In addition, estrogens also directly regulate the expression of mitochondrial stress responsive factors encoded by nuclear DNA. The Bcl-2 family of proteins is important regulators of the mitochondrial pathway of apoptosis, determining whether the mitochondria initiate the cell death program by releasing proapoptotic factors such as cytochrome c. The family of Bcl-2 proteins consists of anti- and proapoptotic members and their interactions play a key role in regulating apoptosis in cells [88]. Estrogens increase anti-apoptotic proteins, Bcl-2 and Bcl-xL, which prevent permeability transition [68]. In primary neuronal cultures, estrogens upregulate expression of anti-apoptotic Bcl-w and downregulate expression of proapoptotic bim in an ERdependent manner [89].