Ferroptosis Is Regulated by Mitochondria in Neurodegenerative Diseases

2020 ◽  
Vol 20 (1) ◽  
pp. 20-34 ◽  
Author(s):  
Juepu Zhou ◽  
Yao Jin ◽  
Yuhong Lei ◽  
Tianyi Liu ◽  
Zheng Wan ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Iron Homeostasis ◽  
Cell Metabolism ◽  
Lipid Peroxide ◽  
Mitochondrial Damage ◽  
Mitochondrial Activity ◽  
Dependent Form

Background: Neurodegenerative diseases are characterized by a gradual decline in motor and/or cognitive function caused by the selective degeneration and loss of neurons in the central nervous system, but their pathological mechanism is still unclear. Previous research has revealed that many forms of cell death, such as apoptosis and necrosis, occur in neurodegenerative diseases. Research in recent years has noticed that there is a new type of cell death in neurodegenerative diseases: ferroptosis. An increasing body of literature provides evidence for an involvement of ferroptosis in neurodegenerative diseases. Summary: In this article, we review a new form of cell death in neurodegenerative diseases: ferroptosis. Ferroptosis is defined as an iron-dependent form of regulated cell death, which occurs through the lethal accumulation of lipid-based reactive oxygen species when glutathione-dependent lipid peroxide repair systems are compromised. Several salient and established features of neurodegenerative diseases (including lipid peroxidation and iron dyshomeostasis) are consistent with ferroptosis, which means that ferroptosis may be involved in the progression of neurodegenerative diseases. In addition, as the center of energy metabolism in cells, mitochondria are also closely related to the regulation of iron homeostasis in the nervous system. At the same time, neurodegenerative diseases are often accompanied by degeneration of mitochondrial activity. Mitochondrial damage has been found to be involved in lipid peroxidation and iron dyshomeostasis in neurodegenerative diseases. Key Messages: Based on the summary of the related mechanisms of ferroptosis, we conclude that mitochondrial damage may affect neurodegenerative diseases by regulating many aspects of ferroptosis, including cell metabolism, iron dyshomeostasis, and lipid peroxidation.

Theoretical insights into the mechanism of ferroptosis suppression via inactivation of a lipid peroxide radical by liproxstatin-1

2017 ◽  
Vol 19 (20) ◽  
pp. 13153-13159 ◽  
Author(s):  
Xiehuang Sheng ◽  
Chao Shan ◽  
Jianbiao Liu ◽  
Jintong Yang ◽  
Bin Sun ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Lipid Peroxide ◽  
Membrane Lipid ◽  
Peroxide Radical ◽  
Membrane Lipid Peroxidation ◽  
Pathological Conditions ◽  
Dependent Form ◽  
The Brain

Ferroptosis is a recently discovered iron-dependent form of non-apoptotic cell death caused by the accumulation of membrane lipid peroxidation products, which is involved in various pathological conditions of the brain, kidneys, liver and heart.

scholarly journals Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

2020 ◽  
Vol 21 (22) ◽  
pp. 8765 ◽  
Author(s):  
Cadiele Oliana Reichert ◽  
Fábio Alessandro de Freitas ◽  
Juliana Sampaio-Silva ◽  
Leonardo Rokita-Rosa ◽  
Priscila de Lima Barros ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Intracellular Iron ◽  
The Central Nervous System ◽  
The 1960S ◽  
The Brain

Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer’s, Parkinson’s, and Huntington’s diseases, has also been addressed.

scholarly journals Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Hironari Nishizawa ◽  
Mitsuyo Matsumoto ◽  
Guan Chen ◽  
Yusho Ishii ◽  
Keisuke Tada ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Lipid Peroxide ◽  
Nih3t3 Cells ◽  
Regulated Cell Death ◽  
Primary Mouse ◽  
Ischemic Diseases ◽  
A Chain ◽  
Dying Cells

