Kalervo Hiltunen

 

Short CV

Mitochondrial lipid metabolism and regulation of cell function

Our research work will be carried out at the Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, and it is the basic research in lipid biology and biochemistry with the tight link to biomedicine and nutrition. The work includes two interlinked focus areas:

  1. Mitochondrial lipid metabolism and regulation
  2. Physiological role of mitochondrial fatty acid synthesis

The subprojects require a deep understanding of lipid- and protein biochemistry, and address the regulatory interplay between cells and intracellular organelles and metabolic compartmentalization in a physiological context. Different model organisms (yeast, mouse, rat and human) and technical approaches (e.g. protein chemistry, molecular genetics, molecular biology, membrane electrophysiology and structural biology) will be used to address particular biological questions.

Background and Significance

Cell organelles are key players in maintaining of physiological homeostasis of cells and organs. The scope how we gather interplay of metabolic control mechanism in cellular setting has undergone a major revision during the last years. In reference to human health, several inherited diseases are known that are caused by malfunction of cell organelles and they contribute also to pathophysiology of almost all acquired human diseases.

A large number of studies have demonstrated significance of the polyunsaturated fatty acids (PUFAs) for human health. In spite of international research and progress many key aspects on molecular mechanisms translating PUFA sensing into changes in gene expression have remained largely enigmatic. As one approach to shed light on the responses of animals to PUFAs, we have generated a mouse line defective in mitochondrial dienoyl-CoA reductase (Decr), which is a key enzyme required for mitochondrial break-down of PUFAs, with an outcome of accumulation of PUFAs in these mice. The Decr null mutant mice are asymptomatic until exposed to fasting, during which they switch on ketogenesis, but simultaneously develop hypoglycemia and the mice do not tolerate cold. These observations highlight the necessity of Decr and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state.

Major recent discoveries on many previously unknown or neglected aspects of mitochondrial physiology and biochemistry have brought these organelles into the spotlight of research interest in the field of life sciences. These discoveries include mechanisms of mitochondrial fusion and fission events, linkage of mitochondrial fusion events to the progression of the cell cycle, mitochondrial-nuclear crosstalk, mitochondrial DNA replication, transcription and translation, iron-sulfur cluster biogenesis, aging, mitophagy, the role of mitochondria in apoptosis and mitochondrial inheritance as a tool for the tracking of maternal lineages. Among the recently recognized features of mitochondrial functions is their ability to synthesize fatty acids in an acyl carrier protein (ACP)-dependent manner. The failure in mitochondrial fatty acid synthesis (mtFAS) in yeast leads to loss of mitochondrial respiratory function and to defective mitochondrial RNA processing and there is mounting evidence pointing to an essential function of mtFAS for well-being of mammals. Recently pieces of evidences have been emerging which link the mtFAS pathway to diseases in mammals. Our report on the development of cardiomyopathy in mice overexpressing Etr1 established a possible connection between mtFAS and heart disease. It has been recently demonstrated that compromised mtFAS results in dysfunction of mitochondrial respiration and accelerated aging in genetically modified mice. Furthermore, compromising protein lipoylation and respiratory complex I result in cell death in cultured human embryonic kidney 293T cells upon shutdown of ACP.  The expression of 17βHSD8, encoding a subunit in 3-ketoacyl reductase (KAR1), was severely repressed in kidney and liver.

Figure 1. Mitochondrial fatty acid synthesis and its interaction with mitochondrial functions

Goals

The research will focus on mitochondrial fatty acid synthesis (mtFAS), that has very recently recognized to participate in many ways to mitochondrial cellular function including cellular lipoic acid metabolism, mitochondrial RNA processing, protein synthesis in mitochondrial ribosomes, respiratory chain complex assembly and Fe-S-cluster synthesis. The proposed work knits together an unexpected triangle of mitochondrial lipids, flow of information on cellular metabolic state to the mitochondrial genome and maintenance of respiratory-competent mitochondrial populations in mammals. The driving forces of the work are open fundamental questions and very recent identification of diseases in humans due to dysfunction of this pathway.. Specifically, our research will address the following subprojects:

  1. Organization of mitochondrial fatty acid synthesis systems
  2. Pathophysiology of inborn errors of mitochondrial fatty acid synthesis
  3. Mitochondrial fatty acid synthesis as regulator of intermediary metabolism and mitochondrial biogenesis

Depending on the scientific questions, we used as model mice, yeast strains with perturbations in mitochondrial lipid metabolism, in vitro reconstituted systems, protein engineering and analysis mtFAS defective human cell lines, and employ genetic, physiological, biochemical, biophysical and bioimaging approaches to characterize signaling pathways that respond to lipid metabolic cues.

