Forkhead Box O3A (FOXO3) and the Mitochondrial Disulfide Relay Carrier (CHCHD4) Regulate p53 Protein Nuclear Activity in Response to Exercise

Jie Zhuang,William M Kamp,Jie Li,Chengyu Liu,Ju-Gyeong Kang,Ping-Yuan Wang,Paul M Hwang

doi:10.1074/jbc.m116.745737

Abstract

Although exercise is linked with improved health, the specific molecular mechanisms underlying its various benefits require further clarification. Here we report that exercise increases the nuclear localization and activity of p53 by acutely down-regulating coiled-coil-helix-coiled-coil-helix domain 4 (CHCHD4), a carrier protein that mediates p53 import into the mitochondria. This response to exercise is lost in transgenic mice with constitutive expression of CHCHD4. Mechanistically, exercise-induced nuclear transcription factor FOXO3 binds to the CHCHD4 promoter and represses its expression, preventing the translocation of p53 to the mitochondria and thereby increasing p53 nuclear localization. The synergistic increase in nuclear p53 and FOXO3 by exercise can facilitate their known interaction in transactivating Sirtuin 1 (SIRT1), a NAD+-dependent histone deacetylase that mediates adaptation to various stresses. Thus, our results reveal one mechanism by which exercise could be involved in preventing cancer and potentially other diseases associated with aging.

Highlights

The nuclear transcriptional activities of p53, well established to play a critical role in tumor suppression, are dynamically regulated by multiple factors, including posttranslational modifications and protein-protein interactions [1,2,3]
CHCHD4 Prevents Nuclear Localization and Transcriptional Activities of p53 in Vivo—To investigate the physiological significance of our previous finding that CHCHD4 mediates the import of p53 into mitochondria [9], we created a CHCHD4 transgenic (Tg) mouse line that overexpresses the mouse CHCHD4 gene under control of the mouse ROSA26 promoter
Confocal immunofluorescence of CHCHD4 in cross-sections of gastrocnemius skeletal muscle revealed an intense green fluorescence signal in CHCHD4 Tg mice that co-localized with the red fluorescence signal of c oxidase subunit 4 (COX4) as a mitochondrial marker (Fig. 1A)

Summary

Edited by Linda Spremulli

Exercise is linked with improved health, the specific molecular mechanisms underlying its various benefits require further clarification. We report that exercise increases the nuclear localization and activity of p53 by acutely down-regulating coiled-coil-helix-coiled-coil-helix domain 4 (CHCHD4), a carrier protein that mediates p53 import into the mitochondria. This response to exercise is lost in transgenic mice with constitutive expression of CHCHD4. The nuclear transcriptional activities of p53, well established to play a critical role in tumor suppression, are dynamically regulated by multiple factors, including posttranslational modifications and protein-protein interactions [1,2,3]. Exercise elicits many complex physiological responses, including the induction of specific transcription factors such as PGC-1␣ and peroxisome proliferator-activated receptors, which transactivate mitochondrial biogenesis genes [14, 15]. We generated a CHCHD4 transgenic mouse model to investigate how the interaction between CHCHD4 and p53 is regulated by exercise

Results

Discussion

Experimental Procedures