Fig. 6.

Cooperative gene regulation for mitochondrial quality control by Nrf2 and ATF4. It is becoming clear that mitochondrial stress activates ATF4. In certain tissues, such as in the heart, mitochondrial stresses can also activate Nrf2 in a tissue-dependent manner. ATF4 and Nrf2 induce certain stress response genes (ER chaperone and amino acid synthetic genes by ATF4 and antioxidant genes by Nrf2), but both factors regulate the genes that are important for the mitochondrial quality control. Notably, Nrf2 and ATF4 physically interact. Nrf2 inhibits ATF4 binding to the CHOP promoter region and cooperatively regulates antioxidant genes, such as HO-1 and xCT, and the anti-apoptotic gene ORP150.