Selected Publications

Pietikäinen, L.P., Rahman, M.T., Hiltunen,J.K., Dieckmann, C.L. & Kastaniotis, A. (2021) Genetic dissection of the mitochondrial lopylation pathway in yeast. BMC Biology. 19:14. doi.org/ doi.org/10.1186/s12915-021-00951-3

Sridhar, S,, Schmitz, W., Hiltunen, J.K., Venkatesan, R., Bergmann, U., Kiema, T.R., & Wierenga, R,K. (2020) Crystallographic binding studies of rat peroxisomal multifunctional enzyme type 1 with 3-ketodecanoyl-CoA: capturing active and inactive states of its hydratase and dehydrogenase catalytic sites. Acta Crystallogr D Struct Biol. 76(Pt 12):1256-1269. doi: 10.1107/S2059798320013819

Kangasniemi, M.H., Haverinen, A., Luiro, K., Hiltunen, J.K., Komsi, E.K., Arffman, R.K., Heikinheimo, O., Tapanainen, J.S., Piltonen, T.T. (2020) Estradiol Valerate in COC Has More Favorable Inflammatory Profile Than Synthetic Ethinyl Estradiol: A Randomized Trial. J. Clin. Endocrinol. Metab. 105.dgaa186. doi: 10.1210/clinem/dgaa186

Masud, A.J., Kastaniotis, A.J., Rahman, M.T., Autio, K.J. & Hiltunen, J.K. (2019) Mitochondrial acyl carrier protein (ACP) at the interface of metabolic state sensing and mitochondrial function. BBA-Mol. Cell Research. 1866, 118540. doi: 10.1016/j.bbamcr.2019.118540

Mäkelä, A., Hohtola, E, Miinalainen, I.J,. Autio, J. Schmitz, W., Niemi, K.J., Hiltunen, J.K & Autio, K.J. (2019) Mitochondrial 2,4-dienoyl-CoA reductase (Decr) deficiency and impairment of thermogenesis in mouse brown adipose tissue. Sci Rep. 9, 12038 doi.org/10.1038/s41598-019-48562-x

Hiltunen, J.K., Kastaniotis, A.J., Autio, K.J., Jiang, G.,1,  Chen, Z. & Glumoff, T. (2018) 17B-Hydroxysteroid dehydrogenases as acyl thioester metabolizing enzymes. Mol. Cell Endocrin. doi: 10.1016/j.mce.2018.11.01

Nair, R.R., Koivisto, H., Jokivarsi, K., Miinalainen, I.J., Autio, K.J., Manninen, A., Poutiainen, P., Tanila, H., Hiltunen, J.K. & Kastaniotis, A.J. (2018) Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice. J. Neurosci. 38, 9781-9800

Nair, R.R., Kerätär, J.M., Autio, K.J., Masud, A.J., Finnilä, M.A.J., Autio-Harmainen, H.I., Miinalainen, I.J. Nieminen, P.A., Hiltunen, J.K., Kastaniotis, A.J. (2017) Genetic medifications of Mecr reveal a role for mitochondrial 2-enoyl-CoA/ACP reductase in placental development in mice. Human Mol. Genetic, 26, 2104-2117

Kastaniotis, A.J., Autio, K.J., Kerätär, J.M,, Monteuuis, G., Mäkelä, A.M., Nair, R.R., Pietikäinen, L.P., Shvetsova, A., Chen, Z. & Hiltunen, J.K. (2017) Mitochondrial fatty acid synthesis, fatty acids and mitochondrial physiology. Biochim Biophys Acta. 1862, 39-48

Shvetsova, A., Mennerich, D., Kerätär, J. M. Hiltunen, J.K., & Kietzmann, T. (2017) Non-electron transfer chain mitochondrial defects differently regulate HIF-1α degradation and transcription. Redox Biol. 12, 1052-1061

