title: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) phosphorylation by protein kinase Cδ (PKCδ) inhibits mitochondria elimination by lysosomal-like structures following ischemia and reoxygenation-induced injury.
abstract: After cardiac ischemia and reperfusion or reoxygenation (I/R), damaged mitochondria propagate tissue injury by promoting cell death. One possible mechanism to protect from I/R-induced injury is the elimination of damaged mitochondria by mitophagy. Here we identify new molecular events that lead to mitophagy using a cell culture model and whole hearts subjected to I/R. We found that I/R induces glyceraldehyde-3-phosphate dehydrogenase (GAPDH) association with mitochondria and promotes direct uptake of damaged mitochondria into multiorganellar lysosomal-like (LL) structures for elimination independently of the macroautophagy pathway. We also found that protein kinase C δ (PKCδ) inhibits GAPDH-driven mitophagy by phosphorylating the mitochondrially associated GAPDH at threonine 246 following I/R. Phosphorylated GAPDH promotes the accumulation of mitochondria at the periphery of LL structures, which coincides with increased mitochondrial permeability. Either inhibition of PKCδ or expression of a phosphorylation-defective GAPDH mutant during I/R promotes a reduction in mitochondrial mass and apoptosis, thus indicating rescued mitophagy. Taken together, we identified a GAPDH/PKCδ signaling switch, which is activated during oxidative stress to regulate the balance between cell survival by mitophagy and cell death due to accumulation of damaged mitochondria.
authors: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305-5174, USA.
authors: Gouri
authors: G
authors: Yogalingam
authors: Sunhee
authors: S
authors: Hwang
authors: Julio C B
authors: JC
authors: Ferreira
authors: Daria
authors: D
authors: Mochly-Rosen
mesh_terms: D000818:Animals; D017209:Apoptosis; D000071187:Autophagy-Related Protein 5; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007511:Ischemia / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010539:Permeability; D051745:Protein Kinase C-delta / Q000378:metabolism*; D021381:Protein Transport; D015427:Reperfusion Injury / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D051745:Protein Kinase C-delta; D010100:Oxygen
keywords: GAPDH; Heart; Ischemia; Lysosomes; Mitochondria; Mitophagy; PKCδ; Protein Kinase C (PKC)
references: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11114-9
references: 11553773
references: Traffic. 2000 Jul;1(7):570-83
references: 11208145
references: Biochim Biophys Acta. 2009 Sep;1793(9):1508-15
references: 19289147
references: Cell. 2007 Jun 1;129(5):983-97
references: 17540177
references: FEBS Lett. 2006 May 15;580(11):2623-9
references: 16647067
references: Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11233-7
references: 9326592
references: EMBO J. 2003 Jan 2;22(1):47-59
references: 12505983
references: Circ Res. 2005 Jul 8;97(1):78-85
references: 15961716
references: Nat Rev Mol Cell Biol. 2007 Nov;8(11):931-7
references: 17712358
references: J Alzheimers Dis. 2010;20(2):369-93
references: 20164570
references: J Biol Chem. 2006 Jul 7;281(27):18394-400
references: 16672224
references: Nat Cell Biol. 2010 Feb;12(2):104-6
references: 20118996
references: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4527-31
references: 7538674
references: Science. 2010 Dec 3;330(6009):1344-8
references: 21127245
references: Autophagy. 2010 Apr;6(3):433-5
references: 20200478
references: Nat Rev Mol Cell Biol. 2011 Jan;12(1):9-14
references: 21179058
references: Drug Discov Today Dis Mech. 2010 Summer;7(2):e87-e93
references: 21151743
references: Blood. 2008 Aug 15;112(4):1493-502
references: 18539900
references: J Biol Chem. 2008 Nov 21;283(47):32386-93
references: 18818209
references: Arch Biochem Biophys. 2005 Jul 15;439(2):194-9
references: 15963450
references: Proc Natl Acad Sci U S A. 1989 Sep;86(17):6758-62
references: 2505261
references: Autophagy. 2011 Dec;7(12):1573-4
references: 22082870
references: J Biol Chem. 1993 Aug 5;268(22):16688-92
references: 8344947
references: Biochemistry. 1995 Sep 26;34(38):12193-203
references: 7547960
references: J Cardiovasc Transl Res. 2010 Aug;3(4):374-83
references: 20559783
references: FEBS Lett. 1988 Apr 25;231(2):413-6
references: 2834236
references: Circulation. 2003 Nov 11;108(19):2304-7
references: 14597593
references: Dev Cell. 2011 Jan 18;20(1):131-9
references: 21238931
references: Cardiovasc Drugs Ther. 2006 Dec;20(6):425-32
references: 17171295
references: J Biol Chem. 2004 Nov 12;279(46):47985-91
references: 15339931
references: Circulation. 2009 Nov 24;120(21):2105-12
references: 19933949
references: Antioxid Redox Signal. 2011 May 15;14(10):1919-28
references: 21126216
references: Arch Biochem Biophys. 2007 Jun 15;462(2):245-53
references: 17475204
references: Cell Signal. 2011 Feb;23(2):317-23
references: 20727968
references: Biochem J. 1995 May 15;308 ( Pt 1):347-52
references: 7538757
references: Science. 2008 Jan 11;319(5860):210-3
references: 18187657
references: Science. 1996 Jul 26;273(5274):501-3
references: 8662539
references: Science. 2013 Apr 26;340(6131):471-5
references: 23620051
references: PLoS One. 2011;6(6):e20975
references: 21687634
references: Cardiovasc Res. 2007 Mar 1;73(4):699-709
references: 17234167
references: Biochem J. 2009 Sep 25;423(2):253-64
references: 19650766
references: Curr Opin Cell Biol. 2009 Aug;21(4):522-30
references: 19515549
references: Autophagy. 2011 Jul;7(7):673-82
references: 21646866
references: J Biol Chem. 2000 Jul 21;275(29):21793-6
references: 10818086
references: Autophagy. 2010 Nov;6(8):1090-106
references: 20890124
references: J Biol Chem. 2012 Nov 23;287(48):40652-60
references: 23060438
references: Biochemistry. 1985 Apr 9;24(8):1904-9
references: 4016090
references: Cell Mol Life Sci. 2012 Apr;69(7):1125-36
references: 22080117
references: Am J Physiol Cell Physiol. 2010 Aug;299(2):C203-10
references: 20357180
references: J Biol Chem. 1994 Oct 21;269(42):26374-80
references: 7929357
references: Autophagy. 2009 Nov;5(8):1203-5
references: 19770589
references: Circulation. 2010 Sep 14;122(11 Suppl):S179-84
references: 20837911
references: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):378-83
references: 19966284
references: J Biol Chem. 2006 Oct 6;281(40):29776-87
references: 16882669