Peroxisomes and Mitochondria in Lipid Metabolism of a Cell

Background

In living systems, the lipids serve as energy storage, structural molecules of biomembranes, precursors for different hormones, bile acids, several second messengers and modifications of proteins. Lipid metabolism is a compartmentalized process that differs between organs, cell types and also within a cell in different subcellular organelles. Compartmentalized processes require co-ordinated interaction between the cell organelles governed by targeted transport of molecules, signal transduction across biomembranes and special mechanisms for transport of lipids. One way to facilitate the metabolism of lipid carboxylic acids is their esterification to thioesters with CoA or acyl carrier protein (ACP).

The aims of this project:

A multi- and interdisciplinary research effort towards studying lipid biology and the biochemical and structural properties of fatty acyl-thioesters binding proteins has been implemented. Organims have adapted in different ways to the requirements of the lipid metabolism, as shown by the occurrence of, for example, multiple isoforms, organization of multienzyme complexes and regulatory networks at the enzyme as well as the transcriptional level. Within this project there are three important areas of interest:

(i) Mitochondrial fatty acid synthesis and its physiological significance
(ii) Role of peroxisomes and mitochondria in the metabolism of fatty acids and their derivates
(ii) Acyl-thioester binding enzymes in metabolism and their structural enzymology.

These goals will be achieved by:

We are going to achieve the goals by (i) resolving the physiological functions of selected proteins and isozymes of lipid metabolism. This part of the project involves the application of transgenic and knock-out technology using mouse as model organism. Furthermore, we will explore lower eukaryotic micro-organisms as models for studying metabolism in higher eukaryotes; (ii) continuing to identify novel proteins and characterizing them; (iii) providing deep insight into structure-function relationship of fatty acyl-thioester metabolizing enzymes.

Selected publications:

Hiltunen, J.K., Schonauer, M, Autio, K. J., Mittelmeier, T.M., Kastaniotis, A J. & Dieckmann, C. L. (2008) Mitochondrial FAS type II – more than just fatty acids, invited review J. Biol. Chem. doi/10.1074/.jbc.R800068200

Schonauer, M. S., Kastaniotis, A.J., Hiltunen, J.K., & Dieckmann, C. L. (2008) Intersection of RNA Processing and the Type II Fatty Acid Synthesis Pathway in Yeast Mitochondria. Mol. Cell. Biol. 28, 6646-6657

Autio, K.J., Kastaniotis, A.J., Pospiech, H., Miinalainen, I.J., Schonauer, M.S., Dieckmannn, C.L. & Hiltunen, J.K. (2008) An ancient genetic link between vertebrate mitochondrial fatty acid synthesis and RNA processing. FASEB J. 22, 569-578

Ferdinandusse, S., Ylianttila, M. S., Gloerich, J., Koski, M. K., Oostheim, W., Waterham, H. R., Hiltunen, J. K., Wanders, R. J.A. & Glumoff, T. (2006) Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis. Am. J. Hum. Gen., 78, 112-24

Savolainen, K., Bhaumik, P., Schmitz, W., Kotti, T.J., Conzelmann, E., Wierenga, R.K. & Hiltunen, J.K. (2005) α-Methylacyl-CoA racemase from Mycobacterium tuberculosis- mutational and structural characterization of the fold and the active site. J. Biol. Chem., 280, 12611-12620. (“paper of the week”)

Bhaumik, P., Koski, M. K., Glumoff, T., Hiltunen, J. K. & Wierenga, R.K. (2005) Structural biology of the thioester dependent degradation and synthesis of fatty acids. Curr. Opin. Struct. Biol. 15, 1-8

Antonenkov, V.D., Sormunen, R.T. & Hiltunen, J.K. (2004) Rat liver peroxisomal membrane is a permeability barrier for cofactors but not for small molecules in vitro. J. Cell Sci., 117, 5633-5642.

Savolainen, K., Kotti, T.J., Schmitz, W., Savolainen, T., Sormunen, R.T., Ilves, M., Vainio, S.J., Gonzelmann, E. & Hiltunen, J.K. (2004) A mouse model for α-methylacyl-CoA racemase deficiency: adjustment of bile acid synthesis and intolerance to dietary methyl-branched lipids. Hum. Mol. Gen., 13, 955-965.

Ohlmeier, S., Kastaniotis, A.,J. Hiltunen, J.K. & Bergmann U. (2004) The yeast mitochondrial proteome - a study of fermentative and respiratory growth. J. Biol. Chem., 279, 3956 - 3979.

Kastaniotis, A.J., Autio, K.J., Sormunen, R.T. & Hiltunen, J.K. (2004) Htd2p/Yhr067p is a yeast 3-hydroxyacyl-ACP dehydratase essential for mitochondrial essential for mitochondrial function and morphology. Mol. Microbiol., 53, 1407-1421

Hiltunen, J.K., Mursula, A.M., Rottensteiner, H., Wierenga, R., Kastanitois, A..J. & Gurvitz A (2003) The biochemistry of peroxisomal β-oxidation in the yeast Saccaromyces cervisiae. FEMS Microbiol. Rev., 764, 35-64

Research group members:

Kalervo Hiltunen, M.D., Ph.D.
Vasily Antonenkov, Ph.D., visiting professor
Tuomo Glumoff, Ph.D.
Alexander Kastaniotis, Ph.D.
Kaija Autio, M.Sc.
Zhijun Chen, M.Sc.
Hanna Immonen, M.Sc.
Kristian Koski, M.Sc.
Ilkka Miinalainen, M.Sc.
Fumi Okubo, M.Sc.
Francois Pujol, M.Sc.
Aare Rokka, M.Sc.
Kalle Savolainen, M.Sc.
Ana Stojkovic, M.Sc.
Mari Ylianttila, M.Sc.
Samuli Kursu, B.Sc.
Eija Selkälä, B.Sc.
Marika Kamps, lab.assistant
Katri Näppä, lab. assistant