Deficiency Exacerbates Acrolein-Induced Lung Injury through Mitochondrial Redox Environment Deterioration.

Acrolein is known to be involved in acute lung injury and other pulmonary diseases. A number of studies have suggested that acrolein-induced toxic effects are associated with depletion of antioxidants, such as reduced glutathione and protein thiols, and production of reactive oxygen species. Mitochondrial NADP-dependent isocitrate dehydrogenase () regulates mitochondrial redox balance and reduces oxidative stress-induced cell injury via generation of NADPH. Therefore, we evaluated the role of in acrolein-induced lung injury using short hairpin RNA- (shRNA-) transfected Lewis lung carcinoma (LLC) cells and -deficient ( ) mice. Downregulation of expression increased susceptibility to acrolein via induction of apoptotic cell death due to elevated mitochondrial oxidative stress. deficiency also promoted acrolein-induced lung injury in knockout mice through the disruption of mitochondrial redox status. In addition, acrolein-induced toxicity in shRNA-transfected LLC cells and in knockout mice was ameliorated by the antioxidant, N-acetylcysteine, through attenuation of oxidative stress resulting from deficiency. In conclusion, deficiency leads to mitochondrial redox environment deterioration, which causes acrolein-mediated apoptosis of LLC cells and acrolein-induced lung injury in mice. The present study supports the central role of deficiency in inducing oxidative stress resulting from acrolein-induced disruption of mitochondrial redox status in the lung.