Creatine kinase B deficient neurons exhibit an increased fraction of motile mitochondria
© Kuiper et al; licensee BioMed Central Ltd. 2008
Received: 22 January 2008
Accepted: 28 July 2008
Published: 28 July 2008
Neurons require an elaborate system of intracellular transport to distribute cargo throughout axonal and dendritic projections. Active anterograde and retrograde transport of mitochondria serves in local energy distribution, but at the same time also requires input of ATP. Here we studied whether brain-type creatine kinase (CK-B), a key enzyme for high-energy phosphoryl transfer between ATP and CrP in brain, has an intermediary role in the reciprocal coordination between mitochondrial motility and energy distribution. Therefore, we analysed the impact of brain-type creatine kinase (CK-B) deficiency on transport activity and velocity of mitochondria in primary murine neurons and made a comparison to the fate of amyloid precursor protein (APP) cargo in these cells, using live cell imaging.
Comparison of average and maximum transport velocities and global transport activity showed that CK-B deficiency had no effect on speed of movement of mitochondria or APP cargo, but that the fraction of motile mitochondria was significantly increased by 36% in neurons derived from CK-B knockout mice. The percentage of motile APP vesicles was not altered.
CK-B activity does not directly couple to motor protein activity but cells without the enzyme increase the number of motile mitochondria, possibly as an adaptational strategy aimed to enhance mitochondrial distribution versatility in order to compensate for loss of efficiency in the cellular network for ATP distribution.
Neurons, by virtue of their unique architecture, have developed specific transport systems to regulate anterograde and retrograde flow of macromolecules, vesicles or organelles between the cell body and distal regions in the axon and dendrites. To maintain efficiency and directionality in the bidirectional flow of these cellular constituents strict control over movement of cargo by motor proteins on cytoskeletal elements such as microtubules, intermediate filaments, and actin, is needed [1–3]. One of the basic elements in this control is adequate fuelling with ATP, the major carrier of cellular energy. Homeostasis of global and compartmentalized ATP levels, i.e. regulation of production, distribution, and consumption of intracellular ATP, is controlled by an elaborate metabolic network, which varies with cell type. In neurons this circuit involves both cytosolic-glycolytic and oxidative mitochondrial production pathways and a high level of ATP consumption for fuelling of acto-myosin dynamics, ion transporters, and neurotransmitter cycling activity in the synapse [4–6]. Neurons use glucose from the circulation as the main carbohydrate source for ATP production, but – depending on specific physiological conditions – a fair percentage of their energy may also be derived from lactate, which they exchange with astrocytes [7, 8], or from ketone bodies imported from circulation. Because of the highly branched morphology of neurons, sites of energy consumption are usually spatially separated from sites of energy generation in this cell type. Since diffusion of ATP might usually be too slow to achieve optimal supply of high-energy phosphoryl groups (~P), neurons have developed more efficient mechanisms for transport and distribution of ~P. One way to minimize the diffusion distance of ATP and regulating natural inhomogeneity in ATPs intracellular distribution is by redirecting mitochondria to sites were ATP demand is high, e.g. in the vicinity of synapses . This requires active mitochondrial transport, which is mainly driven by members of the kinesin and dynein superfamilies of microtubule directed motor proteins such as KIF1Bα and KIF5 [10, 11], although, actin guided motility may also be involved [12–14].
