Ferredoxin 1 (FDX1) (FDX1)

Ferredoxin 1 (FDX1) is a mitochondrial matrix enzyme that functions as a small iron-sulfur protein involved in essential electron transfer processes. While traditionally recognized for its role in steroid hormone synthesis and heme biosynthesis (UniProt, 2024), FDX1 has recently been identified as the master regulator of cuprotosis, a unique copper-dependent form of regulated cell death (Tsvetkov et al., Science, 2022). In this pathway, copper ionophores like elesclomol deliver copper into the mitochondria, where FDX1 reduces divalent copper (Cu2+) to its more reactive monovalent state (Cu+). This reduction triggers the aggregation of lipoylated enzymes in the tricarboxylic acid (TCA) cycle, such as dihydrolipoamide S-acetyltransferase (DLAT), and causes the depletion of iron-sulfur cluster proteins (NCBI Gene, 2023). The resulting proteotoxic stress and mitochondrial dysfunction make FDX1 a compelling therapeutic target, particularly for treating cancers that exhibit high metabolic dependency on the TCA cycle.

Other names

AdrenodoxinFDXLBPAdrenodoxin, mitochondrialFerredoxin-1

Copper ionophores facilitate the transport of copper into the mitochondria, where FDX1 reduces Cu2+ to Cu+, leading to the aggregation of lipoylated TCA cycle proteins and the loss of iron-sulfur cluster proteins, ultimately inducing a form of regulated cell death known as cuprotosis.