Mitochondrial boundary membrane contact sites in brain: Points of hexokinase and creatine kinase location, and control of Ca2+ transport

Kottke, Matthias; Adam, Volker; Riesinger, I.; Bremm, Gudrun; Bosch, Waltraud; Brdiczka, Dieter; Sandri, Gabriella; Panfili, Enrico

doi:10.1016/0005-2728(88)90111-9

Cited by 116 publications

(50 citation statements)

References 41 publications

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“…Mitochondrial-bound hexokinase was activated at low concentrations of the ionophore (Figure 7), which correlated with the increase in ATP (Figure 6), reaching a maximum at a concentration of 5 µM, and thereafter declined. Hexokinase was shown to bind to porin at the contact sites between the mitochondrial inner and outer membranes (Kottke et al, 1988;Adams et al, 1991;Brdiczka, 1991). The mitochondrially bound hexokinase preferentially utilizes mitochondrially-generated ATP (Gots et al, 1972;Gots and Bessman, 1974;Viitanen et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

“…Glycolysis is controlled by allosteric regulators, among which glucose 1,6-bisphosphate (Glc-1,6-P 2 ) plays a major role in extrahepatic tissues (reviewed in Beitner, 1979Beitner, , 1984Beitner, , 1985Beitner, , 1990, as well as by reversible binding of glycolytic enzymes to cytoskeleton (Arnold and Pette, 1968; reviewed in Clarke et al, 1985;Beitner, 1993;Pagliaro, 1993;Bereiter-Hahn et al, 1997). All glycolytic enzymes bind to cytoskeleton except hexokinase (EC 2.7.1.1), which binds reversibly to mitochondria, where it is linked to oxidative phosphorylation (Gots et al, 1972;Gots and Bessman, 1974;Viitanen et al, 1984;Wilson, 1985;Kottke et al, 1988;Adams et al, 1991). An increase in mitochondrially bound hexokinase was found in tumour cells and it has been suggested that this binding plays an important role in cancer cell metabolism (Arora and Pedersen, 1988;Fanciulli et al, 1994;reviewed in Golshani-Hebroni and Bessman, 1997).…”

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confidence: 99%

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Ca2+-induced changes in energy metabolism and viability of melanoma cells

1999

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Summary Cancer cells are characterized by a high rate of glycolysis, which is their primary energy source. We show here that a rise in intracellular-free calcium ion (Ca 2+ ), induced by Ca 2+ -ionophore A23187, exerted a deleterious effect on glycolysis and viability of B16 melanoma cells. Ca 2+ -ionophore caused a dose-dependent detachment of phosphofructokinase (EC 2.7.1.11), one of the key enzymes of glycolysis, from cytoskeleton. It also induced a decrease in the levels of glucose 1,6-bisphosphate and fructose 1,6-bisphosphate, the two stimulatory signal molecules of glycolysis. All these changes occurred at lower concentrations of the drug than those required to induce a reduction in viability of melanoma cells. We also found that low concentrations of Ca 2+ -ionophore induced an increase in adenosine 5′-triphosphate (ATP), which most probably resulted from the increase in mitochondrial-bound hexokinase, which reflects a defence mechanism. This mechanism can no longer operate at high concentrations of the Ca 2+ -ionophore, which causes a decrease in mitochondrial and cytosolic hexokinase, leading to a drastic fall in ATP and melanoma cell death. The present results suggest that drugs which are capable of inducing accumulation of intracellular-free Ca 2+ in melanoma cells would cause a reduction in energy-producing systems, leading to melanoma cell death.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Ca2+-induced changes in energy metabolism and viability of melanoma cells

1999

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“…It has long been known that such MIM-MOM contact sites are enriched in NDPK and CL. [46][47][48] On the other hand, in healthy mitochondria, NME4/NDPK-D is mainly bound to MIM only and is NDP kinase-active ( Figure 1, left part). Thus, ΔΨ-dependent regulation of CL-triggered mitophagy is mediated by a switch between these two different NME4/NDPK-D topologies (for details see legend to Figure 1 and recent reviews 12,13,38 ).…”