AbstractFerroptosis is a regulated cell death due to the iron-dependent accumulation of lipid peroxide. Ferroptosis is known to constitute the pathology of ischemic diseases, neurodegenerative diseases, and steatohepatitis and also works as a suppressing mechanism against cancer. However, how ferroptotic cells affect surrounding cells remains elusive. We herein report the transfer phenomenon of lipid peroxidation and cell death from ferroptotic cells to nearby cells that are not exposed to ferroptotic inducers (FINs). While primary mouse embryonic fibroblasts (MEFs) and NIH3T3 cells contained senescence-associated β-galactosidase (SA-β-gal)-positive cells, they were decreased upon induction of ferroptosis with FINs. The SA-β-gal decrease was inhibited by ferroptotic inhibitors and knockdown of Atg7, pointing to the involvement of lipid peroxidation and activated autophagosome formation during ferroptosis. A transfer of cell culture medium of cells treated with FINs, type 1 or 2, caused the reduction in SA-β-gal-positive cells in recipient cells that had not been exposed to FINs. Real-time imaging of Kusabira Orange-marked reporter MEFs cocultured with ferroptotic cells showed the generation of lipid peroxide and deaths of the reporter cells. These results indicate that lipid peroxidation and its aftereffects propagate from ferroptotic cells to surrounding cells, even when the surrounding cells are not exposed to FINs. Ferroptotic cells are not merely dying cells but also work as signal transmitters inducing a chain of further ferroptosis.

scholarly journals The disorder of the iron metabolism as a possible mechanism for the development of neurodegeneration after new coronavirus infection of SARS-CoV-2

2021 ◽  
Vol 40 (4) ◽  
pp. 13-24
Author(s):  
Igor V. Litvinenko ◽  
Igor V. Krasakov
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Brain Structures ◽  
Pathological Process ◽  
Parkinsons Disease ◽  
Neurodegenerative Process ◽  
Coronavirus Infection

The involvement of the nervous system in the pathological process that occurs when COVID-19 is infected is becoming more and more obvious. The question of the possibility of the debut or progression of the already developed Parkinsonism syndrome in patients who have undergone COVID-19 is regularly raised. A large number of hypotheses are put forward to explain this relationship. It is assumed that a violation of iron metabolism in the brain may underlie the development and progression of neurodegenerative diseases, including after the new coronavirus infection SARS-CoV-2. The analysis of stu dies on the possible influence of iron metabolism disorders on the occurrence and mechanism of development of neurodegenerative diseases after infection with SARS-CoV-2 has been carried out. The processes of physiological maintenance of iron homeostasis, as well as the influence of physiological aging on the accumulation of iron in the central nervous system are described. The relationship between hyperferritinemia occurring in COVID-19 and ferroptosis as the basis of the neurodegenerative process in Parkinsons disease and Alzheimers disease is discussed. The main molecular mechanisms involved in ferroptosis are described. Examples of involvement of metal homeostasis disorders in the process of altering the structure of -synuclein, synthesis of -amyloid, hyperphosphorylated tau- protein are given. The causes of excessive iron accumulation in certain brain structures are discussed. The question of the possibility of using the assessment of changes in iron metabolism as a new biomarker of the progression of Parkinsons disease is analyzed. (1 figure, bibliography: 62 refs)

scholarly journals SUN-211 Active Steroid Hormone Synthesis Renders Adrenocortical Cells Highly Susceptible to Type II Ferroptosis Induction

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Isabel Weigand ◽  
Jochen Schreiner ◽  
Florian Roehrig ◽  
Na Sun ◽  
Landwehr Laura-Sophie ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Treatment Options ◽  
Cortical Cell ◽  
Current Treatment ◽  
Adrenocortical Cells ◽  
Hormone Synthesis ◽  
Steroidogenic Cell ◽  
Coa Ligase ◽  
Dependent Form

