaran, Jun-Sung Moon, and Kyu-Chang Won. 2022. "Ferroptosis Signaling in Pancreatic β-Cells: Novel Insights & Therapeutic Targeting" International Journal of Molecular Sciences 23, no. 22: 13679. https://doi.org/10.3390/ijms232213679

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop