Journal articles: 'Creatine, brain, mitochondria'

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O'Gorman, E., K. H. Fuchs, P. Tittmann, H. Gross, and T. Wallimann. "Crystalline mitochondrial inclusion bodies isolated from creatine depleted rat soleus muscle." Journal of Cell Science 110, no. 12 (June 15, 1997): 1403–11. http://dx.doi.org/10.1242/jcs.110.12.1403.

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Rats were fed a 2% guanidino propionic acid diet for up to 18 weeks to induce cellular creatine depletion by inhibition of creatine uptake by this creatine analogue. Ultrastructural analysis of creatine depleted tissues showed that mitochondrial intermembrane inclusion bodies appeared in all skeletal muscles analysed, after 11 weeks of feeding. Heart had relatively few even after 18 weeks of analogue feeding and none were evident in kidney, brain or liver. These structures were strongly immuno-positive for sarcomeric mitochondrial creatine kinase and upon removal from mitochondria, the inclusion bodies were shown to diffract to a resolution of 2.5 nm. Two-dimensional image analysis and three-dimensional reconstruction revealed arrays of creatine kinase octamers with additional components between the octameric structures. The same mitochondria had a 3-fold higher extractable specific creatine kinase activity than controls. Molecular mass gel filtration of inclusion body containing mitochondrial extracts from analogue fed rat solei revealed mitochondrial creatine kinase eluting as an aggregate of an apparent molecular mass > or = 2,000 kDa. Mitochondrial creatine kinase of control soleus mitochondrial extract eluted as an octamer, with a molecular mass of 340 kDa. Respiration measurements of control solei mitochondria displayed creatine mediated stimulation of oxidative phosphorylation that was absent in analogue-fed rat solei mitochondria. The latter also had 19% and 14% slower rates of state 4 and maximal state 3 respiration, respectively, than control mitochondria. These results indicate that mitochondrial creatine kinase co-crystallises with another component within the inter membrane space of select mitochondria in creatine depleted skeletal muscle, and is inactive in situ.

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Kottke, M., T. Wallimann, and D. Brdiczka. "Dual Electron Microscopic Localization of Mitochondrial Creatine Kinase in Brain Mitochondria." Biochemical Medicine and Metabolic Biology 51, no. 2 (April 1994): 105–17. http://dx.doi.org/10.1006/bmmb.1994.1015.

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Bojinca, Mihai, Violeta Claudia Bojinca, Andra Rodica Balanescu, and Serban Mihai Balanescu. "Macro Creatine Kinase (macro CK) in Clinical Practice." Revista de Chimie 69, no. 8 (September 15, 2018): 2107–9. http://dx.doi.org/10.37358/rc.18.8.6483.

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Creatine kinase (CK) is an important enzyme involved in energy metabolism. CK is found in the cytosol and mitochondria of various tissues, mainly those with increased energy necessities as skeletal muscle, cardiac muscle and brain, but also in visceral tissues. CK is a dimeric molecule composed of two identical or different subunits, type M - muscular and type B - brain. The combination of M and B subunits leads to formation of three isozymes: CK - MM found mainly in the skeletal muscle, CK - BB found mainly in the brain and CK - MB found mainly in the cardiac muscle, but also in small quantities in the skeletal muscle. The serum increase of different isozymes of CK is a consequence of cell disruption in various clinical situations like physical training, rhabdomyolysis, myositis, muscular dystrophy, myocardial infarction and others, CK being an important biomarker for this diseases. Macro CK is a complex of CK and immunoglobulin (macro CK type 1) or a polymer of mitochondrial CK (macro CK type 2) that induces false and persistent elevation of CK levels that could mislead the clinician. We present a review of the literature concerning the appearance and clinical significance of macro CK.

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Gonçalves, Cinara L., Gislaine T. Rezin, Gabriela K. Ferreira, Isabela C. Jeremias, Mariane R. Cardoso, Milena Carvalho-Silva, Alexandra I. Zugno, João Quevedo, and Emilio L. Streck. "Differential effects of escitalopram administration on metabolic parameters of cortical and subcortical brain regions of Wistar rats." Acta Neuropsychiatrica 24, no. 3 (June 2012): 147–54. http://dx.doi.org/10.1111/j.1601-5215.2011.00592.x.

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Objective: Considering that mitochondria may be drug targets and some characteristics of drug–mitochondria interactions may still be misjudged because of the difficulty in foreseeing and understanding all possible implications of the complex pathophysiology of mitochondria, our study aimed to investigate the effect of escitalopram on the activity of enzymes of mitochondrial energy metabolism.Methods: Animals received daily administration of escitalopram dissolved in saline [10 mg/kg, intraperitoneal (IP)] at 1.0 ml/kg volume for 14 days. Control rats received an equivalent volume of saline, 1.0 ml/kg (IP), for the same treatment period. Twelve hours after last injection, rats were killed by decapitation and brain areas were rapidly isolated. The samples were homogenised and the activities of mitochondrial respiratory chain complexes, some enzymes of Krebs cycle (citrate synthase, malate dehydrogenase and succinate dehydrogenase) and creatine kinase were measured.Results: We verified that chronic administration of escitalopram decreased the activities of complexes I and II–III in cerebellum, hippocampus, striatum and posterior cortex whereas prefrontal cortex was not affected. Complex II activity was decreased only in striatum without affecting prefrontal cortex, hippocampus, cerebellum and posterior cortex. However, chronic administration of escitalopram did not affect complex IV and enzymes of Krebs cycle activities as well as creatine kinase.Conclusion: In this study we showed a decrease in the activities of complexes I and II–III in most of the brain structures analysed and complex II activity was decreased only in striatum. However, it remains to be determined if mitochondrial dysfunction is rather a causal or a consequential event of abnormal signalling.

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Kostadinova, Ivanka, Magdalena Kondeva-Burdina, Lyubomir Marinov, Lubomir L. Vezenkov, and Rumyana Simeonova. "Newly Synthesized Creatine Derivatives as Potential Neuroprotective and Antioxidant Agents on In Vitro Models of Parkinson’s Disease." Life 13, no. 1 (January 4, 2023): 139. http://dx.doi.org/10.3390/life13010139.

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Oxidative stress is one of the key factors responsible for many diseases–neurodegenerative (Parkinson and Alzheimer) diseases, diabetes, atherosclerosis, etc. Creatine, a natural amino acid derivative, is capable of exerting mild, direct antioxidant activity in cultured mammalian cells acutely injured with an array of different reactive oxygen species (ROS) generating compounds. The aim of the study was in vitro (on isolated rat brain sub-cellular fractions–synaptosomes, mitochondria and microsomes) evaluation of newly synthetized creatine derivatives for possible antioxidant and neuroprotective activity. The synaptosomes and mitochondria were obtained by multiple centrifugations with Percoll, while microsomes–only by multiple centrifugations. Varying models of oxidative stress were used to study the possible antioxidant and neuroprotective effects of the respective compounds: on synaptosomes–6-hydroxydopamine; on mitochondria–tert-butyl hydroperoxide; and on microsomes–iron/ascorbate (non-enzyme-induced lipid peroxidation). Administered alone, creatine derivatives and creatine (at concentration 38 µM) revealed neurotoxic and pro-oxidant effects on isolated rat brain subcellular fractions (synaptosomes, mitochondria and microsomes). In models of 6-hydroxydopamine (on synaptosomes), tert-butyl hydroperoxide (on mitochondria) and iron/ascorbate (on microsomes)-induced oxidative stress, the derivatives showed neuroprotective and antioxidant effects. These effects may be due to the preservation of the reduced glutathione level, ROS scavenging and membranes’ stabilizers against free radicals. Thus, they play a role in the antioxidative defense system and have a promising potential as therapeutic neuroprotective agents for the treatment of neurodegenerative disorders, connected with oxidative stress, such as Parkinson’s disease.

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Vyssokikh, Mikhail Y., Susanne Holtze, Olga A. Averina, Konstantin G. Lyamzaev, Alisa A. Panteleeva, Maria V. Marey, Roman A. Zinovkin, et al. "Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program." Proceedings of the National Academy of Sciences 117, no. 12 (March 9, 2020): 6491–501. http://dx.doi.org/10.1073/pnas.1916414117.

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The mitochondria of various tissues from mice, naked mole rats (NMRs), and bats possess two mechanistically similar systems to prevent the generation of mitochondrial reactive oxygen species (mROS): hexokinases I and II and creatine kinase bound to mitochondrial membranes. Both systems operate in a manner such that one of the kinase substrates (mitochondrial ATP) is electrophoretically transported by the ATP/ADP antiporter to the catalytic site of bound hexokinase or bound creatine kinase without ATP dilution in the cytosol. One of the kinase reaction products, ADP, is transported back to the mitochondrial matrix via the antiporter, again through an electrophoretic process without cytosol dilution. The system in question continuously supports H+-ATP synthase with ADP until glucose or creatine is available. Under these conditions, the membrane potential, ∆ψ, is maintained at a lower than maximal level (i.e., mild depolarization of mitochondria). This ∆ψ decrease is sufficient to completely inhibit mROS generation. In 2.5-y-old mice, mild depolarization disappears in the skeletal muscles, diaphragm, heart, spleen, and brain and partially in the lung and kidney. This age-dependent decrease in the levels of bound kinases is not observed in NMRs and bats for many years. As a result, ROS-mediated protein damage, which is substantial during the aging of short-lived mice, is stabilized at low levels during the aging of long-lived NMRs and bats. It is suggested that this mitochondrial mild depolarization is a crucial component of the mitochondrial anti-aging system.

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Kristian, Tibor, Arman J. Karimi, Adam Fearnow, Jaylyn Waddell, and Mary C. McKenna. "Perturbed Brain Glucose Metabolism Caused by Absent SIRT3 Activity." Cells 10, no. 9 (September 8, 2021): 2348. http://dx.doi.org/10.3390/cells10092348.

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Acetylation is a post-translational modification that regulates the activity of enzymes fundamentally involved in cellular and mitochondrial bioenergetic metabolism. NAD+ dependent deacetylase sirtuin 3 (SIRT3) is localized to mitochondria where it plays a key role in regulating acetylation of TCA cycle enzymes and the mitochondrial respiratory complexes. Although the SIRT3 target proteins in mitochondria have been identified, the effect of SIRT3 activity on mitochondrial glucose metabolism in the brain remains elusive. The impact of abolished SIRT3 activity on glucose metabolism was determined in SIRT3 knockout (KO) and wild type (WT) mice injected with [1,6-13C]glucose using ex vivo 13C-NMR spectroscopy. The 1H-NMR spectra and amino acid analysis showed no differences in the concentration of lactate, glutamate, alanine, succinate, or aspartate between SIRT3 KO and WT mice. However, glutamine, total creatine (Cr), and GABA were lower in SIRT3 KO brain. Incorporation of label from [1,6-13C]glucose metabolism into lactate or alanine was not affected in SIRT3 KO brain. However, the incorporation of the label into all isotopomers of glutamate, glutamine, GABA and aspartate was lower in SIRT3 KO brain, reflecting decreased activity of mitochondrial and TCA cycle metabolism in both neurons and astrocytes. This is most likely due to hyperacetylation of mitochondrial enzymes due to suppressed SIRT3 activity in the brain of SIRT3 KO mice. Thus, the absence of Sirt3 results in impaired mitochondrial oxidative energy metabolism and neurotransmitter synthesis in the brain. Since the SIRT3 activity is NAD+ dependent, these results might parallel changes in glucose metabolism under pathologic reduction in mitochondrial NAD+ pools.

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Kaldis, P., M. Stolz, M. Wyss, E. Zanolla, B. Rothen-Rutishauser, T. Vorherr, and T. Wallimann. "Identification of two distinctly localized mitochondrial creatine kinase isoenzymes in spermatozoa." Journal of Cell Science 109, no. 8 (August 1, 1996): 2079–88. http://dx.doi.org/10.1242/jcs.109.8.2079.

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The creatine kinase (CK) isoenzyme system is essential for motility in rooster and sea urchin sperm. In the present study, biochemical characterization as well as immunofluorescence and confocal laser microscopy with highly specific antibodies against various chicken CK isoenzymes revealed that cytosolic brain-type CK isoenzyme (B-CK) is the only CK isoenzyme in rooster seminal plasma, while three isoenzymes, cytosolic B-CK, sarcomeric mitochondrial CK (Mib-CK), and a variant of ubiquitous Mi-CK (‘Mia-CK variant’), are found in rooster spermatozoa. These three isoenzymes are localized in different regions of the sperm cell. B-CK and Mib-CK were localized along the entire sperm tail and in the mitochondria-rich midpiece, respectively. The ‘Mia-CK variant’, on the other hand, was found predominantly at the head-midpiece boundary, in a non-uniform manner in the midpiece itself and, surprisingly, at the distal end of the sperm tail as well as at the acrosome. Several lines of evidence show that the ‘Mia-CK variant’ shares some characteristics with purified Mia-CK from chicken brain, but also displays distinctive features. This is the first evidence for two different Mi-CK isoenzymes occurring in one cell and, additionally, for the co-expression of Mib-CK and cytosolic brain-type B-CK in the same cell. The relevance of these findings for sperm physiology and energetics is discussed.

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Hemmer, W., I. Riesinger, T. Wallimann, H. M. Eppenberger, and A. F. Quest. "Brain-type creatine kinase in photoreceptor cell outer segments: role of a phosphocreatine circuit in outer segment energy metabolism and phototransduction." Journal of Cell Science 106, no. 2 (October 1, 1993): 671–83. http://dx.doi.org/10.1242/jcs.106.2.671.

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Different isoforms of creatine kinase, an important enzyme of vertebrate energy metabolism, were localized in bovine photoreceptor cells, with particular emphasis on the identification and quantification of the brain-type isoform within the outer segment compartment. Using immunofluorescence and immunoelectron microscopy, brain-type creatine kinase was shown to be present in bovine photoreceptor cell outer and inner segments. The presence of this isoenzyme in rod outer segments was additionally confirmed by immunoblotting and immunolabeling of isolated rod outer segments. The content of creatine kinase in rod outer segments was quantified by measuring creatine kinase activity after membrane disruption with detergent. The ATP regeneration potential provided by the creatine kinase in isolated, washed bovine rod outer segments was 1.2 +/- (0.4) i.u. mg-1 rhodopsin. This value was calculated to be at least an order of magnitude larger than that necessary to replenish the energy required for cGMP resynthesis in rod outer segments, and high enough to regenerate the entire ATP pool of rod outer segments within the time span of a photic cycle. A mitochondrial creatine kinase isoenzyme was located within the ellipsoid portions of bovine rod and cone inner segments by immunofluorescence microscopy and, using immunogold staining, was specifically localized in the mitochondria clustered within bovine rod and cone inner segments. These results suggest that vertebrate photoreceptor cells contain a functional phosphocreatine circuit. Outer segment creatine kinase may play an important role in phototransduction by providing energy for the visual cycle, maintaining high local ATP/ADP ratios and consuming protons produced by enzymes located in the outer segment.

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Walzel, Bernd, Oliver Speer, Ernie Boehm, Søren Kristiansen, Sharon Chan, Kierian Clarke, Joseph P. Magyar, Erik A. Richter, and Theo Wallimann. "New creatine transporter assay and identification of distinct creatine transporter isoforms in muscle." American Journal of Physiology-Endocrinology and Metabolism 283, no. 2 (August 1, 2002): E390—E401. http://dx.doi.org/10.1152/ajpendo.00428.2001.

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Despite the pivotal role of creatine (Cr) and phosphocreatine (PCr) in muscle metabolism, relatively little is known about sarcolemmal creatine transport, creatine transporter (CRT) isoforms, and subcellular localization of the CRT proteins. To be able to quantify creatine transport across the sarcolemma, we have developed a new in vitro assay using rat sarcolemmal giant vesicles. The rat giant sarcolemmal vesicle assay reveals the presence of a specific high-affinity and saturable transport system for Cr in the sarcolemma (Michaelis-Menten constant 52.4 ± 9.4 μM and maximal velocity value 17.3 ± 3.1 pmol · min−1 · mg vesicle protein−1), which cotransports Cr into skeletal muscle together with Na+ and Cl− ions. The regulation of Cr transport in giant vesicles by substrates, analogs, and inhibitors, as well as by phorbol 12-myristate 13-acetate and insulin, was studied. Two antibodies raised against COOH- and NH2-terminal synthetic peptides of CRT sequences both recognize two major polypeptides on Western blots with apparent molecular masses of 70 and 55 kDa, respectively. The highest CRT expression occurs in heart, brain, and kidney, and although creatine kinase is absent in liver cells, CRT is also found in this tissue. Surprisingly, immunofluorescence staining of cultured adult rat heart cardiomyocytes with specific anti-CRT antibodies, as well as cell fractionation and cell surface biotinylation studies, revealed that only a minor CRT species with an intermediate molecular mass of ∼58 kDa is present in the sarcolemma, whereas the previously identified major CRT-related protein species of 70 and 55 kDa are specifically located in mitochondria. Our studies indicate that mitochondria may represent a major compartment of CRT localization, thus providing a new aspect to the current debate about the existence and whereabouts of intracellular Cr and PCr compartments that have been inferred from [14C]PCr/Cr measurements in vivo as well as from recent in vivo NMR studies.

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BREWER, G. "Higher respiratory rates and improved creatine stimulation in brain mitochondria isolated with anti-oxidants." Mitochondrion 4, no. 1 (June 2004): 49–57. http://dx.doi.org/10.1016/j.mito.2004.06.001.

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Brown, Guy C., and Vilmante Borutaite. "Nitric oxide, cytochrome c and mitochondria." Biochemical Society Symposia 66 (September 1, 1999): 17–25. http://dx.doi.org/10.1042/bss0660017.

