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Neurochemical Laboratory


Prof. Dr. med. S. Vielhaber


Dr. rer. nat. Grazyna Debska-Vielhaber
PD Dr. rer. nat. habil. Frank N. Gellerich
Dr. rer. nat. habil. Zemfira Gizatullina
Kerstin Kaiser (MTAL)
Jeannette Witzke (MTAL)

What do we offer:

While neurons may be lost for a variety of reasons during the course of neurodegenerative diseases, the final pathway to neuronal death often entails a comparable set of processes. This final pathway has been termed "programed cell death" or "apoptosis." It is characterized by a well-defi ned cascade of biochemical reactions that in part involve the mitochondria, which are the `power plants´ of cells. In Magdeburg, there is a long history of expertise in mitochondrial research. In the Neurochemistry Lab of the Dept. of Neurology we are addressing three major questions:

  • In which of the neurodegenerative diseases do the pathophysiological mechanisms involve the mitochondria, and what is the nature of this involvement?
  • How can basic research improve our insight into mitochondrial functions?
  • Can a better understanding of mitochondrial function lead to new approaches to the treatment of neurodegenerative diseases?

Research Activities

Basic research by F. N. Gellerich has revealed a new calcium-dependent mechanism that activates mitochondrial metabolism. He has dubbed this mechanism the `mitochondrial gas pedal.´ This mechanism regulates how mitochondria are supplied with pyruvate, their primary substrate. It operates in all tissues, but is particularly important in neurons because in neurons mitochondria have no other substrate available (Fig. 1).

