title: Drp1 dephosphorylation in ATP depletion-induced mitochondrial injury and tubular cell apoptosis.
abstract: Recent studies revealed a striking morphological change of mitochondria during apoptosis. Mitochondria become fragmented and notably, the fragmentation contributes to mitochondrial outer membrane permeabilization and consequent release of apoptotic factors. In renal tubular cells, mitochondrial fragmentation involves the activation of Drp1, a key mitochondrial fission protein. However, it is unclear how Drp1 is regulated during tubular cell apoptosis. In this study, we examined Drp1 regulation during tubular cell apoptosis following ATP depletion. Rat kidney proximal tubular cells (RPTC) were subjected to azide treatment or severe hypoxia in glucose-free medium to induce ATP depletion. During ATP depletion, Drp1 was shown to be dephosphorylated at serine-637. Drp1 dephosphorylation could be suppressed by cyclosporine A and FK506, two calcineurin inhibitors. Importantly, cyclosporine A and FK506 could also prevent mitochondrial fragmentation, Bax accumulation, cytochrome c release, and apoptosis following ATP depletion in RPTC. The results suggest that calcineurin-mediated serine-637 dephosphorylation is involved in Drp1 activation during ATP depletion in renal tubular cells. Upon activation, Drp1 contributes to mitochondrial fragmentation and outer membrane permeabilization, resulting in the release of apoptogenic factors and apoptosis.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Sung-Gyu
authors.initials: SG
authors.lastname: Cho
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Du
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000255:Adenosine Triphosphate / Q000172:deficiency*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001386:Azides / Q000633:toxicity; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D015687:Cell Hypoxia; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D034281:Dynamins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D010539:Permeability; D010766:Phosphorylation; D021381:Protein Transport; D051381:Rats; D012694:Serine; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D001386:Azides; C494828:Bax protein, rat; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D051028:bcl-2-Associated X Protein; D012694:Serine; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D019703:Calcineurin; C519851:Dnm1l protein, rat; D034281:Dynamins; D005947:Glucose; D016559:Tacrolimus
references.citation: Science. 1998 Aug 28;281(5381):1322-6
references.pmid: 9735050
references.citation: J Am Soc Nephrol. 2004 Sep;15(9):2320-33
references.pmid: 15339981
references.citation: Am J Physiol Renal Physiol. 2005 Aug;289(2):F410-9
references.pmid: 15755925
references.citation: Am J Pathol. 2003 Aug;163(2):663-71
references.pmid: 12875985
references.citation: J Am Soc Nephrol. 2009 Sep;20(9):1919-28
references.pmid: 19696224
references.citation: J Gerontol A Biol Sci Med Sci. 2005 Jul;60(7):830-9
references.pmid: 16079204
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11649-54
references.pmid: 17606912
references.citation: J Cell Biol. 2007 May 7;177(3):439-50
references.pmid: 17470634
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:117-41
references.pmid: 16879082
references.citation: Transplantation. 2001 Dec 15;72(11):1753-9
references.pmid: 11740384
references.citation: J Am Soc Nephrol. 2006 Jun;17(6):1503-20
references.pmid: 16707563
references.citation: J Clin Invest. 1991 Feb;87(2):581-90
references.pmid: 1991841
references.citation: Kidney Int. 2004 Aug;66(2):500-6
references.pmid: 15253697
references.citation: Science. 1999 Apr 9;284(5412):339-43
references.pmid: 10195903
references.citation: Transplantation. 2003 Jul 15;76(1):50-4
references.pmid: 12865785
references.citation: Genes Dev. 2001 Nov 15;15(22):2922-33
references.pmid: 11711427
references.citation: Biochim Biophys Acta. 2009 Jan;1793(1):154-70
references.pmid: 18694785
references.citation: Kidney Int. 2003 Sep;64(3):864-73
references.pmid: 12911536
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15803-8
references.pmid: 18838687
references.citation: J Clin Invest. 1994 May;93(5):1922-9
references.pmid: 8182125
references.citation: Transplant Proc. 2007 Mar;39(2):417-20
references.pmid: 17362745
references.citation: EMBO Rep. 2007 Oct;8(10):939-44
references.pmid: 17721437
references.citation: J Mol Cell Cardiol. 2009 Jun;46(6):821-31
references.pmid: 19265700
references.citation: Toxicology. 2005 Feb 28;207(3):339-47
references.pmid: 15664262
references.citation: J Clin Invest. 2009 May;119(5):1275-85
references.pmid: 19349686
references.citation: Am J Pathol. 1998 Jan;152(1):231-40
references.pmid: 9422540
references.citation: Cell Cycle. 2007 Dec 15;6(24):3043-7
references.pmid: 18073534
references.citation: J Biol Chem. 2001 Jun 1;276(22):18702-9
references.pmid: 11278985
references.citation: J Biol Chem. 2007 Jul 27;282(30):21583-7
references.pmid: 17553808
references.citation: Genes Dev. 2008 Jun 15;22(12):1577-90
references.pmid: 18559474
references.citation: Am J Med Sci. 2003 Sep;326(3):117-21
references.pmid: 14501225
references.citation: Biochim Biophys Acta. 2009 Nov;1787(11):1395-401
references.pmid: 19576166
references.citation: Transplant Proc. 2002 May;34(3):791-4
references.pmid: 12034184
references.citation: Kidney Int. 1999 Jun;55(6):2224-35
references.pmid: 10354271
references.citation: J Biol Chem. 2004 May 7;279(19):19948-54
references.pmid: 15004018
references.citation: Am J Physiol Renal Physiol. 2003 Apr;284(4):F608-27
references.pmid: 12620919
references.citation: Cell. 2004 Jan 23;116(2):205-19
references.pmid: 14744432
references.citation: Oncogene. 1998 Dec 31;17(26):3401-15
references.pmid: 10030664
references.citation: Science. 2004 Jul 30;305(5684):626-9
references.pmid: 15286356
references.citation: Annu Rev Cell Dev Biol. 2006;22:79-99
references.pmid: 16704336
references.citation: J Biol Chem. 2007 Apr 13;282(15):11521-9
references.pmid: 17301055
references.citation: Am J Physiol Renal Physiol. 2009 Sep;297(3):F749-59
references.pmid: 19553348
references.citation: Ren Fail. 2007;29(8):935-40
references.pmid: 18067037