An alternative strategy to optimize spatial energy transfer within cells is to relay high-energy phosphoryl groups (~P) by enzymatic transfer systems, such as the creatine kinase (CK) family of isozymes . These enzymes buffer ATP and ADP levels by the reversible transfer of ~P onto creatine (Cr) (MgATP2- + Cr ↔ MgADP- + CrP2- + H+) [15, 16]. Indeed, CKs are mainly expressed in tissues with high energy-turnover and sudden rises in energy demand, such as muscle and brain [17, 18]. Ubiquitous mitochondrial CK (UbCKmit) and cytosolic brain-type CK (CK-B) are the two predominant isoforms in brain [17, 19] and broadly distributed throughout neurons (moderate-low expression) and glial cells (high expression in astrocytes and microglia) across different brain areas. The CK system provides cells with both a temporal and spatial energy buffer [15, 16]. During transient rises in energy consumption, the CrP pool is addressed by CK to provide the cell with ATP [18, 20]. In addition, CK isozymes connect spatially separated subcellular locales of ATP generation and ATP hydrolysis [21, 22]
We have demonstrated that genetic ablation of CK-B in mice causes changes in behavior, diminished performance in spatial learning tasks and delayed development of pentylenetetrazole-induced seizures . Furthermore, the intra- and infrapyramidal mossy fiber areas in CK-B-/- mice appeared increased. We explained these features by diminished synaptic plasticity or compensatory adaptation with altered neuronal outgrowth during development.
Intracellular transport in neurons is comprised of membranous organelles and cytoplasmic proteins (or protein complexes) that are conveyed from the cell body to the synapse, and vice versa, by either fast or slow axonal transport . In general, movement of organelles is mediated by fast axonal transport, whereas cytosolic and cytoskeletal proteins move at a slower pace. This difference in velocity is attributed to the duty ratio of the motor proteins involved in both types of transport [1, 26].
CK-B was identified in slow component B (SCb) which, together with slow component A (SCa), make up the branch of slow axonal transport . However, it is not known if CK-B facilitates this particular type of axonal transport, or that it is merely transported as inert cargo to subcellular destinations where it is needed. To address the question whether CK-B enzymatically contributes to axonal transport in more detail, we compared cultured primary hippocampal neurons derived from CK-B knockout and wildtype mice and monitored the fate of YFP tagged amyloid precursor protein (APP) as a representative component in fast transport. This type of transport correlates with a high duty ratio of motor proteins and with high ATPase activity. In addition, we analysed mitochondrial dynamics. Our results suggest that CK-B does not influence the velocity of intracellular transport of APP or mitochondria in neurons. Rather, cells deficient in CK-B display show a conspicuous alteration in magnitude of transport, concomitant with an increase in the fraction of motile mitochondria.
Distribution of CK-B in primary neurons
To assess effects of CK-B efficiency in primary neurons, we used a co-culture system of hippocampus-derived neurons on a monolayer of primary astrocytes (see material and methods). Neuronal expression of CK-B has been demonstrated in several organisms, but not much is known about its subcellular localization [28, 29].
Neurons derived from CK-B knockout mice did not display any positive immunostaining with our antibody, demonstrating specificity of our assay (data not shown). In addition to localization studies, we also performed zymogram analysis on cultured primary neurons to assess enzymatic activity. As expected, CK-B catalytic activity was present in wildtype cells, but was completely absent in CK-B knockout cells (Figure 1d).
APP-transport in CK-B deficient neurons
Mitochondrial transport in CK-B deficient neurons
In conclusion, CK-B is not influencing the speed of intracellular transport of APP or mitochondria once this transport is initiated, however, in cells that lack CK-B a larger fraction of mitochondria is recruited into the actual motile pool.
ATP generation and distribution is essential for the highly compartmentalized eukaryotic cell. Especially in neurons with their extended axonal and dendritic networks, it is important to modulate fuelling logistics. Spatially confined cellular processes like synapse functioning require local supply of energy. In order to fuel these functions optimally, they are coupled to sites of energy production. The CK system provides cells with a temporal and spatial ATP buffer to connect local energy consumption with sites of energy production [16, 28, 37]. Other phosphotransfer enzymes, like adenylate kinases and nucleoside diphosphate kinases are also active in neurons, and serve in the global network that distributes ATP throughout the cell. In addition, neurons have the capacity to relocate their energy production machinery to specialized subcellular sites to help in local ATP generation. Partitioning of glycolytic enzymes on cortical actin or membrane-near sites can provide local energy to membrane pumps by functional coupling [38, 39], whereas oxidative generated ATP can be generated locally, by recruiting mitochondria to sites of high ATP consumption such as synapses and dendritic spines [9, 35, 40].