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Nitric oxide (NO) and its derivative, peroxynitrite (ONOO-), inhibit mitochondrial respiration, and this inhibition may contribute to both the physiological and cytotoxic actions of NO. Nanomolar concentrations of NO rapidly and reversibly inhibited cytochrome oxidase in competition with oxygen, as shown with isolated cytochrome oxidase, mitochondria, brain nerve terminals and cells. Cultured astrocytes and macrophages activated (by cytokines and endotoxin) to express the inducible form of NO synthase produced up to 1 μM NO, and inhibited their own respiration and that of co-incubated cells via reversible NO inhibition of cytochrome oxidase. NO-induced inhibition of respiration in brain nerve terminals resulted in rapid glutamate release, which might contribute to the neurotoxicity of NO. NO inhibition of cytochrome oxidase is reversible; however, incubation of cells with NO donors for 4 hours resulted in an inhibition of complex I, which was reversible by light and thiol reagents and may be due to nitrosylation of thiols in complex I. NO also caused the acute inhibition of catalase, stimulation of hydrogen peroxide production by mitochondria, and reaction with hydrogen peroxide on superoxide dismutase to produce peroxynitrite. Peroxynitrite inhibited complexes I, II and V (the ATP synthase), aconitase, creatine kinase, and increases the proton leak in isolated mitochondria. Peroxynitrite also caused opening of the permeability transition pore, resulting in the release of cytochrome c, which might then trigger apoptosis. Hypoxia/ischaemia also resulted in an acute reversible inhibition of cytochrome oxidase. Heart ischaemia caused the release of cytochrome c from mitochondria into the cytosol, and at the same time caspase-3-like-protease activity was activated in the cytoplasm. Addition of cytochrome c to non-ischaemic cytosol also caused activation of this protease activity, suggesting that caspase activation and consequent apoptosis is at least partly a result of this cytochrome c release.

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Wyss, M., T. Wallimann, and J. Köhrle. "Selective labelling and inactivation of creatine kinase isoenzymes by the thyroid hormone derivative N-bromoacetyl-3,3′,5-tri-iodo-l-thyronine." Biochemical Journal 291, no. 2 (April 15, 1993): 463–72. http://dx.doi.org/10.1042/bj2910463.

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Besides their well-known regulation of transcription by binding to nuclear receptors, thyroid hormones have been suggested to have direct effects on mitochondria. In a previous study, incubation of rat heart mitochondria with 125I-labelled N-bromoacetyl-3,3′,5-tri-iodo-L-thyronine (BrAcT3), a thyroid hormone derivative with an alkylating side chain, resulted in the selective labelling of a protein doublet around M(r) 45,000 on SDS/polyacrylamide gels [Rasmussen, Köhrle, Rokos and Hesch (1989) FEBS Lett. 255, 385-390]. Now, this protein doublet has been identified as mitochondrial creatine kinase (Mi-CK). Immunoblotting experiments with the cytoplasmic and mitochondrial fractions of rat heart, brain and liver, as well as inactivation studies with the purified chicken CK isoenzymes have further demonstrated that all four CK isoenzymes (Mia-, Mib-, M- and B-CK) are indeed selectively labelled by BrAcT3. However, in contrast with their bromoalkyl derivatives, thyroid hormones themselves did not compete for CK labelling, suggesting that not the thyroid hormone moiety but rather the bromoacetyl-driven alkylation of the highly reactive ‘essential’ thiol group of CK accounts for this selective labelling. Therefore the assumption that CK isoenzymes are thyroid-hormone-binding proteins has to be dismissed. Instead, bromoacetyl-based reagents may allow a very specific covalent modification and inactivation of CK isoenzymes in vitro and in vivo.

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Li, Xing-Tai, Rui Chen, Li-Ming Jin, and Hui-Ying Chen. "Regulation on Energy Metabolism and Protection on Mitochondria of Panax Ginseng Polysaccharide." American Journal of Chinese Medicine 37, no. 06 (January 2009): 1139–52. http://dx.doi.org/10.1142/s0192415x09007454.

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Panax ginseng C A Meyer (PG) is one of the most popular qi-invigorating herbal medicine and has been used to promote health, vitality, and longevity in China. Although PG has been used in traditional Chinese medicine for millennia, its qi-invigorating activities still lack convincing evidence. We investigated the effects of Panax ginseng polysaccharide (PGP) on energy metabolism and mitochondrial protection. The chronic hypoxia model was set up. Lipid peroxidation product malondialdehyde (MDA) was assayed by thiobarbituric acid (TBA) colorimetry. Mice liver mitochondria were isolated by differential centrifugation. The spectrophotometric method was used to measure the swelling of mitochondria. The levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) in liver cells were determined by reversed-phase high performance liquid chromatography (RP-HPLC), adenylate energy charge (AEC), total adenylate pool (TAP), ATP/ADP and ATP/AMP ratio were calculated. The creatine kinase (CK) activities in mice skeletal muscle were determined by a commercial monitoring kit. The result showed that PGP could inhibit mitochondrial injury and swelling induced by Fe 2+-L-Cys in a concentration-dependent manner. PGP which was administered by oral gavage daily for 10 days could inhibit the formation of MDA in mice brain, increase levels of ATP, ADP, TAP and AEC, ratio of ATP/ADP and ATP/AMP in liver cells, increase CK activities in mice skeletal muscle under chronic hypoxia condition. These results indicate that PGP protect mitochondria by inhibiting mitochondrial swelling, and improving energy metabolism. PGP functions as a preventive antioxidant by increasing CK activities. Therefore, PGP had the pharmaceutical activities of antihypoxia, antioxidation and improving energy status.

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ANFLOUS, Keltoum, Vladimir VEKSLER, Philippe MATEO, Françoise SAMSON, Valdour SAKS, and Renée VENTURA-CLAPIER. "Mitochondrial creatine kinase isoform expression does not correlate with its mode of action." Biochemical Journal 322, no. 1 (February 15, 1997): 73–78. http://dx.doi.org/10.1042/bj3220073.

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In adult mammalian ventricular tissue, mitochondrial creatine kinase (mi-CK), which is bound to the outer surface of the mitochondrial inner membrane, is functionally coupled to oxidative phosphorylation. This is shown, in saponin-permeabilized rat ventricular fibres, by a shift in the apparent Km of mitochondrial respiration for ADP from 300ŷ56 ƁM to 111ŷ40 ƁM (P < 0.001) on the addition of 25 mM creatine, due to a local accumulation of ADP close to the ATP/ADP translocator. We have found that, in atrial fibres, the apparent Km for ADP is high, but is not decreased by creatine, suggesting an absence of coupling in this tissue, as has previously been observed in smooth muscle. mi-CK is encoded by two different genes, which are expressed in a tissue-specific manner: the sarcomeric isoform is expressed in ventricular and skeletal muscles, while the ubiquitous isoform is expressed in smooth muscle, brain and other tissues. In order to determine whether a specific function can be attributed to the expression of a specific isoform, we investigated mi-CK mRNA expression by Northern blot analysis. Hybridization with synthetic oligonucleotides specific for each mi-CK isoform showed the expression of only the sarcomeric isoform in rat atria. This result was confirmed by PCR using primers specific for each isoform. In addition, electrophoretic analysis of CK isoforms showed no difference in the octamer/dimer ratio of mi-CK in the atria and ventricles. In atria, unlike the soleus or ventricles, the maximum potential rate of mitochondrial phosphocreatine synthesis was lower than the maximal rate of ATP production by the mitochondria. The total CK/adenylate kinase ratio was also lower in atria than in the other tissues, suggesting a greater contribution of adenylate kinase to adenine nucleotide compartmentation in this tissue. The functional differences between mi-CK in the two cardiac tissues seem to imply a specific arrangement of the proteins in the intermembrane space rather than the expression of specific isoforms.

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Buneeva, O. A., O. V. Gnedenko, M. V. Medvedeva, A. S. Ivanov, and A. E. Medvedev. "The use of immobilized ubiquitin for biosensor analysis of the mitochondrial subinteractome." Biomeditsinskaya Khimiya 60, no. 6 (2014): 615–22. http://dx.doi.org/10.18097/pbmc20146006615.

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Protein ubiquitination is considered as an important mechanism that is responsible not only for specific labeling of proteins for their subsequent degradation but also for localization of proteins in the cell and regulation of protein-protein interactions. In the context of protein-protein interactions binding of (mono/poly)ubiquitinated molecules to proteins containing specific ubiquitin binding domains appear to play the decisive role. Although formation of the ubiquitin interactome has been demonstrated for cytosol, involvement of mitochondria and associated extramitochondrial proteins into such interactions still requires detailed investigation. In this study using an optical biosensor we have demonstrated binding of proteins of mouse brain mitochondrial lysates to immobilized monomeric ubiquitin. Model purified proteins, which are known to be associated with the outer mitochondrial compartment (glyceraldehyde-3-phosphate dehydorgenase, creatine phosphokinase), interacted with immobilized ubiquitin as well as with each other. This suggests that (poly)ubiquitinated chains may be involved in protein-protein interactions between ubiquitinated and non-ubiquitinated proteins and thus may contribute to formation of (mitochondrial) ubiquitin subinteractome.

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Monge, Claire, Nathalie Beraud, Andrey V. Kuznetsov, Tatiana Rostovtseva, Dan Sackett, Uwe Schlattner, Marko Vendelin, and Valdur A. Saks. "Regulation of respiration in brain mitochondria and synaptosomes: restrictions of ADP diffusion in situ, roles of tubulin, and mitochondrial creatine kinase." Molecular and Cellular Biochemistry 318, no. 1-2 (July 16, 2008): 147–65. http://dx.doi.org/10.1007/s11010-008-9865-7.