Jenkins, B.J., Seyssel, K., Chiu, S., Pan, P.H., Lin, S.Y., Stanley, E., Ament, Z., West, J.A., Summerhill, K., Griffin, J.L., Vetter, W., Autio, K.J., Hiltunen, K., Hazebrouck, S., Stepankova, R., Chen, C.J,, Alligier, M., Laville, M., Moore, M., Kraft, G., Cherrington, A., King, S., Krauss, R.M,, de Schryver, E., Van Veldhoven, P.P., Ronis, M. &Koulman, A. (2017) Odd Chain Fatty Acids; New Insights of the Relationship Between the Gut Microbiota, Dietary Intake, Biosynthesis and Glucose Intolerance. Sci. Rep. 7, 44845, doi: 10.1038/srep44845

Heimer, G., Kerätär, J.M,, Riley, L.G., Balasubramaniam, S., Eyal, E., Pietikäinen, L.P., Hiltunen, J.K., Marek-Yagel, D., Hamada, J., Gregory, A., Rogers, C., Hogarth, P., Nance, M.A., Shalva, N., Veber, A., Tzadok, M., Nissenkorn, A., Tonduti, D., Renaldo, F.; University of Washington Center for Mendelian Genomics., Kraoua, I., Panteghini, C., Valletta, L., Garavaglia, B., Cowley, M.J., Gayevskiy, V., Roscioli, T., Silberstein JM, Hoffmann C, Raas-Rothschild A, Tiranti V, Anikster Y, Christodoulou J., Kastaniotis, A.J., Ben-Zeev, B. & Hayflick, S.J.. (2016) MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder. Am. J. Hum. Genet. 99, 1229-1224

Jokipii-Lukkari, S., Kastaniotis A.J., Nymalm, Y., Sundström, R., Kallio, P.T., Fagerstedt, K.V., Salminen, T.A., Hiltunen, J.K. &  Häggman,  H. (2016) Coexpression of hybrid aspen PttHb1 and ferredoxin NADP+ oxidoreductase alleviates nitric oxide sensitivity in vivo. Plant Sci. 247, 138-149

Kettunen, K.M., Karikoski, R., Hämäläinen, R.H., Toivonen, T.T., Antonenkov, V.D., Kulesskaya, N., Voikar, V., Holtta-Vuori, M., Ikonen, E., Sainio, K., Jalanko, A., Karlberg, S., Karlberg, N., Lipsanen-Nyman, M., Toppari, J.,  Jauhiainen, M.,  Hiltunen, J.K., Jalanko, H. & Lehesjoki, A.-E. (2016) Trim37-deficient Mice Recapitulate Several Features of the Multi-organ Disorder Mulibrey Nanism. BiolOpen. 5, 584-595

Mindthoff, S., Grunau, S., Steinfort, L., Girzalsky, W., Hiltunen, J. K., Erdmann, R. & Antonenkov, V.D.  (2016) Peroxisomal Pex11 is a pore-forming protein homologous to TRPM channels. BBA - Molecular Cell Research, 1863, 271-283

Liu P, Wang X, Hiltunen K, Chen Z. (2015) Controllable Drug Release System in Living Cells Triggered by Enzyme-Substrate Recognition. ACS Appl. Mater. Interfaces. 7, 26811-26818

Selkälä, E.M., Nair, R.R., Schmitz, W., Kvist, A.-P., Baes, M.,  Hiltunen, J.K. & Autio, K.J. (2015) Phytol is lethal for Amacr-deficient mice BBA – Molec. Cell Biol. Lipids 1851, 1394-13405

Liu, P.C., Wang, H., Hiltunen, J.K., Chen, Z.J., Shen, J.C., (2015) Cross-Linked Proteins with Gold Nanoclusters: A Dual-Purpose pH-Responsive Material for Controllable Cell Imaging and Antibiotic Delivery  Part. Part. Syst. Char. 32, 749-755

Battersby, B. J. (2015) Quantitative changes in Gimap3 and Gimap5 expression modify mitochondrial DNA segregation in mice. Genetics, 200, 221-235

Antonenkov, V.D., Isomursu, A. Mennerich, D., Vapola, M.H., Weiher, H., Kietzmann, T. & Hiltunen, J. K. (2015) The human mitochondrial mtDNA depletion syndrome gene Mpv17 encodes a sensitive to mitochondrial conditions non-selective channel that modulates membrane protential. J. Biol. Chem. 290, 13840-13861

Venkatesan, R., Sah-Teli, S.K., Awoniyi, L.O., Jiang, G., Prus, P., Kastaniotis, A.J., Hiltunen, J.K., Wierenga, R.K. & Chen, Z. (2014) Insight into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase. Nature Comm. DOI: 10.1038/ncomms5805

 

Last updated: 30.4.2021