We focused on the question whether CK-B facilitates efficient axonal transport by comparing transport of APP and mitochondria in primary murine neurons derived from CK-B deficient and proficient mice.
Active transport of cargo in neurons is achieved by a wide variety of motor proteins, which are guided by the infrastructure of the cellular cytoskeleton . These cargos can travel along actin filaments or microtubules either by plus end or minus end directed trafficing, thus facilitating both anterograde and retrograde axonal transport. Both types of cytoskeletal structures have their own assortment of motor proteins, which can be divided in actin-guided myosins  and microtubule-guided kinesins and dyneins . A common denominator for myosins, dyneins and kinesins is that they require ATP hydrolysis to exert their function.
Fast axonal transport of membranous organelles and membrane proteins depends on highly processive motor activity and, consequently, a steady and adequate ATP/ADP ratio for optimal fuelling of motor proteins. Our data show that the actual speed of fast axonal transport of APP-YFP is not affected by CK-B deficiency. Although the maximum and average velocities observed are lower than reported for rat neurons , this may be a mouse related feature and no differences between wildtype cells and CK-B deficient cells were found. In addition, mitochondrial transport velocities were not affected in CK-B knockout cells. Mitochondria are subject to saltatory movement, which involves cycles of anterograde and retrograde transport driven by kinesins and dyneins, respectively . Because axons and dendrites in 7-day-old cultures of primary neurons are totally intertwined, we were unable to distinguish between axonal/dendritic or anterograde/retrograde transport. Therefore, and also because other groups have reported that mitochondrial velocity and the rate of anterograde and retrograde transport are highly similar in axons and dendrites of hippocampal neurons [42, 43], we decided not to discriminate between CK-B effects further. At this point, we thus consider it unlikely – but can also not fully exclude – that CK-B deficiency affects the ratio of anterograde/retrograde transport of mitochondria.
We hypothesized that CK-B deficiency would bring about an altered capacity to distribute intracellular ATP, and create abnormal inhomogeneity in local ATP. Because neurons rearrange their mitochondria according to local ATP needs [9, 40], altered local ATP distribution may determine altered mitochondrial motility. The fact that no differences in either mitochondrial or YFP-APP velocities in combined anterograde/retrograde transport were found is therefore an interesting finding in its own right. Possibly, flexibility in the energetic network, with higher ~P flux through adenylate kinase (AK) or glycolytic enzymes helps to compensate the loss of CK-B [44–46], or – alternatively – mitochondria produce are still able to produce enough ATP to sustain their own transport.
Indeed, our findings suggest that initiation or abrogation of transport may be steps in the process that are more crucially dependent on cell energy state. Quantification of the fraction of mobile mitochondria revealed that CK-B deficient neurons contain on average 36% more mitochondria in the motile fraction. The metabolic factors that modulate and mobilize mitochondrial motility are largely unknown. Local ATP depletion, or locally elevated H+ and ADP levels caused by CK absence, could serve as a direct or indirect signal to attract mitochondria, or arrest nearby motor activity, arresting mitochondria while passing the "fuel-arid" area [40, 47–49]. A combination of mechanistic events is also possible. In addition, secondary effects like inadequate Ca2+ handling, due to CK-B deficiency [20, 50], could act in signalling pathways for mitochondrial motility and/or docking . For neurons, it has been found that local neuronal growth factor (NGF) application triggers mitochondrial recruitment through PI3K. Moreover, an intact F-actin cytoskeleton is required [52, 53], which is organized by the action of formins and RhoA . Interestingly, we recently found that CK-B increases the F-actin content in phagosomes . Although the underlying molecular mechanisms of this effect on F-actin are yet unclear, it is tempting to speculate that CK-B deficiency in neurons could induce less efficient actin accumulation at sites of mitochondrial arrest. Indeed, a prominent role for actin-state in mitochondrial movement has been proposed . Future research might help to discriminate between these different putative mechanisms.
