p53 and mitochondrial function in neurons

Abstract

The p53 tumor suppressor plays a central role in dictating cell survival and death as a cellular sensor for a myriad of stresses including DNA damage, oxidative and nutritional stress, ischemia and disruption of nucleolar function. Activation of p53-dependent apoptosis leads to mitochondrial apoptotic changes via the intrinsic and extrinsic pathways triggering cell death execution most notably by release of cytochrome c and activation of the caspase cascade. Although it was previously believed that p53 induces apoptotic mitochondrial changes exclusively through transcription-dependent mechanisms, recent studies suggest that p53 also regulates apoptosis via a transcription-independent action at the mitochondria. Recent evidence further suggests that p53 can regulate necrotic cell death and autophagic activity including mitophagy. An increasing number of cytosolic and mitochondrial proteins involved in mitochondrial metabolism and respiration are regulated by p53, which influences mitochondrial ROS production as well. Cellular redox homeostasis is also directly regulated by p53 through modified expression of pro- and anti-oxidant proteins. Proper regulation of mitochondrial size and shape through fission and fusion assures optimal mitochondrial bioenergetic function while enabling adequate mitochondrial transport to accommodate local energy demands unique to neuronal architecture. Abnormal regulation of mitochondrial dynamics has been increasingly implicated in neurodegeneration, where elevated levels of p53 may have a direct contribution as the expression of some fission/fusion proteins are directly regulated by p53. Thus, p53 may have a much wider influence on mitochondrial integrity and function than one would expect from its well-established ability to transcriptionally induce mitochondrial apoptosis. However, much of the evidence demonstrating that p53 can influence mitochondria through nuclear, cytosolic or intra-mitochondrial sites of action has yet to be confirmed in neurons. Nonetheless, as mitochondria are essential for supporting normal neuronal functions and in initiating/propagating cell death signaling, it appears certain that the mitochondria-related functions of p53 will have broader implications than previously thought in acute and progressive neurological conditions, providing new therapeutic targets for treatment.

p53 in survival, death and metabolic health: a lifeguard with a licence to kill

“…p53 also supports the maintenance of mitochondrial mass and DNA 78 . In summary, the expression of p53 balances glucose metabolism to favour energy production through OXPHOS, a situation that is seen in quiescent tissues such as brain and heart tissues.…”

Analgetic effect of docosahexaenoic acid is mediated by modulating the microglia activity in the dorsal root ganglia in a rat model of neuropathic pain

“…Extranuclear deposition and cytoplasmatic accumulation of p53 protein have been described previously as a sign of mitochondrial dysfunction and subsequent mitochondria-related apoptosis or autophagy of damaged neurons in different in vivo and in vitro models (Dong et al, 2012;Endo et al, 2006;Nair et al, 2006). Despite the fact that p53-mediated events have some specific features in neurons, a lot of molecular pathways mediating transcriptional and non-transcriptional apoptotic mechanisms have many similarities (Wang et al, 2014). In our study the accumulation of p53 in DRG neurons of nerve injured rats was accompanied by the changes in cell morphology and the treatment of DHA not only reduced the p53 expression in damaged neurons but also prevented their morphologic alterations.…”

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

“…One mechanism by which Mst1 impacts ESCs apoptosis and migration is through the activation of Drp1-related mitochondrial fission by p53 [50]. p53 amplifies Drp1 activity via a post-transcriptional modification at Ser616.…”