Abstract Context: Cell death in the adrenal cortex is ill understood but of high clinical relevance. Resistance of adrenocortical carcinoma (ACC) to current treatment with mitotane and chemotherapy calls for an improved understanding of adrenal cortical cell death processes. Ferroptosis is an iron-dependent form of regulated cell death which is characterized by polyunsaturated lipids adrenic (AdA) and arachidonic acid (AA) peroxidation. Aim: To address the potential role of ferroptosis in the adrenal gland as a potential treatment target of ACC. Methods: Human ACC cells H295R, CU-ACC1 and 2 were used. Protein expression of key enzymes was determined by western blotting. Lipid peroxidation was quantified with BODIPY 581/591 and cell viability with CellTiterGlo after treatment with known inducers and inhibitors of ferroptosis and steroidogenesis, respectively. Results: Adrenocortical tissues are enriched in AdA and AA and express high levels of genes relevant to ferroptosis, such as glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4). Inhibition of GPX4 with RSL3 led to cell death in H295R, CU-ACC1 and 2 cells at EC50 values of 2.4x10-7, 8.1x10-7 and 1.5x10-8 M, respectively. The steroidogenesis inhibitor ketoconazole completely reversed RSL3 cytotoxicity in all three steroidogenic cell lines by reducing lipid peroxidation. Mitotane induced lipid peroxidation but inhibition of ferroptosis with liproxstatin did not protect mitotane-induced cell death. Conclusion: Adrenocortical cells are highly sensitive to ferroptosis due to active steroidogenesis. Triggering this form of cell death could present future novel treatment options against ACC.

scholarly journals Bioactivity Screening of Antarctic Sponges Reveals Anticancer Activity and Potential Cell Death via Ferroptosis by Mycalols

Marine Drugs ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. 459
Author(s):  
Gennaro Riccio ◽  
Genoveffa Nuzzo ◽  
Gianluca Zazo ◽  
Daniela Coppola ◽  
Giuseppina Senese ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Hepg2 Cells ◽  
Iron Homeostasis ◽  
Protein Levels ◽  
Antarctic Research ◽  
First Time ◽  
Antarctic Sponges

Sponges are known to produce a series of compounds with bioactivities useful for human health. This study was conducted on four sponges collected in the framework of the XXXIV Italian National Antarctic Research Program (PNRA) in November-December 2018, i.e., Mycale (Oxymycale) acerata, Haliclona (Rhizoniera) dancoi, Hemimycale topsenti, and Hemigellius pilosus. Sponge extracts were fractioned and tested against hepatocellular carcinoma (HepG2), lung carcinoma (A549), and melanoma cells (A2058), in order to screen for antiproliferative or cytotoxic activity. Two different chemical classes of compounds, belonging to mycalols and suberitenones, were identified in the active fractions. Mycalols were the most active compounds, and their mechanism of action was also investigated at the gene and protein levels in HepG2 cells. Of the differentially expressed genes, ULK1 and GALNT5 were the most down-regulated genes, while MAPK8 was one of the most up-regulated genes. These genes were previously associated with ferroptosis, a programmed cell death triggered by iron-dependent lipid peroxidation, confirmed at the protein level by the down-regulation of GPX4, a key regulator of ferroptosis, and the up-regulation of NCOA4, involved in iron homeostasis. These data suggest, for the first time, that mycalols act by triggering ferroptosis in HepG2 cells.

scholarly journals Ferroptosis: the potential value target in atherosclerosis

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Siyu Ouyang ◽  
Jia You ◽  
Chenxi Zhi ◽  
Pin Li ◽  
Xiaoyan Lin ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Theoretical Basis ◽  
Vascular Endothelial Cells ◽  
Necrotic Core ◽  
Vascular Endothelial ◽  
Intracellular Iron ◽  
Future Studies ◽  
Dependent Form ◽  
Pathologic Processes

AbstractIn advanced atherosclerosis (AS), defective function-induced cell death leads to the formation of the characteristic necrotic core and vulnerable plaque. The forms and mechanisms of cell death in AS have recently been elucidated. Among them, ferroptosis, an iron-dependent form of necrosis that is characterized by oxidative damage to phospholipids, promotes AS by accelerating endothelial dysfunction in lipid peroxidation. Moreover, disordered intracellular iron causes damage to macrophages, vascular smooth muscle cells (VSMCs), vascular endothelial cells (VECs), and affects many risk factors or pathologic processes of AS such as disturbances in lipid peroxidation, oxidative stress, inflammation, and dyslipidemia. However, the mechanisms through which ferroptosis initiates the development and progression of AS have not been established. This review explains the possible correlations between AS and ferroptosis, and provides a reliable theoretical basis for future studies on its mechanism.

scholarly journals Gossypitrin, A Naturally Occurring Flavonoid, Attenuates Iron-Induced Neuronal and Mitochondrial Damage