We conclude that different types of axonal and dendritic transport in neurons do not directly require ATP generated by CK-B. However, CK-B mediated phosphotransfer is functionally interconnected to events that determine the transport-initiation or -docking efficiency of mitochondria in neurons.
Isolation and culture of primary neurons
The generation of CK-B knockout mice and the study of genotype-phenotype relationships of these animals in comparison to wildtype controls has been described in detail elsewhere (also [17, 57]). Primary cultures of mouse hippocampal neurons were established using a modified protocol . In short, brains were isolated from CK-B(-/-)  fetuses (E16.5) or fetuses of mixed background (C57BL/6 × 129Ola). Meninges were removed and hippocampi were separated from the hemispheres. Hippocampi were incubated for 20 minutes at 37°C in Hanks' Balanced Saline Solution (HBSS, Gibco) containing 0.05% trypsin, 1 mM EDTA and 20 mM HEPES (pH 7.35) and subsequently dissociated by pipetting and seeded onto 24 mm coverslips. Cells were allowed to attach for 3–4 hours in Neurobasal medium (Gibco), after which they were placed inverted on a layer of primary astrocytes (also see ). The co-culture was maintained in Neurobasal medium containing 1× B27 supplement (Gibco), 0.5 mM glutamine and 0.05 mg/ml gentamycin (= NBM+).
Creatine kinase activity (zymogram)
Cultured primary neurons (5 days in vitro) were lysed in buffer containing 12.6 mM Na2HPO4, 2.8 mM KH2PO4, 0.05% Triton-x-100 and 0.3 mM DTT. Zymogram analysis was performed as described  and, zymograms were subsequently developed using the colorimetric detection kit from Sigma Diagnostics (procedure number 715-EP).
Neurons (3–7 days in vitro) grown on glass coverslips were fixed with 2% paraformaldehyde in PHEM buffer (25 mM HEPES, 10 mM EGTA, 60 mM PIPES, 2 mM MgCl2, pH 6.9), permeabilized with 0.1% Triton X-100 and incubated 20 min in PBS containing 4% bovine serum albumine (BSA). CK-B was detected by subsequent incubation of monoclonal 21E10 (1:2000)  and goat-anti-mouse IgG conjugated to Alexa Fluor 488 (Molecular Probes). Images were taken with a Biorad MRC1024 confocal microscope using an oil immersion 60× objective.
Transfection and rhodamine 123 labeling of neurons
Neurons (7 days in vitro) grown in glass bottomed 35 mm Willco dishes (GWSt-3522) were transfected using Nupherin-neuron (Biomol) transfection reagent in combination with Lipofectamine (Invitrogen). Per dish 0.5 μg pcDNA3-APP-YFP (kind gift from Carlos Dotti ) and 2.5 μl Nupherin were premixed in phenol red free Neurobasal medium and incubated for 10 minutes. An equal volume of phenol red free NBM with 1 μl Lipofectamine was added and after 30 minutes this mix was added to the neurons. After 2 hours the medium was replaced by NBM+ medium and neurons were cultured for 24 hours prior imaging. For tracking mitochondria cells were loaded with rhodamine 123 (10 μM) for 1 minute in NBM+ w/o phenol red.
