Cyclophilin D Is Involved in the Regulation of Autophagy and Affects the Lifespan of P. anserina in Response to Mitochondrial Oxidative Stress.
The mitochondrial permeability transition pore plays a key role in programmed cell death and the induction of autophagy. Opening of the pore is regulated by the mitochondrial peptidyl prolyl-cis, trans-isomerase cyclophilin D (CYPD). Previously it was shown in the aging model organism Podospora anserina that PaCYPD abundance increases during aging and that PaCypD overexpressors are characterized by accelerated aging. Here, we describe a role of PaCYPD in the regulation of autophagy. We found that the accelerated aging phenotype observed in a strain overexpressing PaCypD is not metacaspase-dependent but is accompanied by an increase of general autophagy and mitophagy, the selective autophagic degradation of mitochondria. It thus is linked to what has been defined as "autophagic cell death" or "type II" programmed cell death. Moreover, we found that the previously demonstrated age-related induction of autophagy in wild-type aging depends on the presence of PaCYPD. Deletion of PaCypD leads to a decrease in autophagy in later stages of age and under paraquat-mediated oxidative stress. Finally, we report that PaCYPD is also required for mitohormesis, the beneficial effect of mild mitochondrial stress. Thus, PaCYPD plays a key role in the context-dependent regulation of pathways leading to pro-survival and pro-death effects of autophagy.
Department of Biosciences, Molecular Developmental Biology, Institute of Molecular Biosciences and Cluster of Excellence Frankfurt Macromolecular Complexes, J. W. Goethe University Frankfurt, Germany.
Piet
P
Kramer
Department of Biosciences, Molecular Developmental Biology, Institute of Molecular Biosciences and Cluster of Excellence Frankfurt Macromolecular Complexes, J. W. Goethe University Frankfurt, Germany.
Alexander T
AT
Jung
Department of Biosciences, Molecular Developmental Biology, Institute of Molecular Biosciences and Cluster of Excellence Frankfurt Macromolecular Complexes, J. W. Goethe University Frankfurt, Germany.
Andrea
A
Hamann
Department of Biosciences, Molecular Developmental Biology, Institute of Molecular Biosciences and Cluster of Excellence Frankfurt Macromolecular Complexes, J. W. Goethe University Frankfurt, Germany.
Heinz D
HD
Osiewacz
aging; autophagy; cyclophilin D; lifespan; mitohormesis; oxidative stress
Nat Cell Biol. 2009 Jul;11(7):852-8
19543272
Cell. 2011 Sep 2;146(5):682-95
21884931
Oncogene. 2015 Mar 19;34(12):1475-86
24727893
Autophagy. 2010 Aug;6(6):794-7
20523132
Curr Genet. 2010 Jun;56(3):225-35
20306265
FEBS Lett. 2002 Aug 28;526(1-3):71-6
12208507
Trends Microbiol. 2008 Jun;16(6):276-83
18440231
Exp Gerontol. 2010 Aug;45(7-8):525-32
20080171
Circ J. 2013;77(5):1111-22
23538482
Nature. 2005 Mar 31;434(7033):652-8
15800626
Methods Mol Biol. 2013;965:439-62
23296676
Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15301-6
24006361
Mech Ageing Dev. 2011 Jan-Feb;132(1-2):33-42
21145908
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15123-8
20696905
Nature. 1989 Dec 21-28;342(6252):953-5
2531848
Oxid Med Cell Longev. 2016;2016:3565127
27247702
Autophagy. 2006 Jan-Mar;2(1):39-46
16874071
Autophagy. 2010 May;6(4):462-72
20364102
Autophagy. 2014 May;10(5):822-34
24584154
Trends Cell Biol. 2016 Sep;26(9):655-67
27161573
C R Hebd Seances Acad Sci. 1953 Oct 12;237(15):838-40
13107134
Aging (Albany NY). 2009 Mar 03;1(3):328-34
20157520
Exp Gerontol. 2015 Mar;63:8-17
25616172
Mol Microbiol. 2007 Aug;65(4):948-58
17627766
Cell Death Differ. 2009 Jul;16(7):1040-52
19407826
FASEB J. 2001 Oct;15(12):2286-7
11511528
Aging Cell. 2010 Oct;9(5):761-75
20626725
Cardiovasc Res. 2007 Aug 1;75(3):530-5
17512507
J Biol Chem. 2005 May 13;280(19):18558-61
15792954
PLoS One. 2013 Dec 20;8(12):e83109
24376646
Int J Physiol Pathophysiol Pharmacol. 2013 May 27;5(2):61-72
23750305
J Gerontol A Biol Sci Med Sci. 2002 Mar;57(3):B109-14
11867647
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12005-10
16103352
PLoS Biol. 2010 Dec 07;8(12 ):e1000556
21151885
Exp Gerontol. 2014 Feb;50:72-81
24316036
Nature. 2005 Mar 31;434(7033):658-62
15800627
Sci STKE. 2005 Jun 07;2005(287):pe26
15942033
Teratology. 1973 Jun;7(3):253-66
4807128
Cell Death Differ. 2012 Jan;19(1):107-20
21760595
Fungal Genet Biol. 2007 May;44(5):307-14
17320431
Aging Cell. 2008 Oct;7(5):651-62
18616635
Curr Genet. 1994 Feb;25(2):122-3
8087879
Eukaryot Cell. 2013 Jun;12(6):900-12
23584991
Arch Biochem Biophys. 2009 Nov;491(1-2):39-45
19735641
Exp Gerontol. 2007 Sep;42(9):887-98
17689904
Cell Death Differ. 2005 Nov;12 Suppl 2:1463-7
16247491
Curr Genet. 2005 Oct;48(4):270-5
16160832
Cardiovasc Res. 2010 Oct 1;88(1):67-74
20400621