A Unified Mechanistic Framework for Copper Toxicity in Neutrophils: Metabolic Rewiring, Cell-Death Crosstalk, and Immune Dysfunction.
TL;DR
By tracing individual routes from copper-pool disruption to defined cellular and tissue-level outcomes, this model distinguishes systemic copper overload from inflammatory copper redistribution and identifies the measurements required to establish copper-dependent neutrophil pathology in human disease.
Abstract
SIGNIFICANCE Copper is an essential redox-active micronutrient, but failure of copper compartmentalization can convert it from a catalytic cofactor into a source of oxidative, proteotoxic, and mitochondrial stress. Neutrophils are a plausible target of this transition because their antimicrobial functions depend on tightly organized redox reactions, whereas their short lifespan and limited biosynthetic reserve may restrict adaptation to metal stress. RECENT ADVANCES This review develops a unified framework in which copper dyshomeostasis first reshapes intracellular copper pools, antioxidant buffering, reduced nicotinamide adenine dinucleotide phosphate-dependent redox metabolism, and mitochondrial signaling; these metabolic disturbances then lower the threshold for several copper-associated cell-death programs; and the combined lesions alter granulopoiesis, chemotaxis, phagocytic killing, neutrophil extracellular trap formation, survival, and inflammatory resolution. Canonical ferredoxin 1-dihydrolipoamide S-acetyltransferase-dependent cuproptosis is treated as a testable, but not yet established, mechanism in mature neutrophils. Stronger evidence supports a broader spectrum of copper-induced injury that includes mitochondrial apoptosis, inflammasome-associated pyroptotic signaling, lipid peroxidation with ferroptosis-like features, and dysregulated neutrophil extracellular trap formation (NETosis). CRITICAL ISSUES The inflammatory outcome of neutrophil death cannot be inferred from cell loss alone: Efficiently cleared apoptotic or early ferroptotic cells may contract the functional neutrophil pool, whereas lytic death, late membrane rupture, defective efferocytosis, and release of oxidized lipids, chromatin, histones, or granular proteins may amplify local inflammation. FUTURE DIRECTIONS By tracing individual routes from copper-pool disruption to defined cellular and tissue-level outcomes, this model distinguishes systemic copper overload from inflammatory copper redistribution and identifies the measurements required to establish copper-dependent neutrophil pathology in human disease. Antioxid. Redox Signal. 00, 000-000.