Live imaging and image analysis
Cells cultured on Willco dishes were imaged on an inverted microscope (Axiovert 200 M; Zeiss, Jena, Germany) equipped with a temperature controlled CO2 incubator (type S) and sample stage, and using a PlanApochromatic 63 × 1.4 oil immersion Plan NeoFluar DIC lens (Carl Zeiss GmbH, Jena, Germany). Rhodamine 123 was excited using a monochromator (Polychrome IV; TILL Photonics, Gräfelfing, Germany) set at 488 nm. Images were recorded with the appropriate filter set (Omega Optical, Brattleboro, VT, USA) on a CoolSNAP HQ monochrome charge-coupled device (CCD) camera (Roper Scientific, Vianen, The Netherlands). All hardware was controlled with Metafluor 6 software (Molecular Devices Corp., Downingtown, PA, USA).
For particle (i.e. APP-cargo vesicles or mitochondria) tracing, sequential images were taken every 2 seconds to obtain image stacks of 100 images each. Particles were tracked using Metamorph 6 software (Molecular Devices Corp., Downingtown, PA, USA) software by marking them manually in subsequent frames (only particles that moved at least in 3 subsequent frames were tracked). The velocity per particle-vesicle was calculated by dividing the travelled distance by time. Additionally, for each moving particle the maximal velocity (during two subsequent frames) was determined. The number of analysed particles is mentioned in the text or legends.
To estimate the percentage moving mitochondria the same dataset as mentioned above was analyzed with ImageJ software version 1.34s (U. S. National Institutes of Health, Bethesda, Maryland, USA, http://rsb.info.nih.gov/ij/). The original image stacks were converted to binary stacks by manually applying a threshold, according to the quality of each individual stack. The total number of mitochondria in the stack was counted using the particle count function (5 < mitochondria <50 pixels). To distinguish between moving and stationary mitochondria, every frame "n" was compared to an earlier frame "n-3" ("stackdifference" option from the ImageJ kymograph plugin, EMBL, Heidelberg, Germany). The resulting stack of images contains motile mitochondria, which were counted. Numbers obtained were divided by two to compensate for double counting of both "old and new" mitochondrial positions in "difference-stack" images. Finally, percentages of motile mitochondria in the stacks were calculated. For more information see Additional file 1.
This work was supported by NWO ZON-MW Program grant 901-01-191 and partly by grants KUN 2002-1763 and KUN 2004-3125 from the Dutch Cancer Society (Nederlandse Kankerbestrijding NKB/KWF to B.W.).
- Brown A: Axonal transport of membranous and nonmembranous cargoes: a unified perspective. J Cell Biol. 2003, 160: 817-821.PubMed CentralPubMedGoogle Scholar
- Chen H, Chan DC: Critical dependence of neurons on mitochondrial dynamics. Curr Opin Cell Biol. 2006, 18: 453-459.PubMedGoogle Scholar
- Goldstein LS, Yang Z: Microtubule-based transport systems in neurons: the roles of kinesins and dyneins. Annu Rev Neurosci. 2000, 23: 39-71.PubMedGoogle Scholar
- Lipton P, Robacker K: Glycolysis and brain function: [K+]o stimulation of protein synthesis and K+ uptake require glycolysis. Fed Proc. 1983, 42: 2875-2880.PubMedGoogle Scholar
