Exercise regulates the partitioning of p53 between the mitochondrial and nuclear compartments

Authors

• J Zhuang
• PY Wang
• PM Hwang

Abstract

Abstract Large human observational studies consistently show an inverse relationship between cardiorespiratory fitness and various cancer mortality however the underlying molecular mechanisms remain unclear. We have previously reported that the tumor suppressor p53 regulates mitochondrial respiration, promotes aerobic exercise capacity and mediates its adaptive improvement with exercise training. We also recently uncovered a mechanism by which p53 protein and its activities can be partitioned between the nucleus and mitochondria via the disulfide relay system involving mitochondrial import protein CHCHD4. Based on these studies, we have now investigated whether exercise stimulus can partition the subcellular activities of p53 to help explain the association between exercise and cancer prevention. Herein, we report a genetic mechanism by which exercise suppresses CHCHD4 expression, thus preventing the import of p53 into mitochondria while increasing its nuclear localization and activity. To further explore the biology of the interaction between CHCHD4 and p53 in vivo, we generated CHCHD4 transgenic mice which showed decreased resting and exercise stimulated levels of nuclear p53 transactivated genes. These results suggest that the suppression of CHCHD4 expression by exercise, which in turn partitions the subcellular localization of p53 to the nucleus, may contribute to the observed benefits of exercise against cancer.

Scientific Focus Area: Cancer Biology

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