Mitochondrial Liaisons of p53

Abstract

Mitochondria play a central role in cell survival and cell death. While producing the bulk of intracellular ATP, mitochondrial respiration represents the most prominent source of harmful reactive oxygen species. Mitochondria participate in many anabolic pathways, including cholesterol and nucleotide biosynthesis, yet also control multiple biochemical cascades that contribute to the programmed demise of cells. The tumor suppressor protein p53 is best known for its ability to orchestrate a transcriptional response to stress that can have multiple outcomes, including cell cycle arrest and cell death. p53-mediated tumor suppression, however, also involves transcription-independent mechanisms. Cytoplasmic p53 can physically interact with members of the BCL-2 protein family, thereby promoting mitochondrial membrane permeabilization. Moreover, extranuclear p53 can suppress autophagy, a major prosurvival mechanism that is activated in response to multiple stress conditions. Thirty years have passed since its discovery, and p53 has been ascribed with an ever-increasing number of functions. For instance, p53 has turned out to influence the cell's redox status, by transactivating either anti- or pro-oxidant factors, and to regulate the metabolic switch between glycolysis and aerobic respiration. In this review, we will analyze the mechanisms by which p53 affects the balance between the vital and lethal functions of mitochondria.

Molecular mechanisms of cisplatin resistance

“…Activated TP53 exerts lethal functions via nuclear and cytoplasmic mechanisms that eventually lead to mitochondrial outer membrane permeabilization or increased signaling via death receptors followed by cell death (Kroemer et al, 2007;Galluzzi et al, 2011) In response to cisplatin, CHEK1 has also been shown to activate various branches of the mitogenactivated protein kinase (MAPK) system, including those mediated by extracellular signal-regulated kinases, c-JUN N-terminal kinases and stress-activated protein kinases (Persons et al, 2000;Wang et al, 2000;Dent and Grant, 2001;Yeh et al, 2002). The relative contribution of these signaling modules to the cytotoxic effects of cisplatin remain to be deciphered, as contrasting reports can be found in literature (Dent and Grant, 2001).…”

Antioxidant Role of p53 and of Its Target TP53INP1

“…In particular, p53 influences mitochondrial functions such as apoptosis and respiration which is the most prominent source of ROS. p53 was shown to indirectly promote mitochondrial functions and inhibit glycolysis [21][22][23]. The consequence of this promotion of oxidative phosphorylation is a decrease in oxidative stress and thus prevention of DNA damage.…”

RECQL4 is essential for the transport of p53 to mitochondria in normal human cells in the absence of exogenous stress

“…However, in recent years the role of p53 in cytoplasm especially during autophagy, energy metabolism and mitochondrial functions (reviewed by Galluzzi et al, 2011;Green and Kroemer, 2009) have also come into sharper focus.…”