FP6 priority

1.1.1   Genomics and Biotechnology for Health

1.1.1.1

Title of the proposal

Proteins involved in mitochondrial biogenesis

Institute

Slovak Academy of Sciences, Institute of Molecular Biology
Dubravska cesta 21, 842 51 Bratislava, Slovak Republic

Contact

Research subject for a potential FP6 project

The main subject of our recent research is ATP-dependent Lon proteases, in mitochondria and their endogeneous substrates. The ATP-dependent Lon protease of Saccharomyces cerevisiae mitochondria is important for mitochondrial biogenesis because of the requirement for selective proteolysis in the matrix, maitenance of mitochondrial DNA and respiration-dependent growth. Lon protease is a heat-shock protein overproduced at elevated temperature and highly active at 30-45ºC in vitro. Mitochondrial Lon from Saccharomyces cerevisiae was identified as a flexible ring-shaped heptamer stabilized by ATP. We have found the subunits of yeast mitochondrial processing peptidase (MPP) as substrates of the Lon protease. Formation of MPPalpha-MPPbeta complex protects subunits against degradation. Modifications of either N- or C-terminus of the MPPalpha change its stability and recognition by Lon protease. The Lon protease supposes selectively degrade oxidatively modified aconitase, and my thus play an important role in defending against the accumulation of oxidized proteins in mitochondria. The hypothesis that the Lon protease might protect against mitochondrial protein damage from free radicals during oxidative stress and aging is interesting in light of experimental evidence that expression of the Lon protease declines about four-fold in ageing murine skeletal muscles, and that this phenomenon can be prevented by caloric restriction. Because the reaction mechanism of the Lon protease degradation is not known and would be hardly known before the crystal structure elucidation, we would like to determine the tertial structure of the Lon protease as well as their endogenous substrates.

Recent international cooperation of the research team

Institute of Microbiology, Czech Academy of Sciences, Prague, Czech Republic
Depertment of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medecine and Dentistry of New Jersey, Newark, New Jersey,USA
M.E.Muller Institute, University of Basel, Basel, Switzerland

Proposer´s relevant publications related to the research subject

1.E.Kutejova , G.Durcova , E.Surovkova , S.Kuzela. Yeast mitochondrial ATP-dependent protease: purification and comparison with the homologous rat enzyme and the bacterial ATP-dependent protease La. FEBS Letters 329 (1993) 47-50
2. J.M.van Dijl*, E.Kutejova*, K Suda, D.Perecko, G.Schatz and C.K.Suzuki *) autors contributed equally to this work.The ATPase and protease domains of yeast mitochondrial Lon: Roles in proteolysis and respiration dependent growth. Proc.Natl.Acad.Sci.USA 95 (1998) 10584-10589
3. H.Stahlberg*, E.Kutejova*,K.Suda, B.Wolpensinger, A.Lustig, G.Schatz, A.Engel, and C.K.Suzuki *) autors contributed equally to this work. Mitochondrial Lon of Saccharomyces cerevisiae is a ring-shaped protease with seven flexible subunits. Proc. Natl. Acad. Sci. USA 96 (1999) 6787-6790