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Tokarska-Schlattner, Malgorzata, Michael Zaugg, Rafaela da Silva, Eliana Lucchinetti, Marcus C. Schaub, Theo Wallimann, and Uwe Schlattner. "Acute toxicity of doxorubicin on isolated perfused heart: response of kinases regulating energy supply." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 1 (July 2005): H37—H47. http://dx.doi.org/10.1152/ajpheart.01057.2004.

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Doxorubicin (DXR) is a widely used and efficient anticancer drug. However, its application is limited by the risk of severe cardiotoxicity. Impairment of cardiac high-energy phosphate homeostasis is an important manifestation of both acute and chronic DXR cardiotoxic action. Using the Langendorff model of the perfused rat heart, we characterized the acute effects of 1-h perfusion with 2 or 20 μM DXR on two key kinases in cardiac energy metabolism, creatine kinase (CK) and AMP-activated protein kinase (AMPK), and related them to functional responses of the perfused heart and structural integrity of the contractile apparatus as well as drug accumulation in cardiomyocytes. DXR-induced changes in CK were dependent on the isoenzyme, with a shift in protein levels of cytosolic isoenzymes from muscle-type CK to brain-type CK, and a destabilization of octamers of the mitochondrial isoenzyme (sarcometric mitochondiral CK) accompanied by drug accumulation in mitochondria. Interestingly, DXR rapidly reduced the protein level and phosphorylation of AMPK as well as phosphorylation of its target, acetyl-CoA-carboxylase. AMPK was strongly affected already at 2 μM DXR, even before substantial cardiac dysfunction occurred. Impairment of CK isoenzymes was mostly moderate but became significant at 20 μM DXR. Only at 2 μM DXR did upregulation of brain-type CK compensate for inactivation of other isoenzymes. These results suggest that an impairment of kinase systems regulating cellular energy homeostasis is involved in the development of DXR cardiotoxicity.

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Scaini, Giselli, Natália Rochi, Meline O. S. Morais, Débora D. Maggi, Bruna T. De-Nês, João Quevedo, and Emilio L. Streck. "In vitro effect of antipsychotics on brain energy metabolism parameters in the brain of rats." Acta Neuropsychiatrica 25, no. 1 (February 2013): 18–26. http://dx.doi.org/10.1111/j.1601-5215.2012.00650.x.

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ObjectiveTypical and atypical antipsychotic drugs have been shown to have different clinical, biochemical and behavioural profiles. It is well described that impairment of metabolism, especially in the mitochondria, leads to oxidative stress and neuronal death and has been implicated in the pathogenesis of a number of diseases in the brain. In this context, we investigated the in vitro effect of antipsychotic drugs on energy metabolism parameters in the brain of rats.MethodsClozapine (0.1, 0.5 and 1.0 mg/ml), olanzapine (0.1, 0.5 and 1.0 mg/ml) and aripiprazole (0.05, 0.15 and 0.3 mg/ml) were suspended in buffer and added to the reaction medium containing rat tissue homogenates and the respiratory chain complexes, succinate dehydrogenase and creatine kinase (CK) activities were evaluated.ResultsOur results showed that olanzapine and aripriprazole increased the activities of respiratory chain complexes. On the other hand, complex IV activity was inhibited by clozapine, olanzapine and aripriprazole. CK activity was increased by clozapine at 0.5 and 1.0 mg/ml in prefrontal cortex, cerebellum, striatum, hippocampus and posterior cortex of rats. Moreover, olanzapine and aripiprazole did not affect CK activity.ConclusionIn this context, if the hypothesis that metabolism impairment is involved in the pathophysiology of neuropsychiatric disorders is correct and these results also occur in vivo, we suggest that olanzapine may reverse a possible diminution of metabolism.

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Pichumani, Kumar, Omkar Ijare, Martyn Sharpe, Lisa Nguyen, Santosh Helekar, and David Baskin. "NIMG-48. USE OF MOBILE LIPIDS AS METABOLIC MARKERS FOR THE ASSESSMENT OF TREATMENT-INDUCED NECROSIS IN A RECURRENT GLIOBLASTOMA PATIENT TREATED WITH A NEW OSCILLATING MAGNETIC FIELD GENERATING DEVICE." Neuro-Oncology 22, Supplement_2 (November 2020): ii158. http://dx.doi.org/10.1093/neuonc/noaa215.661.

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Abstract The FDA has approved tumor treating fields (Optune) to treat glioblastoma (GBM) and unresectable mesothelioma. Optune uses scalp electrodes to pass a strong alternating electric field through the head, slowing GBM growth. We have recently developed and tested a novel device that uses an oscillating magnetic field (OMF) generated by rotating magnets to treat GBM. Our first GBM patient had a recurrent GBM with leptomeningeal spread. A custom-made Oncomagnetic device consisting of a multi-sport helmet with three OMF generators called oncoscillators, was worn by the patient at home. Changes in the brain and GBM tumor metabolism were examined using in vivo1H MRS on a 7T Siemens MRI scanner. 1H MRS data of the “tumor” and “non-tumor” regions during OMF treatment was obtained using sLASER pulse sequences. Both non–tumor and tumor regions showed the most common brain metabolites – myo-inositol, creatine, choline, glutamine/glutamate, and N-acetyl aspartate (NAA). 30 days after initiation of treatment, choline, creatine and NAA levels in the shrunken tumor region had collapsed. The tumor region displayed broad proton signals centered at 1.30 ppm and 0.88 ppm. These peaks have been observed following successful brain tumor radiation therapy and have been attributed to the presence of mobile lipids due to tumor necrosis. Our in vitro experiments suggest OMF-induced damage to mitochondria and elevated levels of reactive oxygen species, leading to cancer cell death via apoptosis and necrosis. We propose that loss of choline and elevation of lipid levels may be used as a metabolite ‘fingerprint’ to noninvasively assess the Oncomagnetic treatment response. This powerful new treatment holds great promise for treatment of patients with GBM, and produces rapid changes in brain chemistry during treatment.

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Rae, Caroline D., Vincent H. C. Lee, Roger J. Ordidge, Angelo Alonzo, and Colleen Loo. "Anodal transcranial direct current stimulation increases brain intracellular pH and modulates bioenergetics." International Journal of Neuropsychopharmacology 16, no. 8 (September 1, 2013): 1695–706. http://dx.doi.org/10.1017/s1461145713000084.

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Abstract Transcranial direct current stimulation is an emerging treatment for brain disorders but its mode of action is not well understood. We applied 10 min 1 mA anodal transcranial direct current stimulation (tDCS) inside the bore of a 3 T MRI scanner to the left dorsolateral prefrontal cortex of 13 healthy volunteers (aged 19–28 yr) in a blinded, sham-controlled, cross-over design. Brain bioenergetics were measured from the left temporo-frontal region using 31P magnetic resonance spectroscopy before, during and for 20 min following tDCS. Brain pH rose during tDCS and remained elevated afterwards. Phosphomonoesters were significantly decreased while inorganic phosphate (Pi) also fell. Partial-least squares discriminant analysis of the data revealed two significantly different subject groups: one where phosphocreatine (PCr), ATP and Pi fell along with a larger increase in pH and one where PCr and ATP increased along with a smaller increase in pH and a slower and more sustained decrease in Pi. Group membership was predicted by baseline pH and ATP. We interpreted the effects of tDCS as driving two biochemical processes: cellular consumption of ATP causing hydrolysis of PCr via the creatine kinase reaction driving the increase in pH; synthesis of ATP and PCr by mitochondria with concomitant drop in Pi and phosphomonoester levels.

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DÜMMLER, Katrin, Stefan MÜLLER, and Hans J. SEITZ. "Regulation of adenine nucleotide translocase and glycerol 3-phosphate dehydrogenase expression by thyroid hormones in different rat tissues." Biochemical Journal 317, no. 3 (August 1, 1996): 913–18. http://dx.doi.org/10.1042/bj3170913.

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Thyroid hormone (T3)-dependent gene expression of the adenine nucleotide translocase (ANT) and the FAD-linked glycerol 3-phosphate dehydrogenase (mGPDH) was investigated in several rat tissues. Both proteins provide an important link between cytosolic and mitochondrial metabolic pathways and seem to be involved in the stimulation of mitochondrial oxygen consumption in response to T3. Here we show that two ANT isoforms are expressed in rat, the muscle-specific ANT1 form and the ubiquitous ANT2 form. The expression of ANT1 mRNA is not sensitive to T3 whereas the amount of ANT2 mRNA is increased 7–9-fold in liver and heart within 12–48 h after T3 application. Little or no effect of T3 on ANT2 mRNA was observed in kidney and brain. The mRNA changes are paralleled by an increase in ANT protein, thus explaining the accelerated ADP/ATP exchange observed in mitochondria isolated from hyperthyroid rats. The key role of ANT2 in the control of hyperthyroid metabolism is evident because the expression of the mersalyl-sensitive phosphate carrier and the mitochondrial creatine kinase mRNA, which are functionally linked to ANT, did not respond to T3. Similarly to the ADP/ATP exchange, the transfer of cytosolic NADH to the respiratory chain via the glycerophosphate shuttle is very sensitive to T3. Recently we demonstrated the 10–15-fold induction of mGPDH mRNA in rat liver after administration of T3 [Müller and Seitz (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 10581–10585]. Here we show that, in contrast with ANT2, the time course of induction is fast (4–6 h). Furthermore, mGPDH mRNA is induced 6-fold by T3 in heart and 4-fold in kidney. From these results we conclude that the T3-mediated transcriptional induction leading to increased activity of ANT2 and mGPDH contributes considerably to the increase in mitochondrial oxygen consumption in rat tissues.