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3364
Author(s):  
María Ángeles Bécquer-Viart ◽  
Adonis Armentero-López ◽  
Daniel Alvarez-Almiñaque ◽  
Roberto Fernández-Acosta ◽  
Yasser Matos-Peralta ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Iron Homeostasis ◽  
Cell Damage ◽  
Protective Action ◽  
Neuronal Cell ◽  
Mitochondrial Damage ◽  
Atp Depletion ◽  
Neural Cells ◽  
Ht22 Cells ◽  
Naturally Occurring

The disruption of iron homeostasis is an important factor in the loss of mitochondrial function in neural cells, leading to neurodegeneration. Here, we assessed the protective action of gossypitrin (Gos), a naturally occurring flavonoid, on iron-induced neuronal cell damage using mouse hippocampal HT-22 cells and mitochondria isolated from rat brains. Gos was able to rescue HT22 cells from the damage induced by 100 µM Fe(II)-citrate (EC50 8.6 µM). This protection was linked to the prevention of both iron-induced mitochondrial membrane potential dissipation and ATP depletion. In isolated mitochondria, Gos (50 µM) elicited an almost complete protection against iron-induced mitochondrial swelling, the loss of mitochondrial transmembrane potential and ATP depletion. Gos also prevented Fe(II)-citrate-induced mitochondrial lipid peroxidation with an IC50 value (12.45 µM) that was about nine time lower than that for the tert-butylhydroperoxide-induced oxidation. Furthermore, the flavonoid was effective in inhibiting the degradation of both 15 and 1.5 mM 2-deoxyribose. It also decreased Fe(II) concentration with time, while increasing O2 consumption rate, and impairing the reduction of Fe(III) by ascorbate. Gos–Fe(II) complexes were detected by UV-VIS and IR spectroscopies, with an apparent Gos-iron stoichiometry of 2:1. Results suggest that Gos does not generally act as a classical antioxidant, but it directly affects iron, by maintaining it in its ferric form after stimulating Fe(II) oxidation. Metal ions would therefore be unable to participate in a Fenton-type reaction and the lipid peroxidation propagation phase. Hence, Gos could be used to treat neuronal diseases associated with iron-induced oxidative stress and mitochondrial damage.

scholarly journals Current Trends in Neurodegeneration: Cross Talks between Oxidative Stress, Cell Death, and Inflammation

2021 ◽  
Vol 22 (14) ◽  
pp. 7432
Author(s):  
Tapan Behl ◽  
Rashita Makkar ◽  
Aayush Sehgal ◽  
Sukhbir Singh ◽  
Neelam Sharma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Neurological Diseases ◽  
Organ Systems ◽  
Ability To Regenerate ◽  
The Central Nervous System ◽  
Neuronal Degradation ◽  
Turn Over

The human body is highly complex and comprises a variety of living cells and extracellular material, which forms tissues, organs, and organ systems. Human cells tend to turn over readily to maintain homeostasis in tissues. However, postmitotic nerve cells exceptionally have an ability to regenerate and be sustained for the entire life of an individual, to safeguard the physiological functioning of the central nervous system. For efficient functioning of the CNS, neuronal death is essential, but extreme loss of neurons diminishes the functioning of the nervous system and leads to the onset of neurodegenerative diseases. Neurodegenerative diseases range from acute to chronic severe life-altering conditions like Parkinson’s disease and Alzheimer’s disease. Millions of individuals worldwide are suffering from neurodegenerative disorders with little or negligible treatment available, thereby leading to a decline in their quality of life. Neuropathological studies have identified a series of factors that explain the etiology of neuronal degradation and its progression in neurodegenerative disease. The onset of neurological diseases depends on a combination of factors that causes a disruption of neurons, such as environmental, biological, physiological, and genetic factors. The current review highlights some of the major pathological factors responsible for neuronal degradation, such as oxidative stress, cell death, and neuroinflammation. All these factors have been described in detail to enhance the understanding of their mechanisms and target them for disease management.

scholarly journals Foxos Suppress Lipid Peroxidation to Promote AML Progression and Chemotherapy Resistance