Moderate changes in the available intracellular free Ca2+ can alter the substrate supply to the mitochondria by as much as 500%. In contrast to earlier views, Ca2+does not have to be taken up by the organelle to induce activity. Instead, it activates the glutamate/aspartate carrier (aralar) via a regulating binding site for Ca2+ at the mitochondrial surface. Aralar is the Ca2+-modulated part of the malate-aspartate shuttle (MAS). Together with the oxidative reactions of glycolysis it generates pyruvate. The mitochondrial gas pedal regulates the mitochondrial pyruvate supply in the normal concentration range of 50 to 400 nM. This is the precise range of values over which the concentration of Ca2+ changes in neurons of the N. suprachiasmaticus during the course of diurnal rhythmicity (Colwell, C.S., 2000) (Fig.2). Accordingly, in at least some of the neurons of our brain a signifi cant mitochondrial substrate limitation appears at night due to a reduced Ca2+ concentration, and seems to be connected to the resting state during sleep. As no pyruvate can be produced under these reduced Ca2+ conditions, its concentration decreases and the mitochondria become de-energized, i.e., switched off like a hotplate. The advantage of this de-energized state is that the mitochondria are unable to produce reactive oxygen species [ROS] that could cause damage or aging. This mechanism explains how the increased cytosolic Ca2+-concentrations previously demonstrated during neurodegeneration may contribute to mitochondrial damage by increasing ROS production. (see Fig.2).
Interestingly, the MAS-connected gas pedal does not operate in astrocytes. We found that this is a consequence of a difference in enzyme mechanisms. The functional properties of mitochondria from astrocytes are therefore different from those found in neurons. Consequently, there are differences in the mitochondria isolated from brain regions with different levels of neurons and astrocytes. This causes characteristic changes when neurons are lost during neurodegeneration. Thus, our results allow a new interpretation of the functional changes we have found in different models of neurodegeneration (ALS-mouse, Parkinson-rat, Huntington-rat). Severe acute and genetic defects of the mitochondrial cytochrome c oxidase are lethal. The application of an alternative cytochrome oxidase (AOX) in the cells of an affected region is a possible therapeutic option. In cooperation with Marten Szibor from the Max-Planck-Institut Bad Nauheim and the research group Molecular Neurology of the University of Helsinki, Finland, we studied AOX-containing mitochondria from the AOX mouse. We found that the oxidative phosphorylation (OXPHOS) of AOX-mitochondria only changed a little when complex I-related substrates were employed. In contrast, only non-phosphorylating respiration occurred when succinate was used as substrate. Since succinate is not a mitochondrial in vivo-substrate the non-phosphorylating respiration will not occur in intact cells which agrees with the observation that the AOX animals appear to be healthy. We can show that even AOX mitochondria in which COX is completely inhibited are capable of using OXPHOS though with reduced effi ciency. Therefore, introduction of AOX into ischemic brain regions could be an option for re-vitalizing these regions. Our results indicate that AOX is connected to complex II rather than to the other complexes in the respiratory chain.
The permeability transition pore (PTP), a large pore extending across the inner mitochondrial membrane, plays a key role in apoptosis. Some years ago, it was hoped that the blockade of this pore by the antibiotic minocycline (a tetracycline) could suppress apoptosis. However, following successful in vitro- and in vivo-experiments, a large clinical study on patients suffering from amyotrophic lateral sclerosis (ALS) had to be terminated because minocycline caused some of the patients to become worse. In cooperation with Profs. P. Schönfeld, D. Siemen, and L. Wojtczak, we were able to show that minocycline binds magnesium ions diluted inside the mitochondria and thereby opens chloride and potassium channels in the inner mitochondrial membrane. This can explain the detrimental effect on the patient. In addition, minocycline causes mitochondria to become permeable for NAD+ and cytochrome c, thus impairing the function of the respiratory chain. Thus, minocycline does not appear to be suitable as a neuroprotective agent. Matrix soluble cyclophiline D attaches to the PTP on the inside of the inner mitochondrial membrane. It is able to modulate the pore because the PTP inhibitor cyclosporine A (CsA) binds to it. Cyclophiline D also is able to infl uence PTP binding of stimulating phosphate ions. Interestingly, CsA can also block the PTP in a cyclophiline D knock-out mouse, though with a 1,500 fold lower sensitivity. We studied this effect on liver and brain mitochondria in more detail than has been done previously, and compared binding in knock-out mice with binding in wild-type mice. It is possible to modulate the PTP by regulating another ion channel. An open calcium-sensitive potassium channel (K(Ca)) keeps the PTP closed, while a closed K(Ca) channel opens the PTP. Thus, control of the K(Ca) represents another interesting approach to the protection of neurons. In our lab in Magdeburg, P. Bednarczyk and D. Siemen have shown in singlechannel experiments employing the patch-clamp-technique that a K(Ca) can be inhibited by respiratory chain substrates such as NADH, succinate and glutamate/malate. This effect can be cancelled by several inhibitors of the respiratory chain. This is the fi rst direct proof of a structural and functional coupling of an ion channel to the respiratory chain. These results gain further signifi cance because we have also shown in our lab that the proapoptotic protein Bax can inhibit the K(Ca) and the antiapoptotic Bcl-xL inhibits the effect of Bax on the K(Ca) (cooperation with E. Gulbins). Furthermore, Bcl-xL can inhibit the PTP itself. This result underlines the role of both ion channels in apoptosis and, therefore, their possible value for neuroprotective interventions.

Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases:

