Saleem A, Iqbal S, Zhang Y, Hood DA. Effect of p53 on mitochondrial morphology, import, and assembly in skeletal muscle. Am J Physiol Cell Physiol. 2015 Feb 15;308(4):C319-29.
The tumor suppressor protein p53 needs little introduction with respect to its abilities to serve as the Guardian of the Genome – for both the mitochondrial and nuclear DNA. Upon a cellular insult, p53 is rapidly mobilized to either halt cell proliferation and repair the damage, or to mediate the death of the cell. In addition to responding to stressful stimuli, p53 plays a important role in the cell during the resting state. We, and others, have previously shown that the presence of p53 is indispensible for maintaining optimal mitochondrial content and function. Indeed mice knockout (KO) for p53 protein have diminished mitochondrial content, reduced exercise capacity and an attenuated drive for adaptations post-exercise. Here, we shed further light on the underlying mechanism by which p53 controls mitochondrial bioenergetics. Skeletal muscle mitochondria in p53 KO mice displayed ultra-structural alterations and disorganized cristae structure as revealed by electron microscopy. This occurred along with the loss of mitochondrial content, and changes in mitochondrial fission, fusion and mitophagy-related proteins. Since the majority of mitochondrial proteins are imported into the organelle, the protein import pathway is of utmost importance in regulating the function of mitochondria. Despite depot-specific reductions in core proteins involved in orchestrating protein import, the rate of protein import itself was not changed in p53 KO mitochondria vs. their wild-type counterparts. We have previously observed impaired mitochondrial respiration in p53 KO muscle. We next sought to evaluate if alterations in assembly of electron transport chain complex IV, the site of cellular respiration, contributes to this impairment. Using two-dimensional BN-PAGE analysis, we observed that complex IV assembly was lower in the intermyofibrillar (IMF) mitochondrial pool, along with lower levels of expression of assembly co-factor, Surf1. The work summarized here alludes to an alternative pathway by which p53 further controls respiration and aerobic capacity. Further research endeavors are warranted to fully establish the mechanism.