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COX4i2 – oxidative phosphorylation as target for the treatment of asthma?

Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial electron transport chain. The recently discovered subunit of COX, cytochrome c oxidase subunit 4 isoform 2 (COX4i2), is specifically expressed in lung and trachea. To study the role of the subunit in lung function, Maik Hüttemann and his colleagues from the Center for Molecular Medicine and Genetics at the Wayne State University School of Medicine in Detroit performed in vitro as well as in vivo studies with COX4i2-knockout mice. In collaboration with the German Mouse Clinic (GMC) a comprehensive functional screen was conducted.
COX4i2-knockout mice show reduced COX activity, despite the presence of ubiquitously expressed subunit COX4i1, and decreased energy levels in the lung. The study suggests that mitochondrial oxidative phosphorylation might be a novel functional target for lung pathologies with increased airway reactivity, such as asthma.
Additionally, alterations in the lungs tissue were found in the pathology screen. All other tested organs (skin, heart, muscle, lung, cerebrum, cerebellum, thymus, spleen, cervical lymph nodes, trachea, thyroid and parathyroid glands, adrenal glands, esophagus, stomach, intestine, liver, pancreas, kidneys, reproductive organs and urinary bladder) were not altered. Knockout animals exhibited lung inflammation and/or Charcot-Leyden crystals. These are hexagonal colorless crystals within the granulomas or the bronchi. They are mostly found in organisms (people, animals), who have allergic diseases such as asthma or parasitic infections.
Furthermore, sex-specific differences were found in several screens: Lean mass of COX4i2-knockout female mice was reduced, muscle force of female knockout mice was reduced consistently, knockout females tolerated glucose challenge better than control females, and the IgE levels in female knockouts were increased. The scientists suppose that some of the sex-specific differences may be explained by the presence of a putative estrogen responsive element in the COX4i2 promoter. Earlier work revealed that estrogen up-regulates COX activity in the brain. Taken together these results, estrogen may modulate COX4i2 expression.


Maik Hüttemann et al., Cytochrome c oxidase subunit 4 isoform 2 knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology, Faseb J., June 22, 2012, doi: 10.1096/fj.11-203273 fj.11-203273