TY - JOUR
TI - Mitochondrial iron chelation ameliorates cigarette smoke-induced
bronchitis and emphysema in mice
AU - Cloonan, Suzanne M.
AU - Glass, Kimberly
AU - Laucho-Contreras, Maria E.
AU - and Bhashyam, Abhiram R.
AU - Cervo, Morgan
AU - Pabon, Maria A. and
AU - Konrad, Csaba
AU - Polverino, Francesca
AU - Siempos, Ilias I.
AU - Perez,
AU - Elizabeth
AU - Mizumura, Kenji
AU - Ghosh, Manik C.
AU - Parameswaran,
AU - Harikrishnan
AU - Williams, Niamh C.
AU - Rooney, Kristen T.
AU - Chen,
AU - Zhi-Hua
AU - Goldklang, Monica P.
AU - Yuan, Guo-Cheng
AU - Moore, Stephen
AU - C.
AU - Demeo, Dawn L.
AU - Rouault, Tracey A.
AU - D'Armiento, Jeanine M.
AU - and Schon, Eric A.
AU - Manfredi, Giovanni
AU - Quackenbush, John and
AU - Mahmood, Ashfaq
AU - Silverman, Edwin K.
AU - Owen, Caroline A.
AU - Choi,
AU - Augustine M. K.
JO - Journal of Natural Medicines
PY - 2016
VL - 22
TODO - 2
SP - 163-174
PB - Nature Publishing Group
SN - 1861-0293
TODO - 10.1038/nm.4021
TODO - null
TODO - 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 and have shown that IRP2 protein is 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 RNA immunoprecipitation followed by sequencing
(RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional
enrichment clustering analysis, we identified Irp2 as a regulator of
mitochondrial function in the lungs of mice. Irp2 increased
mitochondrial iron loading and levels of cytochrome c oxidase (COX),
which led to mitochondrial dysfunction and subsequent experimental COPD.
Frataxin-deficient mice, which had higher mitochondria! iron loading,
showed impaired airway mucociliary clearance (MCC) and higher pulmonary
inflammation at baseline, whereas mice deficient in the synthesis of
cytochrome c oxidase, which have reduced COX, were protected from
CS-induced pulmonary inflammation and impairment of MCC. Mice treated
with a mitochondria! iron chelator or mice fed a low-iron diet were
protected from CS-induced COPD. Mitochondrial iron chelation also
alleviated CS-induced 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.
ER -