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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 ( idh2 ) regulates mitochondrial redox balance and reduces oxidative stress-induced cell injury via generation of NADPH. Therefore, we evaluated the role of  idh2  in acrolein-induced lung injury using  idh2  short hairpin RNA- (shRNA-) transfected Lewis lung carcinoma (LLC) cells and  idh2 -deficient ( idh2 −/−  ) mice. Downregulation of  idh2  expression increased susceptibility to acrolein via induction of apoptotic cell death due to elevated mitochondrial oxidative stress.  Idh2  deficiency also promoted acrolein-induced lung injury in  idh2  knockout mice through the disruption of mitochondrial redox status. In addition, acrolein-induced toxicity in  idh2  shRNA-transfected LLC cells and in  idh2  knockout mice was ameliorated by the antioxidant, N-acetylcysteine, through attenuation of oxidative stress resulting from  idh2  deficiency. In conclusion,  idh2  deficiency leads to mitochondrial redox environment deterioration, which causes acrolein-mediated apoptosis of LLC cells and acrolein-induced lung injury in  idh2 −/−   mice. The present study supports the central role of  idh2  deficiency in inducing oxidative stress resulting from acrolein-induced disruption of mitochondrial redox status in the lung.

Idh2 Deficiency Exacerbates Acrolein-Induced Lung Injury through Mitochondrial Redox Environment Deterioration