Mitochondria play a central role in ageing-related neurodegenerative diseases. They are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. Thus, therapies that target basic mitochondrial processes, such as energy metabolism or free-radical generation, hold great promise for the treatment of these diseases. Sporadic and familial amyotrophic lateral sclerosis (sALS, fALS) is characterized clinically by progressive motor neuron loss with muscle wasting and spasticity, and constitutes a promising model disease for the study the mitochondrial contribution to cell death. We and other groups have demonstrated that in cases of ALS there is mitochondrial dysfunction in both the muscle tissue and at the spinal cord level. To verify a putative impairment of mitochondrial function in the extra- neuronal tissue of patients with sporadic or familial ALS, the oxygen consumption (respiration rate) of human skin fibroblasts was measured using high resolution respirometry. In the case of both sALS and fALS, defects in mitochondrial function were detected. Specifically, the activity of the respiratory chain complex I seems to be reduced. In addition, we assessed putative benefits of antioxidative agents on mitochondrial function. Interestingly, the antioxidants Trolox and CoQ10 were found to ameliorate the functional impairment of mitochondria, most probably by a direct antioxidative and membrane-stabilizing action. No mitochondrial DNA depletion (differences in mtDNA copy number or common deletion level) could be detected in the fibroblasts of ALS patients relative to healthy controls. This stands in contrast to some other neurodegenerative diseases such as Charcot-Marie-Tooth neuropathy type 2A ( CMT2A ), which is associated with heterozygous mutations in the mitochondrial protein mitofusin 2 (Mfn2) that alter mitochondrial oxidative phosphorylation by affecting mtDNA replication. This underlines the heterogeneity of mitochondrial mediated cell death. Our results support the viewpoint that mitochondrial impairments are detectable in extraneuronal tissues of patients with ALS and other chronic neurogenic atrophies. Fibroblasts may serve as a relatively easily accessible readout system to test the anti-oxidative properties of specific substances in ALS. Further work is addressing the role of mitochondria in the context of calcium homeostasis, in order to better understand the underlying biochemical mechanisms and to consider further therapeutic options.

Figure 1

The mitochondrial gas pedal regulates the mitochondrial pyruvate supply in the normal concentration range of 50 to 400 nM Ca2+cyt. Within this range, enhanced activation of the brain mitochondria can be changed by as much as 500%. Only at Ca2+cyt concentrations >400 nM mitochondria can take up Ca2+ leading to activation of the intramitochondrial dehydrogenases. Pyruvate consumption is thereby increased by only 20%. The cytosolic enzymes required for pyruvate supply, GAPDH (glyceraldehyde-3-phosphate dehydrogenase), LDH (lactate dehydrogenase) and α-GPDH (α-glycerol- 3-phosphate dehydrogenase), need NAD+ and deliver NADH, regenerated by the malate-aspartate shuttle [MAS]. The MAS moves the reduced hydrogen into the mitochondria and is controlled by the cytosolic Ca2+-concentration. At low Ca2+-concentrations MAS is inactive. The already low Ca2+-concentration continues to decline and the mitochondria become de-energized. With rising Ca2+- levels the pyruvate concentration and the degree of activation enhancement is increased.

Figure 2

Hypothetical consequences of diurnal changes in Ca2+-concentration on mitochondrial energization in N. suprachiasmaticus neurons. At night, when cytosolic Ca2+ is low, MAS is inactivated via the regulatory Ca2+-binding site. NAD+ and pyruvate are lowered in cytosol leading to a decrease in NADH and a lowered membrane potential. Consequently, ATP production, and particularly the production of reactive oxygen radicals (ROS) also decline. During daytime, cytosolic Ca2+ is raised, pyruvate production is increased and the mitochondria are fit for work. However, ROS production may be increased, too.


Available Methods

  • Experiments on freshly prepared cells, cultured cells, and homogenates Swelling assays
  • Measurements of mitochondrial membrane potentials
  • Measurement of mitochondrial and intracellular calcium
  • High-resolution respirometry
  • Measurement of single-channel currents at the inner mitochondrial membrane using patch-clamp-techniques
  • Flux control analysis
  • Enzymatic measurements


