DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice

被引：305

作者：

Vermulst, Marc ^{[1
]}

Wanagat, Jonathan ^{[2
]}

Kujoth, Gregory C. ^{[3
,4
]}

Bielas, Jason H. ^{[1
]}

Rabinovitch, Peter S. ^{[1
]}

Prolla, Tomas A. ^{[3
,4
]}

Loeb, Lawrence A. ^{[1
]}

机构：

[1] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[2] Univ Washington, Dept Gerontol & Geriat Med, Seattle, WA 98195 USA

[3] Univ Wisconsin, Dept Genet, Madison, WI 53706 USA

[4] Univ Wisconsin, Dept Med Genet, Madison, WI 53706 USA

来源：

NATURE GENETICS | 2008年 / 40卷 / 04期

关键词：

D O I：

10.1038/ng.95

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Mitochondrial DNA (mtDNA) mutations are thought to have a causal role in many age-related pathologies. Here we identify mtDNA deletions as a driving force behind the premature aging phenotype of mitochondrial mutator mice, and provide evidence for a homology-directed DNA repair mechanism in mitochondria that is directly linked to the formation of mtDNA deletions. In addition, our results demonstrate that the rate at which mtDNA mutations reach phenotypic expression differs markedly among tissues, which may be an important factor in determining the tolerance of a tissue to random mitochondrial mutagenesis.

引用

收藏

页码：392 / 394

页数：3

相关论文

共 15 条

[1] High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease [J].

Bender, A ;

Krishnan, KJ ;

Morris, CM ;

Taylor, GA ;

Reeve, AK ;

Perry, RH ;

Jaros, E ;

Hersheson, JS ;

Betts, J ;

Klopstock, T ;

Taylor, RW ;

Turnbull, DM .

NATURE GENETICS, 2006, 38 (05) :515-517

[2] Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission [J].

Greaves, LC ;

Preston, SL ;

Tadrous, PJ ;

Taylor, RW ;

Barron, MJ ;

Oukrif, D ;

Leedham, SJ ;

Deheragoda, M ;

Sasieni, P ;

Novelli, MR ;

Jankowski, JAZ ;

Turnbull, DM ;

Wright, NA ;

McDonald, SAC .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (03) :714-719

[3] Direct repeats in mitochondrial DNA and mammalian lifespan [J].

Khaidakov, Magomed ;

Siegel, Eric R. ;

Shmookler Reis, Robert J. .

MECHANISMS OF AGEING AND DEVELOPMENT, 2006, 127 (10) :808-812

[4] Does premature aging of the mtDNA mutator mouse prove that mtDNA mutations are involved in natural aging? [J].

Khrapko, Konstantin ;

Kraytsberg, Yevgenya ;

de Grey, Aubrey D. N. J. ;

Vijg, Jan ;

Schon, Eric A. .

AGING CELL, 2006, 5 (03) :279-282

[5] Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons [J].

Kraytsberg, Y ;

Kudryavtseva, E ;

Mckee, AC ;

Geula, C ;

Kowall, NW ;

Khrapko, K .

NATURE GENETICS, 2006, 38 (05) :518-520

[6] Recombination of human mitochondrial DNA [J].

Kraytsberg, Y ;

Schwartz, M ;

Brown, TA ;

Ebralidse, K ;

Kunz, WS ;

Clayton, DA ;

Vissing, J ;

Khrapko, K .

SCIENCE, 2004, 304 (5673) :981-981

[7] Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging [J].

Kujoth, GC ;

Hiona, A ;

Pugh, TD ;

Someya, S ;

Panzer, K ;

Wohlgemuth, SE ;

Hofer, T ;

Seo, AY ;

Sullivan, R ;

Jobling, WA ;

Morrow, JD ;

Van Remmen, H ;

Sedivy, JM ;

Yamasoba, T ;

Tanokura, M ;

Weindruch, R ;

Leeuwenburgh, C ;

Prolla, TA .

SCIENCE, 2005, 309 (5733) :481-484

[8] The role of mitochondrial DNA mutations in mammalian aging [J].

Kujoth, Gregory C. ;

Bradshaw, Patrick C. ;

Haroon, Suraiya ;

Prolla, Tomas A. .

PLOS GENETICS, 2007, 3 (02) :161-173

[9] MITOCHONDRIAL-DNA MUTATIONS AS AN IMPORTANT CONTRIBUTOR TO AGEING AND DEGENERATIVE DISEASES [J].

LINNANE, AW ;

OZAWA, T ;

MARZUKI, S ;

TANAKA, M .

LANCET, 1989, 1 (8639) :642-645

[10] RECOMBINATION VIA FLANKING DIRECT REPEATS IS A MAJOR CAUSE OF LARGE-SCALE DELETIONS OF HUMAN MITOCHONDRIAL-DNA [J].

MITA, S ;

RIZZUTO, R ;

MORAES, CT ;

SHANSKE, S ;

ARNAUDO, E ;

FABRIZI, GM ;

KOGA, Y ;

DIMAURO, S ;

SCHON, EA .

NUCLEIC ACIDS RESEARCH, 1990, 18 (03) :561-567