Section: Nme4/ndpk-d In CL Signalingmentioning

confidence: 99%

NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

Schlattner

Tokarska‐Schlattner

Epand

et al. 2018

Laboratory Investigation

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Mitophagy is an emerging paradigm for mitochondrial quality control and cell homeostasis. Dysregulation of mitophagy can lead to human pathologies such as neurodegenerative disorders and contributes to the aging process. Complex protein signaling cascades have been described that regulate mitophagy. We have identified a novel lipid signaling pathway that involves the phospholipid cardiolipin (CL). CL is synthesized and normally confined at the inner mitochondrial membrane. However, upon a mitophagic trigger, ie, collapse of the inner membrane potential, CL is rapidly externalized to the mitochondrial surface with the assistance of the hexameric nucleoside diphosphate kinase D (NME4, NDPK-D, or NM23-H4). In addition to its NDP kinase activity, NME4/NDPK-D shows intermembrane phospholipid transfer activity in vitro and in cellular systems, which relies on NME4/NDPK-D interaction with CL, CL-dependent crosslinking of inner and outer mitochondrial membranes by symmetrical, hexameric NME4/NDPK-D, and a putative NME4/NDPK-Dbased CL-transfer pathway. CL exposed at the mitochondrial surface then serves as an 'eat me' signal for the mitophagic machinery; it is recognized by the LC3 receptor of autophagosomes, targeting the dysfunctional mitochondrion to lysosomal degradation. Similar NME4-supported CL externalization is likely also involved in apoptosis and inflammatory reactions.

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“…This non-random distribution of the two kinases agreed with the analysis of isolated mitochondrial contact sites. In contact fractions enriched from osmotically disrupted liver, brain and kidney mitochondria, hexokinase and mitochondrial creatine kinase (except in liver) were concentrated [2,7,8]. Hexokinase had a significantly higher affinity to this membrane fraction compared to isolated outer membrane [7,9].…”

Section: Introductionmentioning

confidence: 94%

“…Hexokinase distribution at the mitochondrial surface studied by electron microscopic techniques, and by removing unattached outer membrane with digitonin, led to preferential localisation of the enzyme in the contact sites [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore

et al. 1996

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In vitro incubation of isolated hexokinase isozyme I or isolated dimer of mitochondrial creatine kinase with the outer mitochondrial membrane pore led to high molecular weight complexes of enzyme oligomers. Similar complexes of hexokinase and mitochondrial creatine kinase could be extracted by 0.5% Triton X-100 from homogenates of rat brain. Hexokinase and creatine kinase complexes could be separated by subsequent chromatography on DEAE anion exchanger. The molecular weight, as determined by gel-permeation chromatography, was approximately 400 kDa for both complexes. The Mr suggested tetramers of hexokinase (monomer 100 kDa) and creatine kinase (active enzyme is a dimer of 80 kDa). The composition of the complexes was further characterised by specific antibodies. Besides either hexokinase or creatine kinase molecules the complexes contained porin and adenylate translocator. It was possible to incorporate the complexes into artificial bilayer membranes and to measure conductance in 1 M KCI. The incorporating channels had a high conductance of 6 nS that was asymmetrically voltage dependent. The complexes were also reconstituted in phospholipid vesicles that were loaded with ATP. Complex containing vesicles retained ATP while vesicles reconstituted with pure porin were leaky. The internal ATP could be used by creatine kinase and bexokinase in the complex to phosphorylate external creatine or glucose. This process was inhibited by atractyloside. The hexokinase complex containing vesicles were furthermore loaded with malate or ATP that was gradually released by addition of Ca 2+ between 100 and 600 IJNI. The liberation of malate or ATP by Ca 2+ could be inhibited by N-methylVal-4-cyclosporin, suggesting that the porin translocator complex constitutes the permeability transition pore. The results show the physiological existence of kinase porin translocator complexes at the mitochondrial surface. It is assumed that such complexes between inner and outer membrane components are the molecular basis of contact sites observed by electron microscopy. Kinase complex formation may serve three regulatory functions, firstly regulation of the kinase activity, secondly stimulation of oxidative phosphorylation and thirdly regulation of the permeability transition pore.

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Mitochondrial boundary membrane contact sites in brain: Points of hexokinase and creatine kinase location, and control of Ca2+ transport

Cited by 116 publications

References 41 publications

Ca2+-induced changes in energy metabolism and viability of melanoma cells

Ca2+-induced changes in energy metabolism and viability of melanoma cells

NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore

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