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Chang, Kuo-Hsuan, and Chiung-Mei Chen. "The Role of Oxidative Stress in Parkinson’s Disease." Antioxidants 9, no. 7 (July 8, 2020): 597. http://dx.doi.org/10.3390/antiox9070597.

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Parkinson’s disease (PD) is caused by progressive neurodegeneration of dopaminergic (DAergic) neurons with abnormal accumulation of α-synuclein in substantia nigra (SN). Studies have suggested the potential involvement of dopamine, iron, calcium, mitochondria and neuroinflammation in contributing to overwhelmed oxidative stress and neurodegeneration in PD. Function studies on PD-causative mutations of SNCA, PRKN, PINK1, DJ-1, LRRK2, FBXO7 and ATP13A2 further indicate the role of oxidative stress in the pathogenesis of PD. Therefore, it is reasonable that molecules involved in oxidative stress, such as DJ-1, coenzyme Q10, uric acid, 8-hydroxy-2’-deoxyguanosin, homocysteine, retinoic acid/carotenes, vitamin E, glutathione peroxidase, superoxide dismutase, xanthine oxidase and products of lipid peroxidation, could be candidate biomarkers for PD. Applications of antioxidants to modulate oxidative stress could be a strategy in treating PD. Although a number of antioxidants, such as creatine, vitamin E, coenzyme Q10, pioglitazone, melatonin and desferrioxamine, have been tested in clinical trials, none of them have demonstrated conclusive evidence to ameliorate the neurodegeneration in PD patients. Difficulties in clinical studies may be caused by the long-standing progression of neurodegeneration, lack of biomarkers for premotor stage of PD and inadequate drug delivery across blood–brain barrier. Solutions for these challenges will be warranted for future studies with novel antioxidative treatment in PD patients.

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Zhang, Yang, Xiao-Yan Ma, Tong Zhang, Meng Qin, Bo Sun, Qi Li, Dian-Wen Hu, and Li-Qun Ren. "Protective Effects of Apocynum venetum Against Pirarubicin-Induced Cardiotoxicity." American Journal of Chinese Medicine 47, no. 05 (January 2019): 1075–97. http://dx.doi.org/10.1142/s0192415x19500551.

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Pirarubicin (THP) is an anthracycline antibiotic, frequently used for the treatment of various human cancers. Unfortunately, the clinical effectiveness of THP is limited by its dose-related cardiotoxicity. Apocynum leaf extract is an extract of the dried leaves of Apocynum venetum L. (a member of the Apocynaceae family, AVLE) that has many positive effects on the cardiovascular system and is widely consumed as tea in China. In this study we established a cardiactoxicity rat model, which showed that pretreatment with AVLE attenuated THP-induced myocardial histopathological injury, electrocardiogram abnormalities, and cardiac dysfunction. AVLE also significantly reduced serum levels of malondialdehyde (MDA), brain natriuretic peptide (BNP), creatine kinase (CK-MB), cardiac troponin (CTnT), and lactate dehydrogenase (LDH); and increased serum superoxide dismutase (SOD) levels. Treatment with AVLE or dexrazoxane (DZR) resulted in an increase Cytochrome C (cytc) in the mitochondria and reduced Cytc and cleaved-caspase-3 levels ([Formula: see text]) in cytoplasm. We also found that AVLE significantly reduced voltage-dependent anion channel 1 (VDAC1), adenosine nucleotide transporter 1 (ANT1), and cyclophilin D (CYPD) mRNA expression ([Formula: see text]). Furthermore, AVLE appeared to exert therapeutic effects in a dose-dependent manner. Our study suggests the anti-oxidant and anti-apoptotic properties of AVLE may be responsible for the observed cardioprotective effects.

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Shestakova, Maia A., Polina A. Vishnyakova, and Timur Kh Fatkhudinov. "Placenta: an organ with high energy requirements." RUDN Journal of Medicine 26, no. 4 (December 23, 2022): 353–63. http://dx.doi.org/10.22363/2313-0245-2022-26-4-353-363.

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Placenta is a unique organ, without which the very phenomenon of human pregnancy is impossible. Semiallogeneous nature, localization of the placenta, complex and heterogeneous cellular composition determines its complex and multifaceted role in the course of physiological pregnancy, indicates the importance of studying this organ in a number of reproductive pathologies. The purpose of this review was to analyze the literature sources illustrating the importance of energydependent processes in placental metabolism and to determine the molecular basis of placental energy conversion. Publications of foreign and Russian authors from PubMed database and scientific electronic library eLIBRARY.ru were used when writing the review. The review highlights the main functions of the placenta: transport and synthetic functions in terms of their place in the structure of energy expenditure of the organ. The systems by which the transport of ions and gases from maternal blood through the placental barrier is performed, are considered. The role of the placenta in the synthesis of steroid hormones and glucocorticoids is detailed. The main bioenergetic systems are also considered: placental glucose metabolism, the functional activity of mitochondria and the creatine kinase system of the placenta. These data allow us to put the placenta on a par with other organs with high energy requirements (brain, transverse striated skeletal muscles, heart, kidneys, liver), which are most susceptible to metabolic disorders. Maintaining a balance between expenditure and synthesis of macroergic compounds in the placenta is critical for an adequate course of physiological pregnancy, and imbalances can lead to such pathologies as fetal retardation syndrome or preeclampsia. Further study of placental energy supply systems seems important for understanding the mechanisms of intrauterine development disorders and developing their pathogenetic treatment.

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Bürklen, Tanja S., Uwe Schlattner, Ramin Homayouni, Kathleen Gough, Margaret Rak, Adriana Szeghalmi, and Theo Wallimann. "The Creatine Kinase/Creatine Connection to Alzheimer's Disease: CK Inactivation, APP-CK Complexes and Focal Creatine Deposits." Journal of Biomedicine and Biotechnology 2006 (2006): 1–11. http://dx.doi.org/10.1155/jbb/2006/35936.

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Cytosolic brain-type creatine kinase (BB-CK), which is coexpressed with ubiquitous mitochondrial uMtCK, is significantly inactivated by oxidation, in Alzheimer's disease (AD) patients. Since CK has been shown to play a fundamental role in cellular energetics of the brain, any disturbance of this enzyme may exasperate the AD disease process. Mutations in amyloid precursor protein (APP) are associated with early onset AD and result in abnormal processing of APP, and accumulation of Aβpeptide, the main constituent of amyloid plaques in AD brain. Recent data on a direct interaction between APP and the precursor of uMtCK support an emerging relationship between AD, cellular energy levels and mitochondrial function. In addition, recently discovered creatine (Cr) deposits in the brain of transgenic AD mice, as well as in the hippocampus from AD patients, indicate a direct link between perturbed energy state, Cr metabolism and AD. Here, we review the roles of Cr and Cr-related enzymes and consider the potential value of supplementation with Cr, a potent neuroprotective substance. As a hypothesis, we consider whether Cr, if given at an early time point of the disease, may prevent or delay the course of AD-related neurodegeneration.

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Muccini, Anna Maria, Nhi T. Tran, Nadia Hale, Matthew McKenzie, Rod J. Snow, David W. Walker, and Stacey J. Ellery. "The Effects of In Utero Fetal Hypoxia and Creatine Treatment on Mitochondrial Function in the Late Gestation Fetal Sheep Brain." Oxidative Medicine and Cellular Longevity 2022 (January 29, 2022): 1–19. http://dx.doi.org/10.1155/2022/3255296.

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Near-term acute hypoxia in utero can result in significant fetal brain injury, with some brain regions more vulnerable than others. As mitochondrial dysfunction is an underlying feature of the injury cascade following hypoxia, this study is aimed at characterizing mitochondrial function at a region-specific level in the near-term fetal brain after a period of acute hypoxia. We hypothesized that regional differences in mitochondrial function would be evident, and that prophylactic creatine treatment would mitigate mitochondrial dysfunction following hypoxia; thereby reducing fetal brain injury. Pregnant Border-Leicester/Merino ewes with singleton fetuses were surgically instrumented at 118 days of gestation (dGa; term is ~145 dGA). A continuous infusion of either creatine ( n = 15 ; 6 mg/kg/h) or isovolumetric saline ( n = 16 ; 1.5 ml/kg/h) was administered to the fetuses from 121 dGa. After 10 days of infusion, a subset of fetuses (8 saline-, 7 creatine-treated) were subjected to 10 minutes of umbilical cord occlusion (UCO) to induce a mild global fetal hypoxia. At 72 hours after UCO, the fetal brain was collected for high-resolution mitochondrial respirometry and molecular and histological analyses. The results show that the transient UCO-induced acute hypoxia impaired mitochondrial function in the hippocampus and the periventricular white matter and increased the incidence of cell death in the hippocampus. Creatine treatment did not rectify the changes in mitochondrial respiration associated with hypoxia, but there was a negative relationship between cell death and creatine content following treatment. Irrespective of UCO, creatine increased the proportion of cytochrome c bound to the inner mitochondrial membrane, upregulated the mRNA expression of the antiapoptotic gene Bcl2, and of PCG1-α, a driver of mitogenesis, in the hippocampus. We conclude that creatine treatment prior to brief, acute hypoxia does not fundamentally modify mitochondrial respiratory function, but may improve mitochondrial structural integrity and potentially increase mitogenesis and activity of antiapoptotic pathways.

