"ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis"--a critical commentary.
In a recent publication (K. Ishikawa et al., 2008, Science320, 661-664), the authors described how replacing the endogenous mitochondrial DNA (mtDNA) in a weakly metastatic mouse tumor cell line with mtDNA from a highly metastatic cell line enhanced tumor progression through enhanced production of reactive oxygen species (ROS). The authors attributed the transformation from a low-metastatic cell line to a high-metastatic phenotype to overproduction of ROS (hydrogen peroxide and superoxide) caused by a dysfunction in mitochondrial complex I protein encoded by mtDNA transferred from the highly metastatic tumor cell line. In this critical evaluation, using the paper by Ishikawa et al. as an example, we bring to the attention of researchers in the free radical field how the failure to appreciate the complexities of dye chemistry could potentially lead to pitfalls, misinterpretations, and erroneous conclusions concerning ROS involvement. Herein we make a case that the authors have failed to show evidence for formation of superoxide and hydrogen peroxide, presumed to be generated from complex I deficiency associated with mtDNA mutations in metastatic cells.
Zielonka
Jacek
J
Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Kalyanaraman
B
B
D004272:DNA, Mitochondrial / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D005456:Fluorescent Dyes / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008954:Models, Biological; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010617:Phenanthridines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013481:Superoxides / Q000494:pharmacology
C521281:5-(6'-triphenylphosphoniumhexyl)-5,6-dihydro-6-phenyl-3,8-phenanthridinediammine; D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D005456:Fluorescent Dyes; D010617:Phenanthridines; D017382:Reactive Oxygen Species; D013481:Superoxides; C058428:hydroethidine; D006861:Hydrogen Peroxide
J Biol Chem. 1999 Oct 1;274(40):28161-8
10497168
Science. 2008 May 2;320(5876):661-4
18388260
Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5727-32
15824309
Arch Biochem Biophys. 2006 Dec 1;456(1):39-47
17081495
Free Radic Biol Med. 2006 Aug 15;41(4):657-67
16863999
Free Radic Biol Med. 1999 Oct;27(7-8):873-81
10515592
Free Radic Biol Med. 2006 Mar 15;40(6):968-75
16540392
Biochem Soc Symp. 2004;(71):97-106
15777015
Free Radic Biol Med. 2007 Oct 1;43(7):995-1022
17761297
Nat Protoc. 2008;3(1):8-21
18193017
Free Radic Biol Med. 1999 Jan;26(1-2):148-61
9890650
Anal Biochem. 2004 Sep 15;332(2):290-8
15325298
Anal Bioanal Chem. 2005 Mar;381(5):1065-72
15690180
Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15038-43
17015830
J Biol Chem. 2003 Aug 8;278(32):29410-9
12748170
Free Radic Biol Med. 2003 Jun 1;34(11):1359-68
12757846
Free Radic Biol Med. 2005 Oct 1;39(7):853-63
16140206
Circ Res. 2003 Jan 10;92(1):56-63
12522121
Am J Physiol Cell Physiol. 2004 Oct;287(4):C895-902
15306539
Chem Res Toxicol. 1992 Mar-Apr;5(2):227-31
1322737
Free Radic Biol Med. 2008 Jan 1;44(1):56-62
18045547
Biochem Biophys Res Commun. 2001 Mar 23;282(1):329-33
11264011
FEBS Lett. 2002 Jan 30;511(1-3):21-7
11821042
Free Radic Biol Med. 2008 Mar 1;44(5):835-46
18155177
Free Radic Biol Med. 2006 Oct 1;41(7):1050-7
16962930
Free Radic Biol Med. 2005 Jan 15;38(2):262-70
15607909