|
Mitochondrial
DNA mutations result in a bewildering array of pathological
phenotypes. One key goal of our work is to use model systems
to dissect the processes at the cellular and organismal levels
which lead to these pathological manifestations, and test out possible
approaches to therapy.
Studies in cell culture have revealed the key role of nuclear
genetic background in determining the outcome of mitotic segregation,
where heteroplasmic mixtures of wild-type and mutant mtDNA
co-exist. They have also demonstrated, for specific
mitochondrial tRNA mutations, the importance of pre-tRNA processing
and base-modification defects in the expression of pathological
phenotypes. We are also studying the regulation of key
nuclear genes for the mitochondrial translational apparatus,
which impinge upon mitochondrial disease phenotypes.
Whole organism models such as Drosophila
give clues as to the ways in which defective mitochondrial
oxidative phosphorylation affects physiology, development
and even behaviour. Our current approach focuses on identifying
the pathways that are induced in response to mitochondrial
stress. We are also using genetic analysis of inbred or mutant
lines in which pathological phenotypes are suppressed, to reveal
ways in which human mitochondrial diseases might be overcome.
Lastly, we are testing the effects of using molecular bypasses,
such as the allotopic expression of the alternative oxidase (AOX)
from the ascidian Ciona intestinalis, as a strategy
for overcoming the deleterious consequences of mitochondrial
disease mutations.
The work involves long-term collaborations
with the laboratories of Kevin
O'Dell in Glasgow, Pierre Rustin in Paris,
Tsutomu Suzuki
in Tokyo and Ian Holt in
Cambridge, as well as with numerous 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.
|
Selected recent publications:
Kirino Y, Yasukawa
T, Marjavaara SK, Jacobs HT, Holt IJ, Watanabe
K, Suzuki T (2006) Acquisition
of the wobble modification in mitochondrial
tRNALeu(CUN) bearing
the G12300A mutation suppresses the MELAS
molecular defect. Hum Mol Genet
15(6), 897-904.
Hakkaart
GA, Dassa EP, Jacobs HT, Rustin P (2006) Allotopic
expression of a mitochondrial alternative
oxidase confers cyanide-resistance to
human cell respiration. EMBO Rep. Mar;7(3):341-5.
(in press, e-pub before print).
Smeitink
JA, Zeviani M, Turnbull DM, Jacobs HT (2006)
Mitochondrial medicine: a metabolic
perspective on the pathology of oxidative
phosphorylation disorders. Cell Metab.
3, 9-13.
Turner
CJ, Granycome C, Hurst R, Pohler E, Juhola MK,
Juhola MI, Jacobs HT, Sutherland L, Holt IJ (2005)
Systematic
segregation to mutant mitochondrial
DNA abd accompanying loss of mitochondrial
DNA in human NT2 teratocarcinoma cybrids.
Genetics 170, 1879-1885.
Yasukawa T, Kirino
Y, Ishii N, Holt IJ, Jacobs HT, Makifuchi T, Fukuhara
N, Ohta S, Suzuki T, Watanabe K (2005)
Wobble modification deficiency in
mutant tRNAs in patients with mitochondrial diseases .
FEBS Lett. 579, 2948-2952.
Jacobs
HT, Turnbull DM (2005) Nuclear
genes and mitochondrial translation:
a new class of genetic disease. Trends
in Genet. 21, 312-314.
Toompuu
M, Levinger LL, Nadal A, Gomez J, Jacobs HT
(2004)
The 7472insC mtDNA mutation impairs 5´
and 3´ processing of tRNASer(UCN).
Biochem. Biophys. Res.
Commun. 322, 803-813.
Jacobs HT, Fernández-Ayala
DJM, Manjiry S, Kemppainen E, Toivonen
JM, O’Dell KMC (2004)
Mitochondrial disease in flies. Biochim.
Biophys. Acta 1659, 190-196.
Toivonen JM,
Manjiry S, Touraille S, Alziari S, O’Dell KMC,
Jacobs HT (2003)
Gene dosage and selective expression modify
phenotype in a Drosophila model of
human mitochondrial disease. Mitochondrion
3, 83-96.
Jacobs HT (2003)
Disorders
of mitochondrial protein synthesis.
Hum. Mol. Genet. 12, R293-R301.
Toompuu
M, Yasukawa T, Suzuki T, Hakkinen T, Spelbrink
JN, Watanabe K, Jacobs HT (2002)
The 7472insC mitochondrial DNA mutation impairs
the synthesis and extent of aminoacylation and rate
of synthesis of tRNASer(UCN) but
not its structure or rate of turnover. J. Biol.
Chem. 277, 22240-22250.
Lehtinen SK,
Spelbrink JN, Jacobs HT (1999) Heteroplasmic
segregation associated with trisomy-9
in cultured human cells. Somat. Cell Mol.
Genet. 25, 263-274
(accepted 2002 but journal volume dated 1999).
Toivonen JM, O’Dell
KMC, Petit N, Irvine S, Knight GK, Lehtonen
M, Longmuir M, Touraille S, Wang Z, Alziari S, Shah
ZH, Jacobs HT (2001) technical
knockout, a Drosophila model of mitochondrial
deafness. Genetics 159,
241-254.
|
|
|