- Lim L, Hall C, Leung T, Mahadevan L, Whatley S: Neurone-specific enolase and creatine phosphokinase are protein components of rat brain synaptic plasma membranes. J Neurochem. 1983, 41: 1177-1182.PubMedGoogle Scholar
- Bernstein BW, Bamburg JR: Actin-ATP hydrolysis is a major energy drain for neurons. J Neurosci. 2003, 23: 1-6.PubMedGoogle Scholar
- Ames A: CNS energy metabolism as related to function. Brain Res Brain Res Rev. 2000, 34: 42-68.PubMedGoogle Scholar
- Pellerin L, Magistretti PJ: Neuroenergetics: calling upon astrocytes to satisfy hungry neurons. Neuroscientist. 2004, 10: 53-62.PubMedGoogle Scholar
- Verstreken P, Ly CV, Venken KJ, Koh TW, Zhou Y, Bellen HJ: Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron. 2005, 47: 365-378.PubMedGoogle Scholar
- Nangaku M, Sato-Yoshitake R, Okada Y, Noda Y, Takemura R, Yamazaki H, Hirokawa N: KIF1B, a novel microtubule plus end-directed monomeric motor protein for transport of mitochondria. Cell. 1994, 79: 1209-1220.PubMedGoogle Scholar
- Tanaka Y, Kanai Y, Okada Y, Nonaka S, Takeda S, Harada A, Hirokawa N: Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell. 1998, 93: 1147-1158.PubMedGoogle Scholar
- Morris RL, Hollenbeck PJ: Axonal transport of mitochondria along microtubules and F-actin in living vertebrate neurons. J Cell Biol. 1995, 131: 1315-1326.PubMedGoogle Scholar
- Sturmer K, Baumann O, Walz B: Actin-dependent light-induced translocation of mitochondria and ER cisternae in the photoreceptor cells of the locust Schistocerca gregaria. J Cell Sci. 1995, 108 ( Pt 6): 2273-2283.Google Scholar
- Vale RD: The molecular motor toolbox for intracellular transport. Cell. 2003, 112: 467-480.PubMedGoogle Scholar
- Dzeja PP, Terzic A: Phosphotransfer networks and cellular energetics. J Exp Biol. 2003, 206: 2039-2047.PubMedGoogle Scholar
- Wallimann T, Hemmer W: Creatine kinase in non-muscle tissues and cells. Mol Cell Biochem. 1994, 133-134: 193-220.PubMedGoogle Scholar
- Jost CR, Van Der Zee CE, In 't Zandt HJ, Oerlemans F, Verheij M, Streijger F, Fransen J, Heerschap A, Cools AR, Wieringa B: Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility. Eur J Neurosci. 2002, 15: 1692-1706.PubMedGoogle Scholar
- van Deursen J, Heerschap A, Oerlemans F, Ruitenbeek W, Jap P, ter Laak H, Wieringa B: Skeletal muscles of mice deficient in muscle creatine kinase lack burst activity. Cell. 1993, 74: 621-631.PubMedGoogle Scholar
- Tachikawa M, Fukaya M, Terasaki T, Ohtsuki S, Watanabe M: Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis. Eur J Neurosci. 2004, 20: 144-160.PubMedGoogle Scholar
- Steeghs K, Benders A, Oerlemans F, de Haan A, Heerschap A, Ruitenbeek W, Jost C, van Deursen J, Perryman B, Pette D, Bruckwilder M, Koudijs J, Jap P, Veerkamp J, Wieringa B: Altered Ca2+ responses in muscles with combined mitochondrial and cytosolic creatine kinase deficiencies. Cell. 1997, 89: 93-103.PubMedGoogle Scholar
- Dzeja PP, Bortolon R, Perez-Terzic C, Holmuhamedov EL, Terzic A: Energetic communication between mitochondria and nucleus directed by catalyzed phosphotransfer. Proc Natl Acad Sci U S A. 2002, 99: 10156-10161.PubMed CentralPubMedGoogle Scholar
- Saks VA, Khuchua ZA, Vasilyeva EV, Belikova OY, Kuznetsov AV: Metabolic compartmentation and substrate channelling in muscle cells. Role of coupled creatine kinases in in vivo regulation of cellular respiration--a synthesis. Mol Cell Biochem. 1994, 133-134: 155-192.PubMedGoogle Scholar
