Forkhead Box O3A (FOXO3) and the Mitochondrial Disulfide Relay Carrier (CHCHD4) Regulate p53 Protein Nuclear Activity in Response to Exercise.
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.
From the Center for Molecular Medicine and.
Jie
J
Zhuang
From the Center for Molecular Medicine and.
William M
WM
Kamp
From the Center for Molecular Medicine and.
Jie
J
Li
Transgenic Core, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
Chengyu
C
Liu
From the Center for Molecular Medicine and.
Ju-Gyeong
JG
Kang
From the Center for Molecular Medicine and.
Ping-Yuan
PY
Wang
From the Center for Molecular Medicine and hwangp@mail.nih.gov.
Paul M
PM
Hwang
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D020218:Response Elements; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D016159:Tumor Suppressor Protein p53; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
FOXO; exercise; mitochondria; mitochondrial transport; p53
J Appl Physiol (1985). 2012 Apr;112(7):1135-43
22267390
J Appl Physiol Respir Environ Exerc Physiol. 1984 Apr;56(4):831-8
6373687
Prog Mol Biol Transl Sci. 2015 ;135:99-127
26477912
J Cell Biol. 2007 Nov 5;179(3):389-95
17967948
Nature. 2009 Apr 30;458(7242):1127-30
19407794
Front Physiol. 2013 Jun 20;4:147
23801966
Curr Opin Genet Dev. 2016 Jun;38:16-22
27003724
Front Physiol. 2016 Apr 26;7:144
27199762
Science. 2005 Sep 9;309(5741):1732-5
16151013
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17356-61
24101517
J Biol Chem. 2011 Sep 2;286(35):30561-70
21757760
Trends Cell Biol. 2008 Sep;18(9):421-9
18715783
Mitochondrion. 2012 Jan;12(1):5-13
21406254
Mol Pharm. 2016 Jan 4;13(1):73-84
26592738
Nat Rev Mol Cell Biol. 2013 Feb;14(2):83-97
23325358
Science. 2004 Dec 17;306(5704):2105-8
15604409
J Biol Chem. 2012 Feb 10;287(7):4426-33
22157015
FEBS Lett. 2016 Apr;590(7):924-34
26780878
EMBO J. 2004 Nov 24;23(23):4679-89
15526035
J Physiol. 2013 Jul 15;591(14 ):3625-36
23690562
J Physiol. 2014 Sep 15;592(18):4069-82
25063823
Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7605-9
1652755
Sports Med. 2008;38(4):271-96
18348589
Nat Protoc. 2007;2(2):287-95
17406588
Nat Rev Cancer. 2009 May;9(5):371-7
19360021
Science. 2006 Jun 16;312(5780):1650-3
16728594
Cell. 2009 May 15;137(4):609-22
19450511
Cell. 2012 Jun 22;149(7):1536-48
22726440
Cell. 1999 Mar 19;96(6):857-68
10102273
Free Radic Biol Med. 2012 Sep 15;53(6):1279-85
22841759
Physiol Genomics. 2009 Mar 3;37(1):58-66
19106183
Sports Med. 2014 Mar;44(3):303-9
24264057
N Engl J Med. 2013 Mar 14;368(11):1027-32
23484829
Circ Res. 2009 Sep 25;105(7):705-12, 11 p following 712
19696408
Pflugers Arch. 2015 Jul;467(7):1523-37
25104573
Nat Rev Cancer. 2006 Dec;6(12 ):909-23
17128209
Circ Res. 2006 May 26;98(10):1282-9
16614304