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The mitochondrial theory of ageing proposes
that the somatic accumulation of mtDNA mutations (both point
mutations and deletions) progressively compromises energy metabolism,
leading to loss of physiological function, deletion of essential
cells by apoptosis, and increasing oxidative stress.
Our recent work has shed light on this hypothesis in several
respects: firstly, although inherited mtDNA mutations
are frequently associated with progressive, degenerative disorders
such as sensorineural deafness, the evidence that somatic mtDNA
mutations cause age-related pathologies is weaker. Mutation
loads remain modest and highly variable between individuals, but
mitotic segregation and clonal expansion might nevertheless lead
to the accumulation of mutations to deleterious levels in key cells,
and thus account for ageing phenotypes. This is supported
by studies of mtDNA mutation loads in mice carrying a proof-reading
deficient form of the catalytic subunit of the mitochondrial DNA
polymerase, Polg, which accumulate mitochondrial mutations and show
many manifestations of premature ageing. Nevertheless, the analyses
do not support the popular idea of a vicious cycle based on an oxidative
crisis.
Current work in our lab in this area concerns the mechanistic
contribution of POLG defects to male infertility, based on
studies in both humans and mice, and further analyses of mtDNA
in age-related hearing impairment. We also study ageing
phenotypes in Drosophila mutants exhibiting
mitochondrial dysfunction.
The work involves
a long-term collaboration with the laboratories of Aleksandra
Trifunovic and Nils-Göran
Larsson at the Karolinska Institute, Stockholm, as well
as Hans Spelbrink
in IMT Tampere, Anu
Wartiovaara in Helsinki and Ilmari
Pyykkö in Tampere University Hospital, as well as
many other partners. It is funded by the University of Tampere,
the Academy of Finland, Tampere University Hospital Medical Research
Fund, Juselius Foundation and the European Union.
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Selected recent publications:
Trifunovic
A, Hansson A, Wredenberg A, Rovio AT, Dufour
E, Khvorostov I, Spelbrink JN, Wibom R, Jacobs HT,
Larsson NG (2005) Somatic
mtDNA mutations cause aging phenotypes
without affecting reactive oxygen species
production. Proc Natl Acad Sci USA
102(50), 17993-17998.
Jacobs HT, Hutchin TP,
Käppi T, Gillies G, Minkkinen K, Walker
J, Thompson K, Rovio AT, Carella M, Melchionda S,
Zelante L, Gasparini P, Pyykkö I, Shah ZH, Zeviani
M, Mueller RF (2005) Mitochondrial
DNA mutations in patients with postlingual,
non-syndromic hearing impairment. Eur.
J. Hum. Genet. 13, 26-33.
Trifunovic A, Wredenberg
A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder
CE, Bohlooly-Y M, Gidlöf S, Oldfors A, Wibom
R, Jacobs HT, Törnell J, Larsson NG (2004)
Premature
ageing in mice expressing defective mitochondrial
DNA polymerase. Nature 429,
417-423.
Rovio AT, Abel
J, Ahola AL, Andres AM, Bertranpetit J, Blancher
A, Bontrop RE, Chemnick LG, Cooke HJ, Cummins JM,
Davis HL, Elliott DJ, Fritsche E, Hargreave TB,
Hoffman SMG, Jequier AM, Kao SH, Kim HS, Marchington
DR, Mehmet D, Otting N, Poulton J, Ryder OA, Schuppe HC, Takenaka
O, Wei YH, Wichmann L, Jacobs HT (2004)
A prevalent POLG CAG microsatellite length allele
in humans and African great apes. Mammalian Genome
15, 492-502.
Jacobs HT (2003)
The
mitochondrial theory of aging: dead or
alive? Aging Cell 2, 11-17.
Kajander OA, Karhunen
PJ, Jacobs HT (2002)
The relationship between somatic mtDNA
rearrangements, human heart disease and aging.
Hum. Mol. Genet. 11, 317-324.
Rovio AT, Marchington
DR, Donat S, Schuppe HC, Abel J, Fritsche
E, Elliott DJ, Laippala P, Ahola AL, McNay D, Harrison
RF, Hughes B, Barrett T, Bailey DMD, Mehmet
D, JequierAM, Hargreave TB, Kao SH, Cummins JM,
Barton DE, Cooke HJ, Wei YH, Wichmann L, Poulton J, Jacobs
HT (2001)
Mutations at the mitochondrial DNA polymerase
(POLG) locus associated with male infertility.
Nature Genetics 29, 261-262.
Shah ZH, Toompuu
M, Hakkinen T, Rovio A, Smith RJH, Cremers FP,
Cremers CWRJ, Jacobs HT (2001)
Novel coding-region polymorphisms in mitochondrial
seryl-tRNA synthetase (SARSM) and mitoribosomal
protein S12 (RPMS12) genes in DFNA4
autosomal dominant deafness families. Hum.
Mutation 17, 433-434.
Kajander OA, Rovio
AT, Majamaa K, Poulton J, Spelbrink JN, Holt
IJ, Karhunen PJ, Jacobs HT (2000) Human
mtDNA sublimons resemble rearranged mitochondrial
genomes found in pathological states. Hum.
Mol. Genet. 9, 2821-2835.
Spelbrink JN, Toivonen
JM, Hakkaart GAJ, Kurkela JM, Cooper HM, Lehtinen
SK, Lecrenier N, Back JW, Speijer D, Foury F, Jacobs
HT (2000)
In vivo functional analysis of the human
mitochondrial DNA polymerase POLG expressed in
cultured human cells. J. Biol. Chem.
275, 24818-24828
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