  • Piotr Bednarczyk Ph.D., Dept. of Biophysics, Warsaw University of Life Science, SWWG, Polen
  • Prof. Dr. Erich Gulbins, Institut für Molekularbiologie (Tumorforschung), Universitätsklinikum Essen
  • Dr. rer. nat. Katrin S. Lindenberg, Experimental Neurology, Center for Clinical Research, Ulm
  • Prof. Dr. rer. nat. Elmar Kirches, Institut für Neuropathologie, Magdeburg
  • Prof. Bernard Korzeniewski, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Polen
  • Prof. Wolfram Kunz Ph.D. Abt. Neurochemie, Klinik für Epileptologie und Life & Brain Center Universitätsklinikum Bonn
  • Prof. Jeffery Molkentin, Ph. D., Dept. of Pediatrics, University of Cincinnati, USA
  • Anna Olszewska, Ph.D., Nencki Institute of Experimental Biology, Academy of Science, Warschau, Polen
  • Prof. Dr. Dr. Jens Pahnke, German Center for Neurodegenerative Diseases (DZNE), Magdeburg
  • Dr. rer. nat. habil. Kalju Paju Institute of Biomedicine and Translational Medicine, University of Tartu, Estland
  • Prof. Suhel Parvez Ph.D., Dept. of Toxicology, Hamdard Universität, Neu Delhi, Indien
  • Prof. Dr. Peter Schönfeld, Institut für Biochemie und Zellbiologie, OvG-Universität, Magdeburg
  • Prof. Joanna Sczepanowska, Ph.D., Nencki Institute of Experimental Biology, Academy of Science, Warschau, Polen
  • Cand. med. Joosep Seppet, Institute of General and Molecular Pathology, Faculty of Medicine, University of Tartu, Estland
  • Prof. Adam Szewczyk Ph.D., Direktor des Nencki Institute of Experimental Biology, Academy of Science, Warschau, Polen
  • Dr. med. Marten Szibor, Research Program of Molecular Neurology University of HELSINKI, Finnland
  • Prof. Lech Wojtczak Ph. D., Nencki Institute of Experimental Biology, Academy of Science, Warschau, Polen

Selected References

Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-α. Distelmaier. F, Valsecchi F, Liemburg-Apers DC, Lebiedzinska M, Rodenburg RJ, Heil S, Keijer J, Fransen J, Imamura H, Danhauser K, Seibt A, Viollet B, Gellerich FN, Smeitink JA, Wieckowski MR, Willems PH, Koopman WJ. Biochim Biophys Acta. 2015 Mar;1852(3):529-40. doi: 10.1016/j.bbadis.2014.12.012. Epub 2014 Dec 20. PMID: 25536029.

Knockout of cyclophilin D in Ppif-/- mice increases stability of brain mitochondria against Ca2+ stress. Gainutdinov T, Molkentin JD, Siemen D, Ziemer M, Debska-Vielhaber G, Vielhaber S, Gizatullina Z, Orynbayeva Z, Gellerich FN. Arch Biochem Biophys. 2015 May 29. pii: S0003-9861(15)00255-6. doi: 10.1016/

6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson‘s disease: respirometric, histological, and behavioral analyses. Kupsch A, Schmidt W, Gizatullina Z, Debska-Vielhaber G, Voges J, Striggow F, Panther P, Schwegler H, Heinze HJ, Vielhaber S, Gellerich FN. J Neural Transm. 2014 Oct;121(10):1245-57. doi: 10.1007/s00702-014-1185- 3. Epub 2014 Mar 14. PMID: 24627045

Bednarczyk P, Wieckowski MR, Broszkiewicz M, Skowronek K, Siemen D, Szewczyk A. Putative Structural and Functional Coupling of the Mitochondrial BKCa Channel to the Respiratory Chain. PLoS One. 2013 8:e68125. Imp.-Fact.: 4,244 Gellerich FN, Gizatullina Z, Gainutdinov T, Muth K, Seppet E, Orynbayeva Z, Vielhaber S. The control of brain mitochondrial energization by cytosolic calcium: the mitochondrial gas pedal. IUBMB Life. 2013 65(3):180-90. doi: 10.1002/iub.1131. Epub 2013 Feb 8. Imp.-Fact.: 3,508

Roosimaa M, Põdramägi T, Kadaja L, Ruusalepp A, Paju K, Puhke R, Eimre M, Orlova E, Piirsoo A, Peet N, Gellerich FN, Seppet E. Dilation of human atria: increased diffusion restrictions for ADP, overexpression of hexokinase 2 and its coupling to oxidative phosphorylation in cardiomyocytes. Mitochondrion. 2013 13(5):399-409. doi: 10.1016/j.mito.2012.12.005. Epub 2012 Dec 23. Imp.-Fact.: 4,025

