Mitochondrial aconitase ACO2 links iron homeostasis with tumorigenicity in non-small cell lung cancer.

The ability of a patient tumor to engraft an immunodeficient mouse is the strongest known independent indicator of poor prognosis in early-stage non-small cell lung cancer (NSCLC). Analysis of primary NSCLC proteomes revealed low-level expression of mitochondrial aconitase (ACO2) in the more aggressive, engrafting tumours. Knockdown of ACO2 protein expression transformed immortalized lung epithelial cells, whereas up-regulation of ACO2 in transformed NSCLC cells inhibited cell proliferation in vitro and tumour growth in vivo. High level ACO2 increased iron response element binding protein 1 (IRP1) and the intracellular labile iron pool. Impaired cellular proliferation associated with high level ACO2 was reversed by treatment of cells with an iron chelator, whereas increased cell proliferation associated with low level ACO2 was suppressed by treatment of cells with iron. Expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1; also known as mitoNEET) was modulated by ACO2 expression level and inhibition of mitoNEET by RNA interference or by treatment of cells with pioglitazone also increased iron and cell death. Hence, ACO2 is identified as a regulator of iron homeostasis and mitoNEET is implicated as a target in aggressive NSCLC. Implications: Iron-sulfur-cluster associated proteins including mitochondrial aconitase ACO2, mitoNEET (encoded by CISD1), and iron response element binding protein 1 (IRP1; encoded by ACO1) are part of an "ACO2-Iron Axis" that regulates iron homeostasis and is a determinant of a particularly aggressive subset of NSCLC.