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Gellerich F.N.,Leibniz Institute for Neurobiology Magdeburg | Gellerich F.N.,Otto Von Guericke University of Magdeburg | Gizatullina Z.,Leibniz Institute for Neurobiology Magdeburg | Gainutdinov T.,Academy of Science of the Republic Tatarstan | And 5 more authors.

This review focuses on problems of the intracellular regulation of mitochondrial function in the brain via the (i) supply of mitochondria with ADP by means of ADP shuttles and channels and (ii) the Ca2+ control of mitochondrial substrate supply. The permeability of the mitochondrial outer membrane for adenine nucleotides is low. Therefore rate dependent concentration gradients exist between the mitochondrial intermembrane space and the cytosol. The existence of dynamic ADP gradients is an important precondition for the functioning of ADP shuttles, for example CrP-shuttle. Cr at mM concentrations instead of ADP diffuses from the cytosol through the porin pores into the intermembrane space. The CrP-shuttle isoenzymes work in different directions which requires different metabolite concentrations mainly caused by dynamic ADP compartmentation. The ADP shuttle mechanisms alone cannot explain the load dependent changes in mitochondrial energization, and a complete model of mitochondrial regulation have to account the Ca2+-dependent substrate supply too. According to the old paradigmatic view, Ca2+ cyt taken up by the mitochondrial Ca2+ uniporter activates dehydrogenases within the matrix. However, recently it was found that Ca 2+ cyt at low nM concentrations exclusively activates the state 3 respiration via aralar, the mitochondrial glutamate/aspartate carrier. At higher Ca2+ cyt (> 500 nM), brain mitochondria take up Ca2+ for activation of substrate oxidation rates. Since brain mitochondrial pyruvate oxidation is only slightly influenced by Ca 2+ cyt, it was proposed that the cytosolic formation of pyruvate from its precursors is tightly controlled by the Ca 2+dependent malate/aspartate shuttle. At low (50-100 nM) Ca 2+ cyt the pyruvate formation is suppressed, providing a substrate limitation control in neurons. This so called "gas pedal" mechanism explains why the energy metabolism of neurons in the nucleus suprachiasmaticus could be down-regulated at night but activated at day as a basis for the circadian changes in Ca2+ cyt. It also could explain the energetic disadvantages caused by altered Ca2+ cyt at mitochondrial diseases and neurodegeneration. © 2013 IUBMB Life, 65(3):180-190, 2013 Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc. Source

Gizatullina Z.Z.,Leibniz Institute for Neurobiology | Gizatullina Z.Z.,KeyNeurotek Pharmaceuticals AG | Gaynutdinov T.M.,Academy of Science of the Republic Tatarstan | Svoboda H.,KeyNeurotek Pharmaceuticals AG | And 12 more authors.

We studied the functional properties of isolated brain mitochondria (BM) prepared from total rat brain (BMtotal) or from cerebral subregions under basal and Ca2+ overload conditions in order to evaluate the effects of cyclosporine A (CsA) in a regiospecific manner. CsA-induced effects were compared with those of two derivatives-the none-immunosuppressive [O-(NH2(CH2)5NHC(O)CH2)-D-Ser]8-CsA (Cs9) and its congener, the immunosuppressive [D-Ser]8-CsA. The glutamate/malate-dependent state 3 respiration of mitochondria (state 3glu/mal) differed in region-specific manner (cortex > striatum = cerebellum > substantia nigra > hippocampus), but was significantly increased by 1μM CsA (+21±5%) in all regions. Ca2+ overload induced by addition of 20μM Ca2+ caused a significant decrease of state 3glu/mal (-45 to -55%) which was almost completely prevented in the presence of 1μM CsA, 1μM Cs9 or 1μM [D-Ser]8-CsA. Mitochondrial Ca2+ accumulation thresholds linked to permeability transition (PT) as well as the rate and completeness of mitochondrial Ca2+ accumulation differed between different brain regions. For the first time, we provide a detailed, regiospecific analysis of Ca2+-dependent properties of brain mitochondria. Regardless of their immunosuppressive impact, CsA and its analogues improved mitochondrial functional properties under control conditions. They also preserved brain mitochondria against Ca2+ overload-mediated PT and functional impairments. Since Cs9 does not mediate immunosuppression, it might be used as a more specific PT inhibitor than CsA. © 2010 Elsevier B.V. and Mitochondria Research Society. Source

Gellerich F.N.,Leibniz Institute for Neurobiology | Gellerich F.N.,Otto Von Guericke University of Magdeburg | Gellerich F.N.,KeyNeurotek Pharmaceuticals AG | Gizatullina Z.,Leibniz Institute for Neurobiology | And 12 more authors.
Biochemical Journal

The glutamate-dependent respiration of isolated BM (brain mitochondria) is regulated by Ca 2+ cyt (cytosolic Ca 2+ ) (S 0.5 =225±22 nM) through its effects on aralar. We now also demonstrate that the α-glycerophosphate-dependent respiration is controlled by Ca 2+ cyt (S 0.5 =60±10 nM). At higher Ca 2+ cyt (>600 nM), BM accumulate Ca 2+ which enhances the rate of intramitochondrial dehydrogenases. The Ca 2+ - induced increments of state 3 respiration decrease with substrate in the order glutamate>α- oxoglutarate>isocitrate>α- glycerophosphate>pyruvate. Whereas the oxidation of pyruvate is only slightly influenced by Ca 2+ cyt, we show that the formation of pyruvate is tightly controlled by Ca 2+ cyt. Through its common substrate couple NADH/NAD + , the formation of pyruvate by LDH (lactate dehydrogenase) is linked to the MAS (malate-aspartate shuttle) with aralar as a central component. A rise in Ca 2+ cyt in a reconstituted system consisting of BM, cytosolic enzymes of MAS and LDH causes an up to 5-fold enhancement of OXPHOS (oxidative phosphorylation) rates that is due to an increased substrate supply, acting in a manner similar to a 'gas pedal'. In contrast, Ca 2+ mit (intramitochondrial Ca 2+ ) regulates the oxidation rates of substrates which are present within the mitochondrial matrix. We postulate that Ca 2+ cyt is a key factor in adjusting the mitochondrial energization to the requirements of intact neurons. ©The Authors Journal compilation © 2012 Biochemical Society. Source

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