- Guillaud L, Setou M, Hirokawa N: KIF17 dynamics and regulation of NR2B trafficking in hippocampal neurons. J Neurosci. 2003, 23: 131-140.PubMedGoogle Scholar
- Wong RW, Setou M, Teng J, Takei Y, Hirokawa N: Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice. Proc Natl Acad Sci U S A. 2002, 99: 14500-14505.PubMed CentralPubMedGoogle Scholar
- Yuen EY, Jiang Q, Feng J, Yan Z: Microtubule regulation of N-methyl-D-aspartate receptor channels in neurons. J Biol Chem. 2005, 280: 29420-29427.PubMedGoogle Scholar
- Shah JV, Cleveland DW: Slow axonal transport: fast motors in the slow lane. Curr Opin Cell Biol. 2002, 14: 58-62.PubMedGoogle Scholar
- Brady ST, Lasek RJ: Nerve-specific enolase and creatine phosphokinase in axonal transport: soluble proteins and the axoplasmic matrix. Cell. 1981, 23: 515-523.PubMedGoogle Scholar
- Friedman DL, Roberts R: Compartmentation of brain-type creatine kinase and ubiquitous mitochondrial creatine kinase in neurons: evidence for a creatine phosphate energy shuttle in adult rat brain. J Comp Neurol. 1994, 343: 500-511.PubMedGoogle Scholar
- Hemmer W, Zanolla E, Furter-Graves EM, Eppenberger HM, Wallimann T: Creatine kinase isoenzymes in chicken cerebellum: specific localization of brain-type creatine kinase in Bergmann glial cells and muscle-type creatine kinase in Purkinje neurons. Eur J Neurosci. 1994, 6: 538-549.PubMedGoogle Scholar
- Sistermans EA, de Kok YJ, Peters W, Ginsel LA, Jap PH, Wieringa B: Tissue- and cell-specific distribution of creatine kinase B: a new and highly specific monoclonal antibody for use in immunohistochemistry. Cell Tissue Res. 1995, 280: 435-446.PubMedGoogle Scholar
- Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL: Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci U S A. 1990, 87: 1561-1565.PubMed CentralPubMedGoogle Scholar
- Kaether C, Skehel P, Dotti CG: Axonal membrane proteins are transported in distinct carriers: a two-color video microscopy study in cultured hippocampal neurons. Mol Biol Cell. 2000, 11: 1213-1224.PubMed CentralPubMedGoogle Scholar
- Kamal A, Stokin GB, Yang Z, Xia CH, Goldstein LS: Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron. 2000, 28: 449-459.PubMedGoogle Scholar
- Chan DC: Mitochondria: dynamic organelles in disease, aging, and development. Cell. 2006, 125: 1241-1252.PubMedGoogle Scholar
- Li Z, Okamoto K, Hayashi Y, Sheng M: The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell. 2004, 119: 873-887.PubMedGoogle Scholar
- Morris RL, Hollenbeck PJ: The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth. J Cell Sci. 1993, 104 ( Pt 3): 917-927.Google Scholar
- Tombes RM, Shapiro BM: Metabolite channeling: a phosphorylcreatine shuttle to mediate high energy phosphate transport between sperm mitochondrion and tail. Cell. 1985, 41: 325-334.PubMedGoogle Scholar
- Xu KY, Zweier JL, Becker LC: Functional coupling between glycolysis and sarcoplasmic reticulum Ca2+ transport. Circ Res. 1995, 77: 88-97.PubMedGoogle Scholar
- Glitsch HG, Tappe A: The Na+/K+ pump of cardiac Purkinje cells is preferentially fuelled by glycolytic ATP production. Pflugers Arch. 1993, 422: 380-385.PubMedGoogle Scholar
- Hollenbeck PJ, Saxton WM: The axonal transport of mitochondria. J Cell Sci. 2005, 118: 5411-5419.PubMed CentralPubMedGoogle Scholar
- Sellers JR: Myosins: a diverse superfamily. Biochim Biophys Acta. 2000, 1496: 3-22.PubMedGoogle Scholar
