Although these areas continue to be investigated vigorously, a new era in mitochondrial research has emerged that concerns the role of this organelle in intracellular signaling. p53, an important tumor suppressor gene, is recognized as the guardian of the genome because it regulates the transcription of numerous genes that code for life and death processes. However, during the last decade, the transcription-independent activity of the p53 protein has emerged as an important mechanism by which p53 modulates mitochondrial function. p53 interacts with various proteins in the outer membrane as well as in the matrix of the mitochondria, including bcl-2-associated X protein, Bcl2, p53 up-regulated modulator of apoptosis, polymerase gamma, and manganese superoxide dismutase It is well documented that free radical-mediated oxidative stress plays a pivotal role in the cardiac toxicity of Doxorubicin. We have shown that overexpression of human MnSOD, a primary antioxidant enzyme located in the mitochondrial matrix, protects against DOX-induced cardiac injury, suggesting that the DOX-induced cardiac injury is related to the Org 27569 effect of DOX on cardiac mitochondria. However, the pathways that mediate the observed protective effect of MnSOD remain unknown. ROS are highly reactive and, when generated close to cell membranes, oxidize membrane phospholipids, which can lead to the generation and accumulation of lipid peroxidation products, such as malondialdehyde, 4-hydroxy-2nonenal, acrolein and F2-isoprostanes. 4HNE is a highly reactive and specific diffusible end-product of lipid peroxidation and is known to induce/regulate various cellular events such as proliferation and growth inhibition, T cell apoptosis and activation of signaling pathways. Proteins are major targets of 4HNE, which can trigger multiple modifications of the protein structure. 4HNE has a high affinity towards cysteine, histidine and lysine residues forming direct protein-adducts and thereby altering protein function. Autophagy is an intracellular event in which a cell digests its own constituents. The term ����autophagic cell death���� describes a form of programmed cell death morphologically distinct from apoptosis and presumed to result from excessive levels of cellular autophagy. In classical apoptosis, or type I programmed cell death, there is early collapse of cytoskeletal elements but preservation of organelles until late in the process. In contrast, in autophagic, or type II, programmed cell death there is early degradation of organelles but preservation of cytoskeletal elements until late stages. Recent studies have demonstrated interactions between the autophagic and apoptotic pathways. The Bcl-2 family has been implicated in the Nifedipine crosstalk between apoptosis and autophagy. Other apoptosis-related proteins such as p53 have also been shown to play a role in autophagy.