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Inherited Optic Neuropathies
Published in Vivek Lal, A Clinical Approach to Neuro-Ophthalmic Disorders, 2023
Hui-Chen Cheng, Jared Ching, An-Guor Wang, Patrick Yu-Wai-Man
OA can also present as a more variable secondary feature of inherited neurodegenerative diseases (Figure 12.1) (5). Friedreich ataxia (FRDA) is the most common form of hereditary ataxia and optic neuropathy, which can be subclinical, is a well-recognized association. FRDA is caused by recessive mutations in the FXN gene, which encodes for a mitochondrial protein involved in the biosynthetic pathways of iron-sulfur clusters. The latter are essential for mitochondrial oxidative phosphorylation being key components of aconitase and the mitochondrial respiratory chain complexes I, II and III (8). Other neurodegenerative diseases that can result in OA are Charcot-Marie-Tooth (CMT) disease and hereditary spastic paraplegia (HSP) caused by MFN2 and SPG7 mutations, respectively (8).
Nonketotic hyperglycinemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Lipoic acid is required for the function of four mitochondrial enzymes; the E2 subunits of PDHC (see Chapter 50), α-ketoglutarate dehydrogenase, branched-chain α-ketoacid dehydrogenase (see Chapter 20), and the H-protein of the glycine cleavage system. Defects in the generation of lipoic acid variably affect these enzymes. Lipoate synthase has an iron sulfur cluster, which provides the sulfur atoms for the reaction. Multiple genes are involved in the biosynthesis of the iron sulfur clusters as well as of lipoic acid [6] and seven have, as yet, been proven as causes of variant nonketotic hyperglycinemia: LIPT2 and LIAS in lipoate synthase and glutaredoxin 5, IBA57, BOLA3, ISCA2 and NFU1 in the biosynthesis of the iron sulfur clusters.
The Contribution of Iron and Transition Metal Micronutrients to Diabetes and Metabolic Disease
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Lipika Salaye, Zhenzhong Bai, Donald A. McClain
Systemic and cellular iron metabolism have been the subject of excellent recent reviews [9–11] and will be only briefly recapitulated here (Figure 15.1). Intestinal free ferric (Fe3+) iron is reduced to ferrous Fe2+ by duodenal cytochrome B (DCTB) and enters duodenal enterocytes by way of the divalent metal-ion transporter 1 (DMT1) and possibly other carriers. Dietary heme is directly absorbed into enterocytes, where iron is released by heme oxygenase (HMOX). Ferrous iron exits the enterocytes through the iron export channel ferroportin (FPN). After oxidization by hephaestin (HEPH), Fe3+ binds to transferrin (Tf) in the blood, which in turn binds to transferrin receptors (TfR) on the surface of target cells. In most cells (Figure 15.1, lower right), after endocytosis of TfR1 and acidification of the endosome, iron is released, reduced by STEAP (6-transmembrane epithelial antigen of the prostate), and enters the cytosol through DMT1, where it is used (e.g., for heme or Fe-S-cluster synthesis in mitochondria) or, if in excess, sequestered by ferritin. Apoferritin secreted into the circulation is a marker for tissue iron stores, although the trigger for its secretion versus use to sequester more iron is not known. The intracellular trafficking of iron is much more complicated than indicated in the figure. For example, iron is highly controlled and chaperoned to its various targets, as ferrous iron or after iron-sulfur cluster synthesis, by mechanisms that are still under study [6].
A novel treatment strategy to prevent Parkinson’s disease: focus on iron regulatory protein 1 (IRP1)
Published in International Journal of Neuroscience, 2023
Thomas M. Berry, Ahmed A. Moustafa
Iron-sulfur cluster biogenesis is a process that involves many steps [38]. Even with normal levels of iron iron-sulfur biogenesis can be dysregulated. Dysregulation of the acyl carrier protein can impair iron-sulfur cluster biogenesis [39,40]. Many illnesses could be due to dysregulation of iron-sulfur cluster biogenesis [41]. Iron-sulfur cluster biogenesis dysregulations result in mitochondrial iron overload [42]. Research points to there being mitochondrial overload in both Parkinson’s disease and Friedreich ataxia [43]. How iron-sulfur cluster biogenesis could be dysregulated in PD is not completely clear. A way that iron-sulfur cluster biogenesis could be dysregulated in PD is via dysregulation of the acyl carrier protein. Difficulties in iron-sulfur cluster formation can be compensated for by supplemental iron. Supplemental iron can increase activity of aconitase 1(ACO1) [44], which is an iron-sulfur protein. Deficiency states in terms of nutrients can arise when there are extraordinary demands for nutrients. Individuals with PD could have extraordinary demands for iron.
The mechanisms and therapeutic targets of ferroptosis in cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Long Ye, Fengyan Jin, Shaji K. Kumar, Yun Dai
Iron and sulfur ions form the iron-sulfur cluster (ISC), which is crucial for maintaining iron homeostasis and redox balance in the cell. ISC attenuates ferroptosis, while ISC deficiency facilitates ferroptosis. The cysteine desulfurase NFS1 and frataxin play important roles in the biosynthesis of ISC. NFS1 catalyzes the production of sulfur ions from cysteine and inhibits ferroptosis by reducing Fe2+ level[12]. On the other hand, frataxin promotes the synthesis of ISC by transporting Fe2+ to cysteine and initiating NFS1 activity. Thus, abnormal function or deficiency of frataxin disrupts iron homeostasis and promotes ferroptosis[13]. NEET proteins have recently identified as ISC transporters that deliver ISCs to the iron regulatory proteins (IRPs). IRPs and iron response element (IRE) increase TfR1 expression, as well as inhibit ferritin synthesis and FPN expression, which together increase intracellular Fe2+ level and promote ferroptosis[14]. Therefore, targeting NEET proteins inhibits ferroptosis by blocking the binding of ISC to IRP.
Bacterial death from treatment with fluoroquinolones and other lethal stressors
Published in Expert Review of Anti-infective Therapy, 2021
Superoxide induces expression from response genes controlled by SoxRS, and peroxide activates OxyR, which induces a set of protective genes [92]. Indeed, norfloxacin and ampicillin induce the oxidative stress-response promoters of soxS and oxyS [44]. However, efforts to identify anti-oxidant genes/regulons responsible for the protective effect of superoxide have failed (a soxS mutation has no effect on plumbagin-mediated protection from killing by bleomycin [55], and a soxS marA double mutant has no effect on plumbagin- or paraquat-mediated protection from killing by oxolinic acid, kanamycin, or ampicillin when separated from MIC increases [90]). Likewise, levels of ROS scavengers, such as KatG and AhpC, are not elevated by lethal antimicrobials [44,58]. These observations leave destruction of iron-sulfur clusters in energy-metabolism proteins as the best explanation for protection by superoxide.