Mitochondrial iron chelation ameliorates cigarette smoke–induced bronchitis and emphysema in mice

Abstract

Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as an important COPD susceptibility gene, with IRP2 protein increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase (Sco2)-deficient mice with reduced COX were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.

Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2

“…5C,D). We also showed that IRP2 knockout had no effect on intracellular iron content, consistent with a recent study (Cloonan et al 2016). However, IRP2 knockout reversed mitochondrial iron overload by FDXR deficiency to near normal in IRP2 −/− ;FDXR +/−/− cells, suggesting that IRP2 is an important mediator acting downstream from FDXR (Fig.…”

Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes

“…However, while NRF2 activation may be a common outcome of thiol-modifying compounds and Michael acceptors (36,37), any generalizable inhibition of IRP2 repression by endogenous compounds and xenobiotics is premature. Indeed, in opposition to our description of fumarate-mediated decreases in IRP2-IRE binding activity, mice exposed to cigarette smoke showed increased IRP2-IRE binding activity, and a thiophene derivative has been shown to enhance IRP2 binding to the FTL IRE (38,39). Furthermore, fumarate seems to differentially affect the translation of FTL and FTH1.…”

Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer

“…To understand if mitochondrial iron dysregulation is a pathophysiologically relevant mechanism, deferiprone (DFP) was assessed. DFP is a clinically approved reagent that can chelate mitochondrial iron (18)(19)(20)(21). DFP effectively protected the body weight loss, preserved colon length, and reduced histological changes and pathological score in DSS-treated STEAP4 transgenic mice (Fig.…”