Bafilomycin A1 activates respiration of neuronal cells via uncoupling associated with flickering depolarization of mitochondria.
Bafilomycin A1 (Baf) induces an elevation of cytosolic Ca(2+) and acidification in neuronal cells via inhibition of the V-ATPase. Also, Baf uncouples mitochondria in differentiated PC12 ((d)PC12), (d)SH-SY5Y cells and cerebellar granule neurons, and markedly elevates their respiration. This respiratory response in (d)PC12 is accompanied by morphological changes in the mitochondria and decreases the mitochondrial pH, Ca(2+) and ΔΨm. The response to Baf is regulated by cytosolic Ca(2+) fluxes from the endoplasmic reticulum. Inhibition of permeability transition pore opening increases the depolarizing effect of Baf on the ΔΨm. Baf induces stochastic flickering of the ΔΨm with a period of 20 ± 10 s. Under conditions of suppressed ATP production by glycolysis, oxidative phosphorylation impaired by Baf does not provide cells with sufficient ATP levels. Cells treated with Baf become more susceptible to excitation with KCl. Such mitochondrial uncoupling may play a role in a number of (patho)physiological conditions induced by Baf.
Zhdanov
Alexander V
AV
Biochemistry Department, University College Cork, Cavanagh Pharmacy Building, College Road, Cork, Republic of Ireland. a.zhdanov@ucc.ie
Dmitriev
Ruslan I
RI
Papkovsky
Dmitri B
DB
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D016764:Cell Polarity / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D018942:Macrolides; C040929:bafilomycin A1; D025262:Vacuolar Proton-Translocating ATPases; D002118:Calcium
Anal Biochem. 2009 Jul 1;390(1):21-8
19379702
J Exp Biol. 2006 Feb;209(Pt 4):577-89
16449553
J Physiol. 2000 Nov 15;529 Pt 1:57-68
11080251
J Neurosci. 2001 Jul 15;21(14):5054-65
11438581
J Exp Biol. 2009 Feb;212(Pt 3):341-6
19151208
FEBS Lett. 2004 Oct 8;576(1-2):145-50
15474027
J Bioenerg Biomembr. 1994 Oct;26(5):471-85
7896763
Mol Pharmacol. 2006 Dec;70(6):1856-65
16940187
J Cell Physiol. 2006 Feb;206(2):347-53
16110491
Arch Biochem Biophys. 1991 Dec;291(2):383-9
1952951
J Neurosci. 2000 Oct 1;20(19):7208-19
11007877
Cell Calcium. 2000 Nov-Dec;28(5-6):285-96
11115368
Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10758-63
19528657
Anal Biochem. 2010 Mar 1;398(1):24-33
19931212
Annu Rev Physiol. 2008;70:273-99
17850212
J Cell Sci. 2002 Mar 15;115(Pt 6):1175-88
11884517
J Biol Chem. 2008 Feb 29;283(9):5650-61
18086678
J Neurosci Res. 2010 Jan;88(1):95-101
19610106
Mol Pharmacol. 2006 Apr;69(4):1125-36
16391239
FEBS J. 2005 Apr;272(7):1649-59
15794752
Integr Biol (Camb). 2010 Sep;2(9):443-51
20657921
Mol Pharmacol. 2006 Dec;70(6):1841-3
17000862
Biochim Biophys Acta. 2003 Sep 30;1606(1-3):23-41
14507425
Am J Physiol. 1998 Sep;275(3):C810-7
9730965
Biochim Biophys Acta. 2010 Sep;1797(9):1627-37
20550942
J Biol Chem. 2001 Jan 26;276(4):2586-99
11029457
Autophagy. 2008 Oct;4(7):849-50
18758232
J Biol Chem. 2002 Feb 8;277(6):3965-72
11724795
J Neurosci. 1996 Dec 1;16(23):7557-65
8922412
J Physiol. 1996 Oct 1;496 ( Pt 1):111-28
8910200
Anal Chem. 2007 Dec 15;79(24):9414-9
18001129
J Biol Chem. 2004 Aug 6;279(32):33131-8
15180988
Biophys J. 1998 Apr;74(4):2129-37
9545072
Toxicol Sci. 2007 Jun;97(2):539-47
17361016
J Antibiot (Tokyo). 1984 Feb;37(2):110-7
6423597
Microbiol Mol Biol Rev. 2006 Mar;70(1):177-91
16524922
J Bioenerg Biomembr. 2007 Aug;39(4):321-9
17917797
Physiol Rev. 2006 Jan;86(1):369-408
16371601
J Pharmacol Exp Ther. 2006 Nov;319(2):672-81
16895977
Neuroscience. 1994 Jul;61(1):51-61
7969895
Pflugers Arch. 2008 May;456(2):255-66
17909851
Neurotoxicology. 1991 Fall;12(3):473-92
1720882
Nat Rev Mol Cell Biol. 2002 Feb;3(2):94-103
11836511
J Biol Chem. 1989 Jun 25;264(18):10595-600
2543673
Autophagy. 2007 Nov-Dec;3(6):542-5
17611390
J Physiol. 1990 Jun;425:85-115
2213592
Mol Cell Biol. 2005 Feb;25(3):1025-40
15657430
Proc Natl Acad Sci U S A. 1988 Nov;85(21):7972-6
2973058
J Exp Biol. 1992 Nov;172:171-8
1362770
J Neurochem. 2000 Sep;75(3):991-1003
10936180
Biochem Biophys Res Commun. 2009 May 1;382(2):451-6
19289106
Drug Discov Today. 2007 Sep;12(17-18):777-85
17826691
Biochem J. 1992 Apr 1;283 ( Pt 1):41-50
1373604
Cell Tissue Res. 2009 Jun;336(3):521-7
19390865
Sci STKE. 2004 Jan 13;2004(215):re1
14722345
J Cell Sci. 2006 Dec 1;119(Pt 23):4926-34
17105774
Biochemistry. 1982 Sep 14;21(19):4795-9
7138829
Am J Physiol Cell Physiol. 2007 Jan;292(1):C157-63
16870828
Curr Biol. 1995 Jun 1;5(6):635-42
7552174
Physiol Rev. 1990 Apr;70(2):391-425
2157230
Mol Pharmacol. 2007 Mar;71(3):942-8
17178925
Eur J Biochem. 2002 Apr;269(8):1996-2002
11985575
Cardiovasc Res. 1993 Oct;27(10):1790-4
8275525
J Physiol. 2000 Nov 15;529 Pt 1:11-21
11080247
Free Radic Biol Med. 1997;23(4):637-47
9215809
Cell. 2003 Dec 26;115(7):863-77
14697204
Cell Struct Funct. 1998 Feb;23(1):33-42
9639028
J Biol Chem. 2006 May 26;281(21):14864-74
16551630
Biochem J. 2005 Aug 15;390(Pt 1):243-52
15847604
Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13807-12
10570154
J Biol Chem. 2004 Mar 19;279(12):11521-9
14701849