In the present study using proteomics, we gained insight into the role of p53 in the CNS, and tested the hypothesis that knock out of p53 affected the expression of several brain mitochondrial proteins involved in different pathways; thus, loss of p53 may present a target to restore neuronal impairment. Since our investigation was performed on isolated brain mitochondria from p53 mice, our results conceivably could provide insights into progression of many mitochondrial-associated diseases. Hence, the identified proteins are involved in energy and mitochondrial alterations, signal transduction, antioxidant defense, and chaperone proteins, as shown in Table 2. Antioxidant defense Interestingly, MnSOD was significantly increased in mitochondria isolated from the brain of p53 mice compared to WT. This data was already shown in our prior study and are consistent with the notion that MnSOD is transcriptionally repressed by p53 with consequent propagation of oxidative stress, since MnSOD provides critical antioxidant defense. Because the apoptotic programs require oxidative stress for their execution, an overexpression of MnSOD was shown to increase resistance to p53-dependent apoptosis. Drane et al., and St. Clair and colleagues, further demonstrated that MnSOD has a mutual activity on p53 reducing its expression, and even negatively modulating its apoptotic function. Several studies indicate that overexpression of MnSOD protects neurons from oxidative damage thus exerting a defensive role during AD development. St. Clair and co-workers, using APP-PS-1 neurons as a model of AD, found a reduction of MnSOD expression during neuronal maturation with high levels of oxidative stress. These researchers also indicated p53 as a possible factor for the suppression of MnSOD. Therefore, an overexpression of MnSOD through the inhibition of p53 could be helpful to prevent or slow the progression of neurodegenerative processes such as AD. Thioredoxin-dependent peroxide reductase, also called peroxiredoxin 3, is an antioxidant protein localized mainly in the matrix of mitochondria, and it regulates physiological levels of H2O2. The peroxiredoxin system requires a family of proteins called sestrins for its regeneration, and sestrin expression is regulated by p53. Previous studies showed that p53 upregulates the expression of sestrins, including peroxiredoxin. In contrast, in our study, we found an increase of Prdx3 levels in the mitochondrial of p53 mice, and a plausible explanation of this result could be, as proposed in our previous work, that the lack of p53 could disturb cellular homeostasis causing the activation of protective pathways by cells to combat cellular damage. Since H2O2 plays a central role in induction of apoptosis, the reduction of mitochondrial levels of H2O2by overexpression of Prdx3 seems to be antiapoptotic, and therefore beneficial for preserving cell survival. In addition Prdx3 was previously found down-regulated in AD brain. Several findings suggest that p53 has a role in the regulation of pathways involved in glucose metabolism, supporting oxidative phosphorylation and the pentose phosphate shunt, and inhibiting glycolysis. These activities of p53 prevent cancer development. In addition, mitochondria are a major site in which some constituents of these pathways play a role. Therefore, there is a connection between p53 and mitochondria, and a better understanding of this link conceivably could provide insight into the progression of mitochondria Dasatinib related disorders. In our study VDAC was found up-regulated in mitochondria of p53 mice compared to mitochondria from WT mice. VDAC is a component of the mitochondria permeability transition pore, which allows the exchange of metabolities like ATP in and out of mitochondria.