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Pan, J. W., and K. Takahashi. "Cerebral energetic effects of creatine supplementation in humans." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292, no. 4 (April 2007): R1745—R1750. http://dx.doi.org/10.1152/ajpregu.00717.2006.

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There has been considerable interest in the use of creatine (Cr) supplementation to treat neurological disorders. However, in contrast to muscle physiology, there are relatively few studies of creatine supplementation in the brain. In this report, we use high-field MR 31P and 1H spectroscopic imaging of human brain with a 7-day protocol of oral Cr supplementation to examine its effects on cerebral energetics (phosphocreatine, PCr; ATP) and mitochondrial metabolism ( N-acetyl aspartate, NAA; and Cr). We find an increased ratio of PCr/ATP ( day 0, 0.80 ± 0.10; day 7, 0.85 ± 09), with this change largely due to decreased ATP, from 2.7 ± 0.3 mM to 2.5 ± 0.3 mM. The ratio of NAA/Cr also decreased ( day 0, 1.32 ± 0.17; day 7 1.18 ± 0.13), primarily from increased Cr (9.6 ± 1.9 to 10.1 ± 2.0 mM). The Cr-induced changes significantly correlated with the basal state, with the fractional increase in PCr/ATP negatively correlating with the basal PCr/ATP value ( R = −0.74, P < 0.001). As NAA is a measure of mitochondrial function, there was also a significant negative correlation between basal NAA concentrations with the fractional change in PCr and ATP. Thus healthy human brain energetics is malleable and shifts with 7 days of Cr supplementation, with the regions of initially low PCr showing the largest increments in PCr. Overall, Cr supplementation appears to improve high-energy phosphate turnover in healthy brain and can result in either a decrease or an increase in high-energy phosphate concentrations.

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Buhl, Line, David Muirhead, and David Doyle. "Kearns-Sayre syndrome, a mitochondrial myopathy: First diagnosed case in Oman." Proceedings, annual meeting, Electron Microscopy Society of America 50, no. 1 (August 1992): 636–37. http://dx.doi.org/10.1017/s0424820100123581.

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Mitochondrial myopathy of the Kearns-Sayres Syndrome is described as a severe disorder which is progressive with CNS involvement, has metabolic acidotic crisis and is eventually fatal. The proportion of muscle fibres containing abnormal mitochondria maybe as low as 5-10% in cases presenting with severe clinical symptoms. There is no recognised treatment for this degenerative disease.An 11 year old Omani girl well until the age of 5 years, showed increasing symptoms of external ophthalmoplegia, ptosis, tubular vision and retinitis pigmentosa. CT scan showed atrophy of the brain. Biochemistry revealed an elevated creatinine kinase. A muscle biopsy was performed at the age of 11 years. The patient had no known family history.

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Tuon, Lisiane, Clarissa M. Comim, Daine B. Fraga, Giselli Scaini, Gislaine T. Rezin, Bruna R. Baptista, Emilio L. Streck, Mariz Vainzof, and João Quevedo. "Mitochondrial respiratory chain and creatine kinase activities in mdx mouse brain." Muscle & Nerve 41, no. 2 (January 15, 2010): 257–60. http://dx.doi.org/10.1002/mus.21559.

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Lowe, Matthew TJ, Eric H. Kim, Richard LM Faull, David L. Christie, and Henry J. Waldvogel. "Dissociated Expression of Mitochondrial and Cytosolic Creatine Kinases in the Human Brain: A New Perspective on the Role of Creatine in Brain Energy Metabolism." Journal of Cerebral Blood Flow & Metabolism 33, no. 8 (May 29, 2013): 1295–306. http://dx.doi.org/10.1038/jcbfm.2013.84.

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The phosphocreatine/creatine kinase (PCr/CK) system in the brain is defined by the expression of two CK isozymes: the cytosolic brain-type CK (BCK) and the ubiquitous mitochondrial CK (uMtCK). The system plays an important role in supporting cellular energy metabolism by buffering adenosine triphosphate (ATP) consumption and improving the flux of high-energy phosphoryls around the cell. This system is well defined in muscle tissue, but there have been few detailed studies of this system in the brain, especially in humans. Creatine is known to be important for neurologic function, and its loss from the brain during development can lead to mental retardation. This study provides the first detailed immunohistochemical study of the expression pattern of BCK and uMtCK in the human brain. A strikingly dissociated pattern of expression was found: uMtCK was found to be ubiquitously and exclusively expressed in neuronal populations, whereas BCK was dominantly expressed in astrocytes, with a low and selective expression in neurons. This pattern indicates that the two CK isozymes are not widely coexpressed in the human brain, but rather are selectively expressed depending on the cell type. These results suggest that the brain cells may use only certain properties of the PCr/CK system depending on their energetic requirements.

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Giusti, Laura, Angelo Molinaro, Maria Grazia Alessandrì, Claudia Boldrini, Federica Ciregia, Serena Lacerenza, Maurizio Ronci, et al. "Brain mitochondrial proteome alteration driven by creatine deficiency suggests novel therapeutic venues for creatine deficiency syndromes." Neuroscience 409 (June 2019): 276–89. http://dx.doi.org/10.1016/j.neuroscience.2019.03.030.

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Réus, Gislaine Z., Roberto B. Stringari, Gislaine T. Rezin, Daiana P. Pezente, Giselli Scaini, Débora D. Maggi, Bruna T. De-Nês, Emilio L. Streck, João Quevedo, and Gustavo Feier. "Effects of maintenance electroshock on mitochondrial respiratory chain and creatine kinase activities in the rat brain." Acta Neuropsychiatrica 24, no. 5 (October 2012): 275–85. http://dx.doi.org/10.1111/j.1601-5215.2011.00629.x.

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Réus GZ, Stringari RB, Rezin GT, Pezente DP, Scaini G, Maggi DD, De-Nês BT, Streck EL, Quevedo J, Feier G. Effects of maintenance electroshock on mitochondrial respiratory chain and creatine kinase activities in the rat brain.Objective: Electroconvulsive therapy is used efficacious treatment for a variety of complicated psychiatric disorders and evidences have indicated that energy metabolism impairment may be involved in pathophysiology and treatment of mood disorders. This work was performed to determine creatine kinase and mitochondrial respiratory chain activities at different times after the maintenance electroconvulsive shock (ECS).Methods: Male Wistar rats received a protocol mimicking therapeutic of maintenance or simulated ECS (sham) and were subsequently sacrificed immediately after, 48 h and 7 days after the last maintenance ECS. We measured creatine kinase and mitochondrial respiratory chain activities in the prefrontal cortex, hippocampus, cortex, cerebellum and striatum.Results: Our results showed that maintenance ECS alter respiratory chain complexes and creatine kinase activities in the rat brain, but these effects were related to brain area and time after the ECS, in which the animal were killed.Conclusion: Finally, these findings further support the hypothesis that alteration on the energy metabolism could be involved in the therapeutic or adverse effects of ECS.

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Barbiroli, Bruno, Pasquale Montagna, Paolo Martinelli, Raffaele Lodi, Stefano Iotti, Pietro Cortelli, Rosanna Funicello, and Paolo Zaniol. "Defective Brain Energy Metabolism Shown by in vivo 31P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies." Journal of Cerebral Blood Flow & Metabolism 13, no. 3 (May 1993): 469–74. http://dx.doi.org/10.1038/jcbfm.1993.61.

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We studied brain energy metabolism by phosphorus magnetic resonance spectroscopy (31P MRS) in 28 patients with mitochondrial cytopathies, and 20 normal control subjects. Fourteen patients had myopathy alone, six had only mild brain symptoms, and eight showed different degrees of brain involvement. Brain 31P MRS showed a low phosphocreatine content in all patients, accompanied by a high inorganic phosphate in 14 of 28 patients. The average value of the Pi concentration in the patient group was significantly (p = 0.009) different from the control group. The cytosolic pH was normal. From these data were derived a high concentration of ADP (calculated from the creatine kinase equilibrium), a high percent value of V/Vmax for ATP biosynthesis, and a low phosphorylation potential, all features showing a derangement of brain energy metabolism, in all patients with mitochondrial cytopathies. 31P MRS proved to be sensitive enough to disclose a deficit of mitochondrial functionality not only in the affected patients, but also in those without clinically evident brain symptoms.

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Kekelidze, T�a, Igor Khait, Anthony Togliatti, Jorge M. Benzecry, Be Wieringa, and David Holtzman. "Altered brain phosphocreatine and ATP regulation when mitochondrial creatine kinase is absent." Journal of Neuroscience Research 66, no. 5 (2001): 866–72. http://dx.doi.org/10.1002/jnr.10060.

