Cosegregation of novel mitochondrial 16S rRNA gene mutations with the age-associated T414G variant in human cybrids.
Ever increasing evidence has been provided on the accumulation of mutations in the mitochondrial DNA (mtDNA) during the aging process. However, the lack of direct functional consequences of the mutant mtDNA load on the mitochondria-dependent cell metabolism has raised many questions on the physiological importance of the age-related mtDNA variations. In the present work, we have analyzed the bioenergetic properties associated with the age-related T414G mutation of the mtDNA control region in transmitochondrial cybrids. The results show that the T414G mutation does not cause per se any detectable bioenergetic change. Moreover, three mtDNA mutations clustered in the 16S ribosomal RNA gene cosegregated together with the T414G in the same cybrid cell line. Two of them, namely T1843C and A1940G, are novel and associate with a negative bioenergetic phenotype. The results are discussed in the more general context of the complex heterogeneity and the dramatic instability of the mitochondrial genome during cell culture of transmitochondrial cybrids.
Seibel
Peter
P
Department of Molecular Cell Therapy, Center for Biotechnology and Biomedicine, Universität Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany. peter.seibel@bbz.uni-leipzig.de
Di Nunno
Chiara
C
Kukat
Christian
C
Schäfer
Ingo
I
Del Bo
Roberto
R
Bordoni
Andreina
A
Comi
Giacomo P
GP
Schön
Astrid
A
Capuano
Ferdinando
F
Latorre
Dominga
D
Villani
Gaetano
G
D000375:Aging / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism; D020459:Genes, rRNA; D006801:Humans; D006822:Hybrid Cells; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D008969:Molecular Sequence Data; D017354:Point Mutation; D012313:RNA / Q000737:chemistry / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012336:RNA, Ribosomal, 16S / Q000737:chemistry / Q000235:genetics*
D045222:Electron Transport Chain Complex Proteins; D000077278:RNA, Mitochondrial; D012336:RNA, Ribosomal, 16S; D012313:RNA
Nucleic Acids Res. 1998 Feb 15;26(4):967-73
9461455
Nat Genet. 2006 May;38(5):515-7
16604074
Cell. 1990 Jun 15;61(6):931-7
2112427
Reprod Biomed Online. 2000;1(3):96-100
12804188
Nature. 1981 Apr 9;290(5806):457-65
7219534
Somat Cell Mol Genet. 1999 Nov;25(5-6):333-42
15328912
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31
15247418
Nat Genet. 2006 May;38(5):518-20
16604072
Aging Cell. 2007 Aug;6(4):557-64
17578510
Annu Rev Genet. 2005;39:359-407
16285865
Mitochondrion. 2002 Nov;2(1-2):27-37
16120306
Hum Mutat. 2008 Feb;29(2):248-57
17999439
Cell. 2005 Dec 29;123(7):1227-40
16377564
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1116-21
12538859
Methods Cell Biol. 2007;80:121-33
17445691
Nucleic Acids Res. 2006 Aug 02;34(13):e95
16885236
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4022-7
11274426
Nucleic Acids Res. 2007 Jan;35(Database issue):D823-8
17178747
Nat Genet. 2007 Apr;39(4):445-6
17392805
Bioinformatics. 2003 Jan 22;19(2):299-300
12538259
Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1166-71
9037024
Science. 1999 Oct 22;286(5440):774-9
10531063
Neurobiol Aging. 2003 Oct;24(6):829-38
12927765
Biochim Biophys Acta. 2007 Mar;1767(3):222-32
17346667
Science. 1989 Oct 27;246(4929):500-3
2814477
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D101-3
14681368
Rejuvenation Res. 2007 Sep;10(3):349-57
17708691
Nat Genet. 2007 Apr;39(4):540-3
17334366
Nature. 2004 May 27;429(6990):417-23
15164064
Nature. 2001 Oct 25;413(6858):814-21
11677599