Iron Toxicity targeting mitochondrial Iron-Sulfur cluster enzymes

ABSTRACT: Unregulated nutritional iron absorption in hereditary hemochromatosis causes its overload, especially in liver. While this may lead to severe pathology, intriguingly, it may also frequently go unrecognized. Indeed, profound iron loading in hemochromatosis Hfe knockout mice and hemochromatosis Huh7 hepatocytes trigger cellular responses—especially affecting iron storage and release—that plausibly prevent overt iron toxicity. Nevertheless, excess iron caused mild bioenergetic alterations concerning mitochondrial function. Importantly, the addition of copper, even in trace amounts and harmless on their own, dramatically increases this adverse effect to induce profound cell toxicity. We find that this copper-provoked iron vulnerability is independent of Fenton-chemistry ROS-mediated damage but rather driven by proteotoxic stress with a profound loss of iron-sulfur cluster enzyme activity and severe mitochondrial dysfunction. Remarkably, high affinity copper chelation rescued cells, while inhibition of canonical cell death pathways did not. These findings spotlight copper as a critical factor capable of converting compensated iron overload into severe cellular injury. Monitoring and managing copper status could be essential in patients suffering from hepatic iron overload.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: Christine von Toerne  

LAB HEAD: Hans Zischka

PROVIDER: PXD070837 | Pride | 2026-09-28

REPOSITORIES: Pride