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Chen, Lulu, Robert Roberts, and David L. Friedman. "Expression of brain-type creatine kinase and ubiquitous mitochondrial creatine kinase in the fetal rat brain: Evidence for a nuclear energy shuttle." Journal of Comparative Neurology 363, no. 3 (December 18, 1995): 389–401. http://dx.doi.org/10.1002/cne.903630305.

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Holtzman, David, Martin Offutt, Miles Tsuji, Leo J. Neuringer, and Danny Jacobs. "Creatine Kinase-Catalyzed Reaction Rate in the Cyanide-Poisoned Mouse Brain." Journal of Cerebral Blood Flow & Metabolism 13, no. 1 (January 1993): 153–61. http://dx.doi.org/10.1038/jcbfm.1993.18.

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Brain creatine kinase (CK)-catalyzed phosphorus flux from phosphocreatine (PC) to ATP was measured in vivo in young adult mice made reversibly hypoxic by injection of cyanide. Phosphorus spectra and saturation transfer measurements of CK-catalyzed flux were acquired using a high-field (8.45 T) nuclear magnetic resonance (NMR) spectrometer. After low cyanide doses (1–3 mg/kg of body weight), there were no measurable changes in brain pH or in concentrations of PC, the nucleoside triphosphates (including ATP), and Pi, The CK-catalyzed phosphorus flux increased about 75% after the low cyanide dose. Higher doses (4–6 mg/kg) produced a transient 30–40% decrease in PC concentration, doubling of Pi, and a 0.2 unit decrease in pH. The CK-catalyzed phosphorus flux decreased 50–80% after the higher cyanide doses. This decrease in phosphorus flux was present long after reactant concentrations returned to precyanide values. It is proposed that the increase in brain CK-catalyzed phosphorus flux with the lower cyanide doses is due to an increase in ADP concentration. The large, prolonged decrease in CK-catalyzed reaction rate in the moderately poisoned brain may be due to loss of activity of the mitochondrial CK isoform.

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Holtzman, D., R. Meyers, E. O'Gorman, I. Khait, T. Wallimann, E. Allred, and F. Jensen. "In vivo brain phosphocreatine and ATP regulation in mice fed a creatine analog." American Journal of Physiology-Cell Physiology 272, no. 5 (May 1, 1997): C1567—C1577. http://dx.doi.org/10.1152/ajpcell.1997.272.5.c1567.

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Mitochondrial and cytosolic creatine kinase (CK) isozymes are active in cells with high and variable ATP metabolic rates. beta-Guanidinopropionic acid (GPA), a competitive inhibitor of creatine transport, was used to study the hypothesis that the creatine-CK-phosphocreatine (PCr) system is important in regulating brain ATP metabolism. The CK-catalyzed reaction rate and reactant concentrations were measured in vivo with 31P nuclear magnetic resonance spectroscopy during energy deficit (hypoxia) or high-energy turnover (seizures) states in urethane-anesthetized mice fed GPA, creatine, or standard chow (controls). Brain phosphagen (i.e., cellular energy reserves) or PCr plus phosphorylated GPA (GPAP) concentrations were equal. The phosphagen-to-NTP ratio was lower than in controls. In vivo CK reaction rate decreased fourfold, whereas ex vivo CK activity that was biochemically measured was doubled. During seizures, CK-catalyzed fluxes increased only in GPA-fed mice. Phosphagen increased in GPA-fed mice, whereas PCr decreased in controls. Survival was higher and brain phosphagen and ATP losses were less for hypoxic GPA-fed mice than for controls. In contrast to mice fed GPA, hypoxic survival and CK reactant concentrations during hypoxia and seizures were the same in creatine-fed mice and controls. Thus GPA, GPAP, or adaptive changes in ATP metabolism stabilize brain ATP and enhance survival during hypoxia in mice.

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Snow, Wanda M., Chris Cadonic, Claudia Cortes-Perez, Aida Adlimoghaddam, Subir K. Roy Chowdhury, Ella Thomson, Adama Anozie, et al. "Sex-Specific Effects of Chronic Creatine Supplementation on Hippocampal-Mediated Spatial Cognition in the 3xTg Mouse Model of Alzheimer’s Disease." Nutrients 12, no. 11 (November 23, 2020): 3589. http://dx.doi.org/10.3390/nu12113589.

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The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8–9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enhancements with Cr supplementation in both sexes. In females, Cr supplementation increased CREB phosphorylation and levels of IκB (NF-κB suppressor), CaMKII, PSD-95, and high-molecular-weight amyloid β (Aβ) species, whereas Aβ trimers were reduced. These data suggest a beneficial preventative effect of Cr supplementation in females and warrant caution against Cr supplementation in males in the AD-like brain.

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Askenasy, Nadir, and Alan P. Koretsky. "Transgenic livers expressing mitochondrial and cytosolic CK: mitochondrial CK modulates free ADP levels." American Journal of Physiology-Cell Physiology 282, no. 2 (February 1, 2002): C338—C346. http://dx.doi.org/10.1152/ajpcell.00404.2001.

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The function of creatine kinase (CK) and its effect on phosphorus metabolites was studied in livers of transgenic mice expressing human ubiquitous mitochondrial CK (CK-Mit) and rat brain CK (CK-B) isoenzymes and their combination.31P NMR spectroscopy and saturation transfer were recorded in livers of anesthetized mice to measure high-energy phosphates and hepatic CK activity. CK reaction velocity was related to total enzyme activity irrespective of the isoenzyme expressed, and it increased with increasing concentrations of creatine (Cr). The fluxes mediated by both isoenzymes in both directions (phosphocreatine or ATP synthesis) were equal. Over a 20-fold increase in CK-Mit activity (28–560 μmol · g wet wt−1 · min−1), the fraction of phosphorylated Cr increased 1.6-fold. Hepatic free ADP concentrations calculated by assuming equilibrium of the CK-catalyzed reaction in vivo decreased from 84 ± 9 to 38 ± 4 nmol/g wet wt. Calculated free ADP levels in mice expressing high levels of CK-B (920–1,635 μmol · g wet wt−1 · min−1) were 52 ± 6 nmol/g wet wt. Mice expressing both isoenzymes had calculated free ADP levels of 36 ± 4 nmol/g wet wt. These findings indicate that CK-Mit catalyzes its reaction equally well in both directions and can lower hepatic apparent free ADP concentrations.

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Réus, Gislaine Z., Roberto B. Stringari, Cinara L. Gonçalves, Giselli Scaini, Milena Carvalho-Silva, Gabriela C. Jeremias, Isabela C. Jeremias, et al. "Administration of Harmine and Imipramine Alters Creatine Kinase and Mitochondrial Respiratory Chain Activities in the Rat Brain." Depression Research and Treatment 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/987397.

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The present study evaluated mitochondrial respiratory chain and creatine kinase activities after administration of harmine (5, 10, and 15 mg/kg) and imipramine (10, 20, and 30 mg/kg) in rat brain. After acute treatment occurred an increase of creatine kinase in the prefrontal with imipramine (20 and 30 mg/kg) and harmine in all doses, in the striatum with imipramine (20 and 30 mg/kg) and harmine (5 and 10 mg/kg); harmine (15 mg/kg) decreased creatine kinase. In the chronic treatment occurred an increase of creatine kinase with imipramine (20 mg/kg), harmine (5 mg/kg) in the prefrontal with imipramine (20 and 30 mg/kg) and harmine (5 and 10 mg/kg) in the striatum. In the acute treatment, the complex I increased in the prefrontal with harmine (15 mg/kg) and in the striatum with harmine (10 mg/kg); the complex II decreased with imipramine (20 and 30 mg/kg) in the striatum; the complex IV increased with imipramine (30 mg/kg) in the striatum. In the chronic treatment, the complex I increased with harmine (5 mg/kg) in the prefrontal; the complex II increased with imipramine (20 mg/kg) in the prefrontal; the complex IV increased with harmine (5 mg/kg) in the striatum. Finally, these findings further support the hypothesis that harmine and imipramine could be involved in mitochondrial function.

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Nagpal, Latika, Michael D. Kornberg, Lauren K. Albacarys, and Solomon H. Snyder. "Inositol hexakisphosphate kinase-2 determines cellular energy dynamics by regulating creatine kinase-B." Proceedings of the National Academy of Sciences 118, no. 6 (February 5, 2021): e2020695118. http://dx.doi.org/10.1073/pnas.2020695118.

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Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. IP6Ks convert IP6 to pyrophosphates such as diphosphoinositol pentakisphosphate (IP7) and bis-diphosphoinositol tetrakisphosphate (IP8). IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions. The inositol hexakisphosphate kinase 2 (IP6K2) controls cellular apoptosis. To explore roles for IP6K2 in brain function, we elucidated its protein interactome in mouse brain revealing a robust association of IP6K2 with creatine kinase-B (CK-B), a key enzyme in energy homeostasis. Cerebella of IP6K2-deleted mice (IP6K2-knockout [KO]) produced less phosphocreatine and ATP and generated higher levels of reactive oxygen species and protein oxidative damage. In IP6K2-KO mice, mitochondrial dysfunction was associated with impaired expression of the cytochrome-c1 subunit of complex III of the electron transport chain. We reversed some of these effects by combined treatment with N-acetylcysteine and phosphocreatine. These findings establish a role for IP6K2–CK-B interaction in energy homeostasis associated with neuroprotection.