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1861-1861
Author(s):  
Turan Aghayev ◽  
Chun Zhou ◽  
Alyssa Klein ◽  
Esteban Martinez ◽  
Claudia Scholl ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Chemotherapy Resistance ◽  
Lipid Peroxide ◽  
Lipid Peroxides ◽  
Intracellular Lipid ◽  
Redox Biology ◽  
Intracellular Ros ◽  
Intracellular Redox

Abstract Over 30% of acute myeloid leukemia (AML) patients do not respond to first-line chemotherapy, and a significant portion of patients that do initially respond subsequently relapse with resistant disease. These unsatisfactory outcomes indicate that AML cells either rapidly evolve or inherently possess mechanisms for evading standard chemotherapeutic approaches. Several studies have suggested that AML cells utilize pathways that regulate intracellular redox biology to promote chemotherapy resistance; however, the precise pathways governing resistance and redox biology in AML have yet to be fully determined. We recently discovered that the FOXO family of transcription factors, which have been traditionally considered tumor suppressor genes, actually support AML cell survival and the differentiation blockade. Specifically, we observed that the expression of FOXO1 and FOXO3 are significantly increased in approximately 40% of primary human AML samples (p<0.0001) and that short hairpin RNA (shRNA)-mediated inhibition of FOXO3 caused human AML cells to acquire characteristics of myeloid differentiation such as increased CD11b expression, cytoplasmic volume, size and granularity. Moreover, we also found that compound ablation of the FoxO family members FoxO1, FoxO3 and FoxO4 significantly extends disease latency and improves survival (p=0.0009) in a murine model of AML driven by the leukemogenic allele MLL-AF9. Previous studies have shown that, in variety of cell types, FOXOs influence the intracellular redox environment by suppressing the production of reactive oxygen species (ROS). Therefore, to determine the molecular role of FOXOs in AML, we initially focused on the impact of FOXO inhibition on AML cell redox biology. Using fluorogenic probes that detect either total intracellular ROS content (CellRox) or superoxide production (MitoSox), we found that shRNA-mediated inhibition of FOXO3 did not affect total levels of intracellular ROS or superoxides. However, using a lipid peroxidation sensor (BODIPY¨ 581/591 C11), we did observe that two distinct FOXO3-targeting shRNAs increased both homeostatic and stress-induced levels of lipid peroxides in AML cells (shFOXO3-1, p=0.0004; shFOXO3-2, p=0.0023). Consistent with this, we also found that AML cells treated with a chemical inhibitor of FOXOs (AS1842856) display increased steady-state levels of intracellular lipid peroxides (p=0.0076) as well as increased signs of differentiation (CD11b and morphological changes) and death (Annexin V staining). To elucidate the importance of lipid peroxidation in AML, we evaluated how two chemical anti-oxidants, N-acetyl-L-cysteine (NAC) and butylated hydroxyanisole (BHA), impact the anti-leukemia effects and increased lipid peroxidation mediated by FOXO inhibition. From these analyses, we have observed that BHA treatment suppresses lipid peroxide production and partly blocks AML cell death induced by shRNA-mediated FOXO3 inhibition (shFOXO3-1, p=0.0001; shFOXO3-2, p<0.0001). Interestingly, NAC treatment, which does protect healthy hematopoietic stem and progenitor cells from FOXO inhibition, is unable to reverse the anti-leukemia effects or lipid peroxidation induced by FOXO inhibition, suggesting that FOXOs may differentially regulate redox biology between normal and malignant hematopoietic progenitors. Both basic and clinical studies have shown that anthracyclines such as daunorubicin (DNR) induce lipid peroxidation; however, the role of lipid peroxidation in chemotherapy effectiveness is largely unknown. We have discovered that co-treatment of AML cells with DNR and BHA (but not NAC) completely blocks the cytotoxic effects of DNR (p<0.0001), suggesting that suppression of lipid peroxides could promote chemotherapy resistance. Consistent with this idea, we have observed that shRNA-mediated inhibition of FOXO3 enhance DNR-mediated AML cell death (p<0.0001), whereas enforced expression of FOXO3 protects human AML cells from DNR cytotoxicity (p=0.003). Collectively, these results suggest that FOXOs are critical mediators of AML progression and chemotherapy resistance by directly regulating intracellular lipid peroxide levels. Disclosures No relevant conflicts of interest to declare.

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