Schönfeld P, Siemen D, Kreutzmann P, Franz C, Wojtczak L. Interaction of the antibiotic minocycline with liver mitochondria - Role of membrane permeabilisation in the impairment of respiration. FEBS J. 2013 doi: 10.1111/febs.12563. Imp.-Fact.: 4,250 Siemen D, Ziemer M. What is the nature of the mitochondrial permeability transition pore and what is it not? IUBMB Life 2013 65:255-262. Imp.-Fact.: 3,508

Trumbeckaite S, Gizatullina Z, Arandarcikaite O, Röhnert P, Vielhaber S, Malesevic M, Fischer G, Seppet E, Striggow F, Gellerich FN. Oxygen glucose deprivation causes mitochondrial dysfunction in cultivated rat hippocampal slices: protective effects of CsA, its immunosuppressive congener [D-Ser](8)CsA, the novel non-immunosuppressive cyclosporin derivative Cs9, and the NMDA receptor antagonist MK 801. Mitochondrion. 2013 13(5):539-47. doi: 10.1016/j.mito.2012.07.110. Epub 2012 Jul 21. Imp.-Fact.: 4,025

Vielhaber S, Debska-Vielhaber G, Peeva V, Schoeler S, Kudin AP, Minin I, Schreiber S, Dengler R, Kollewe K, Zuschratter W, Kornblum C, Zsurka G, Kunz WS. Mitofusin 2 mutations affect mitochondrial function by mitochondrial DNA depletion. Acta Neuropathol. 2013 125(2):245-56. doi: 10.1007/s00401-012-1036-y. Epub 2012 Aug 28. Imp.-Fact.: 9,734

Gellerich FN, Gizatullina Z, Trumbekaite S, Korzeniewski B, Gaynutdinov T, Seppet E, Vielhaber S, Heinze HJ, Striggow F. Cytosolic Ca2+ regulates the energization of isolated brain mitochondria by formation of pyruvate through the malate-aspartate shuttle. Biochem J. 2012 443:747-55. doi: 10.1042/BJ20110765. Imp.-Fact.: 4,654

Thiede, A., Gellerich, F.N., Schönfeld, P., Siemen, D. Complex effects of 17β-estradiol on mitochondrial function. Biochim. Biophys. Acta - Bioenergetics 2012 1817:1747-1753. Imp.-Fact.: 4,624

Cheng, Y., Gulbins, E., Siemen, D. Activation of the permeability transition pore by Bax via inhibition of the mitochondrial BK channel. Cell. Physiol. Biochem. 2011 27:191-200. Imp.-Fact.: 3,415

Gizatullina ZZ, Gaynutdinov TM, Svoboda H, Jerzembek D, Knabe A, Vielhaber S, Malesevic M, Heinze HJ, Fischer G, Striggow F, Gellerich FN. Effects of cyclosporine A and its immunosuppressive or non-immunosuppressive derivatives [D-Ser]8- CsA and Cs9 on mitochondria from different brain regions. Mitochondrion. 2011 11(3):421-9. doi: 10.1016/j.mito.2010.12.012. Epub 2010 Dec 16. Imp.-Fact.: 4,025

Niehusmann P, Surges R, von Wrede RD, Elger CE, Wellmer J, Reimann J, Urbach H, Vielhaber S, Bien CG, Kunz WS. Mitochondrial dysfunction due to Leber‘s hereditary optic neuropathy as a cause of visual loss during assessment for epilepsy surgery. Epilepsy Behav. 2011 20(1):38-43. doi: 10.1016/j.yebeh.2010.11.008. Epub 2010 Dec 9. Imp.-Fact.: 1,844

Parvez, S., Winkler-Stuck, K., Hertel, S., Schönfeld, P., Siemen, D. The dopamine-D2-receptor agonist ropinirole dose-dependently blocks the Ca2+-triggered permeability transition of mitochondria. Biochim. Biophys. Acta - Bioenergetics 2010 1797:1245-1250. Imp.-Fact.: 4,624.


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