Figure 1. The ferroptotic landscape in Friedreich’s ataxia (IMAGE)
Caption
The ferroptotic landscape in Friedreich's ataxia. Frataxin deficiency in the mitochondrion leads to ISC failure and ROS generation. Simultaneously, impaired cellular defenses, characterized by Nrf2 downregulation, lead to decreased GSH levels and defective GPx4 activity. In the cytosol, aberrant IRP1 activation increases the labile iron pool through enhanced transferrin-mediated iron import and NCOA4-mediated ferritinophagy. At the membrane level, lipid remodeling (orange arrows) is driven by PLA2 which generates LPLs, while ACSL4 activates free PUFAs into PUFA-CoAs, which are subsequently esterified into the membrane by LPCAT3 to form highly vulnerable PUFA-PEs. The convergence of accumulated iron, ROS, and ACSL4-mediated incorporation of PUFA-PEs into the membrane results in unchecked LPO, ultimately driving ferroptotic cell death. Green upward arrows denote upregulation or accumulation; red downward arrows denote downregulation or functional impairment. Created in BioRender. Cozza, G. (2026) https://BioRender.com/9m8dus3. ISC: iron-sulfur cluster; ROS: reactive oxygen species; Nrf2: nuclear factor erythroid 2-related factor 2; GSH: glutathione; GPx4: glutathione peroxidase 4; IRP1: iron regulatory protein 1; NCOA4: nuclear receptor coactivator 4; PLA2: phospholipase A2; LPLs: lysophospholipids; ACSL4: Acyl-CoA synthetase long-chain family member 4; LPCAT3: lysophosphatidylcholine acyltransferase 3; PUFA-PE: polyunsaturated fatty acid-phosphatidylethanolamines; LPO: lipid peroxidation.
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© Cravin G, Cozza G, 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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