- Ligon LA, Steward O: Movement of mitochondria in the axons and dendrites of cultured hippocampal neurons. J Comp Neurol. 2000, 427: 340-350.PubMedGoogle Scholar
- Overly CC, Rieff HI, Hollenbeck PJ: Organelle motility and metabolism in axons vs dendrites of cultured hippocampal neurons. J Cell Sci. 1996, 109 ( Pt 5): 971-980.Google Scholar
- Janssen E, de Groof A, Wijers M, Fransen J, Dzeja PP, Terzic A, Wieringa B: Adenylate kinase 1 deficiency induces molecular and structural adaptations to support muscle energy metabolism. J Biol Chem. 2003, 278: 12937-12945.PubMedGoogle Scholar
- de Groof AJ, Smeets B, Groot Koerkamp MJ, Mul AN, Janssen EE, Tabak HF, Wieringa B: Changes in mRNA expression profile underlie phenotypic adaptations in creatine kinase-deficient muscles. FEBS Lett. 2001, 506: 73-78.PubMedGoogle Scholar
- de Groof AJ, Oerlemans FT, Jost CR, Wieringa B: Changes in glycolytic network and mitochondrial design in creatine kinase-deficient muscles. Muscle Nerve. 2001, 24: 1188-1196.PubMedGoogle Scholar
- Mironov SL: ADP regulates movements of mitochondria in neurons. Biophys J. 2007, 92: 2944-2952.PubMed CentralPubMedGoogle Scholar
- Hollenbeck PJ: The pattern and mechanism of mitochondrial transport in axons. Front Biosci. 1996, 1: d91-102.PubMedGoogle Scholar
- Terada S, Kinjo M, Hirokawa N: Oligomeric tubulin in large transporting complex is transported via kinesin in squid giant axons. Cell. 2000, 103: 141-155.PubMedGoogle Scholar
- de Groof AJ, Fransen JA, Errington RJ, Willems PH, Wieringa B, Koopman WJ: The creatine kinase system is essential for optimal refill of the sarcoplasmic reticulum Ca2+ store in skeletal muscle. J Biol Chem. 2002, 277: 5275-5284.PubMedGoogle Scholar
- Yi M, Weaver D, Hajnoczky G: Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit. J Cell Biol. 2004, 167: 661-672.PubMed CentralPubMedGoogle Scholar
- Chada SR, Hollenbeck PJ: Nerve growth factor signaling regulates motility and docking of axonal mitochondria. Curr Biol. 2004, 14: 1272-1276.PubMedGoogle Scholar
- Chada SR, Hollenbeck PJ: Mitochondrial movement and positioning in axons: the role of growth factor signaling. J Exp Biol. 2003, 206: 1985-1992.PubMedGoogle Scholar
- Minin AA, Kulik AV, Gyoeva FK, Li Y, Goshima G, Gelfand VI: Regulation of mitochondria distribution by RhoA and formins. J Cell Sci. 2006, 119: 659-670.PubMedGoogle Scholar
- Kuiper JW, Pluk H, Oerlemans F, van Leeuwen FN, de Lange F, Fransen J, Wieringa B: Creatine kinase-mediated ATP supply fuels actin-based events in phagocytosis. PLoS Biol. 2008, 6: e51.PubMed CentralPubMedGoogle Scholar
- Boldogh IR, Pon LA: Mitochondria on the move. Trends Cell Biol. 2007, 17: 502-510.PubMedGoogle Scholar
- Streijger F, In 't Zandt HJ, Renema WK, Oerlemans F, Heerschap A, Kuiper JW, Pluk H, Jost C, Van Der Zee CE, Wieringa B: Developmental and functional consequences of disturbed energetic communication in brain of creatine kinase-deficient mice: Understanding CK's role in the fuelling of behavior and learning. Molecular system bioenergetics. Edited by: Saks VA. 2007, Weinheim, Wiley-VCH Verlag GmbH & Co. KGaA, 339-366.Google Scholar
- Hoop de MJ, Meyn L, Dotti CG: Culturing hippocampal neurons and astrocytes from fetal rodent brain. Cell Biology: a laboratory handbook. Edited by: Celis JE. 1998, San Diego, Academic Press, 1: 154-163. 2ndGoogle Scholar