Nrf2 protects mitochondrial decay by oxidative stress

Sublethal levels of oxidative stress are commonly associated with various pathophysiological conditions. Cardiomyocytes have the highest content of mitochondria among all cell types, allowing the study of mitochondria in cells surviving oxidative stress and address whether nuclear factor-erythroid-derived 2-related factor 2 (Nrf2) can reverse these changes. Mitochondria normally exist in elaborated networks, which were replaced by predominately individual punctuate mitochondria 24 h after exposure to a nonlethal dose of H₂O₂. Electron microscopy revealed that cells surviving H₂O₂ show swelling of mitochondria with disorganized cristae and areas of condensation. Measurements of functional mitochondria showed a H₂O₂ dose-dependent decrease over a course of 5 d. At the protein and mRNA levels, cells surviving H₂O₂ treatment show a reduction of mitochondrial components, cytochrome c, and cytochrome b. Nrf2 overexpression prevented H₂O₂ from inducing mitochondria morphologic changes and reduction of cytochrome b/c. Although Nrf2 is known as a transcription factor regulating antioxidant and detoxification genes, Nrf2 overexpression did not significantly reduce the level of protein oxidation. Instead, Nrf2 was found to associate with the outer mitochondrial membrane. Mitochondria prepared from the myocardium of Nrf2 knockout mice are more sensitive to permeability transition. Our data suggest that Nrf2 protects mitochondria from oxidant injury likely through direct interaction with mitochondria.