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Silverlight, J. J., R. A. Prysor-Jones, J. Hoffman, and J. S. Jenkins. "Increased creatine kinase activity in pituitary tumours of rat and man." Acta Endocrinologica 115, no. 1 (May 1987): 131–38. http://dx.doi.org/10.1530/acta.0.1150131.

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Abstract. The demonstration that phosphocreatine is used as an energy source by rat PRL-secreting pituitary tumours prompted the study of the enzyme creatine kinase in both rat and human pituitary tumours. Rats treated with diethylstilbestrol developed greatly enlarged pituitaries and hyperprolactinaemia. Total creatine kinase was significantly increased and fractionation on diethylaminoethyl Sephadex showed that the 'brain' form was increased, whereas the 'muscle' and mitochondrial forms showed no change. Exposure to large concentrations of oestradiol caused similar changes in creatine kinase which increased over a period of 25 weeks. The total creatine kinase content of a series of human pituitary tumours was highly variable, but the mean value of 183 ± 46 (sem) units per gram protein was significantly higher than the mean for normal pituitary tissues (28.4 ± 2.9). The brain:muscle isozyme ratio was measured in six human PRL-secreting tumours with a mean of 3.47 ± 0.73, significantly higher than in 'non-functional' tumours (1.57 ± 0.29) or normal tissue (1.77 ± 0.28). Three of four GH-secreting tumours had a ratio below 0.6. The highest ratio found (8.66) was in an ACTH-secreting tumour. Previous reports have shown that oestradiol rapidly induces brain creatine kinase in oestrogen responsive tissues. This is not the case with the rat pituitary gland or oestrogen responsive human tumour cells in culture. Chronic oestrogen treatment, however, does increase creatine kinase in the proliferating gland and many human pituitary tumours have increased enzyme activity. These results suggest that the phosphocreatine/ATP system and in particular the brain isozyme of creatine kinase are of particular importance in lactotropes.

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Dora, Mohamed F., Nabil M. Taha, Mohamed A. Lebda, Aml E. Hashem, Mohamed S. Elfeky, Yasser S. El-Sayed, Soad Al Jaouni, and Ali H. El-Far. "Quercetin Attenuates Brain Oxidative Alterations Induced by Iron Oxide Nanoparticles in Rats." International Journal of Molecular Sciences 22, no. 8 (April 7, 2021): 3829. http://dx.doi.org/10.3390/ijms22083829.

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Iron oxide nanoparticle (IONP) therapy has diverse health benefits but high doses or prolonged therapy might induce oxidative cellular injuries especially in the brain. Therefore, we conducted the current study to investigate the protective role of quercetin supplementation against the oxidative alterations induced in the brains of rats due to IONPs. Forty adult male albino rats were allocated into equal five groups; the control received a normal basal diet, the IONP group was intraperitoneally injected with IONPs of 50 mg/kg body weight (B.W.) and quercetin-treated groups had IONPs + Q25, IONPs + Q50 and IONPs + Q100 that were orally supplanted with quercetin by doses of 25, 50 and 100 mg quercetin/kg B.W. daily, respectively, administrated with the same dose of IONPs for 30 days. IONPs induced significant increases in malondialdehyde (MDA) and significantly decreased reduced glutathione (GSH) and oxidized glutathione (GSSG). Consequently, IONPs significantly induced severe brain tissue injuries due to the iron deposition leading to oxidative alterations with significant increases in brain creatine phosphokinase (CPK) and acetylcholinesterase (AChE). Furthermore, IONPs induced significant reductions in brain epinephrine, serotonin and melatonin with the downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (mtTFA) mRNA expressions. IONPs induced apoptosis in the brain monitored by increases in caspase 3 and decreases in B-cell lymphoma 2 (Bcl2) expression levels. Quercetin supplementation notably defeated brain oxidative damages and in a dose-dependent manner. Therefore, quercetin supplementation during IONPs is highly recommended to gain the benefits of IONPs with fewer health hazards.

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Koike, Shin, Kazuya Toriumi, Sakura Kasahara, Yosuke Kibune, Yo-ichi Ishida, Takashi Dan, Toshio Miyata, Makoto Arai, and Yuki Ogasawara. "Accumulation of Carbonyl Proteins in the Brain of Mouse Model for Methylglyoxal Detoxification Deficits." Antioxidants 10, no. 4 (April 8, 2021): 574. http://dx.doi.org/10.3390/antiox10040574.

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Recent studies have shown that carbonyl stress is a causative factor of schizophrenia, categorized as carbonyl stress-related schizophrenia (CS-SCZ). However, the correlation between carbonyl stress and the pathogenesis of this disease is not well established. In this study, glyoxalase 1(Glo1)-knockout and vitamin B6-deficient mice (KO/VB6 (-) mice), which are susceptible to methylglyoxal (MGO)-induced oxidative damages, were used as a CS-SCZ model to analyze MGO-modified protein and the carbonyl stress status in the brain. A comparison between Wild/VB6(+) mice and KO/VB6(−) mice for accumulated carbonyl proteins levels, with several advanced glycation end products (AGEs) in the brain, revealed that carbonyl protein levels with the Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl) ornithine (MG-H1) moiety were significantly increased in the hippocampus, prefrontal cortex, striatum, cerebral cortex, and brainstem regions of the brain in KO/VB6(−) mice. Moreover, two-dimensional electrophoresis and Liquid chromatography-tandem mass spectrometry analysis showed MG-H1-modified arginine residues in mitochondrial creatine kinase, beta-adrenergic receptor kinase 1, and T-complex protein in the hippocampus region of KO/VB6(−) mice, but not in Wild/VB6(+) mice. In particular, MG-H1 modification of mitochondrial creatine kinase was quite notable. These results suggest that further studies focusing on MG-H1-modified and accumulated proteins in the hippocampus may reveal the onset mechanism of CS-SCZ induced by MGO-induced oxidative damages.

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Andres, Robert H., Angelique D. Ducray, Alberto Pérez-Bouza, Uwe Schlattner, Alexander W. Huber, Sandra H. Krebs, Rolf W. Seiler, Theo Wallimann, and Hans R. Widmer. "Creatine Supplementation Improves Dopaminergic Cell Survival and Protects against MPP+ Toxicity in an Organotypic Tissue Culture System." Cell Transplantation 14, no. 8 (September 2005): 537–50. http://dx.doi.org/10.3727/000000005783982756.

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Cell replacement therapy using mesencephalic precursor cells is an experimental approach for the treatment of Parkinson's disease (PD). A significant problem associated with this procedure is the poor survival of grafted neurons. Impaired energy metabolism is considered to contribute to neuronal cell death after transplantation. Creatine is a substrate for mitochondrial and cytosolic creatine kinases (CK) and buffers cellular ATP resources. Furthermore, elevated cellular creatine levels facilitate metabolic channeling and show anti-apoptotic properties. Exogenous creatine supplementation therefore might offer a tool for improvement of dopaminergic neuron survival. The present study aimed at investigating the effects of creatine on cell survival of rat embryonic day 14 (E14) ventral mesencephalic neurons grown as organotypic free-floating roller tube (FFRT) cultures. We found that the brain-specific isoform of CK (BB-CK) and the ubiquitous mitochondrial isoform (uMt-CK) are expressed at high levels in FFRT cultures and colocalize with tyrosine hydroxylase immunoreactive (TH-ir) cells. Exposure of these cultures to creatine induced an increase in the content of the BB-CK isotype. Creatine (5 mM) administration starting at day in vitro (DIV) 7 resulted in a significant increase (+35%) in TH-ir cell density at DIV21. In addition, we observed that creatine treatment provided neuroprotection against 1-methyl-4-phenyl pyridinium ion (MPP+)-induced TH-ir cell loss in the FFRT culture system, resulting in a significantly higher density (+19%) of TH-ir neurons in creatine-treated cultures compared to corresponding controls. The decrease of TH-ir neurons in the MPP+-treated group corresponded with an increase in immunoreactivity for active caspase-3, an effect that was not seen in the group receiving creatine supplementation. In conclusion, our data imply that creatine administration is beneficial for the survival of TH-ir neurons encountering harmful conditions.

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SHEN, Wei, Dianna WILLIS, Yanping ZHANG, Uwe SCHLATTNER, Theo WALLIMANN, and George R. MOLLOY. "Expression of creatine kinase isoenzyme genes during postnatal development of rat brain cerebellum: evidence for transcriptional regulation." Biochemical Journal 367, no. 2 (October 15, 2002): 369–80. http://dx.doi.org/10.1042/bj20020709.

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Transcription and accumulation of brain-type creatine kinase (CKB) mRNA and its protein was examined during postnatal development of rat brain cerebellum, the brain region containing highest CKB mRNA in the adult. CKB protein was extremely low at day 1, increased about 10-fold until week 4 and remained constant until week 10. This time course was paralleled by cerebellar CKB mRNA, which was also extremely low at day 1 and increased 5-fold during the first 3 weeks and then remained constant. High levels of CKB protein were also detected in cultured primary cerebellar granular neurons. Nuclear run-on assays directly showed that CKB mRNA accumulation during postnatal cerebellar development was due to increased transcription. When compared with cerebrum and whole brain, cerebellar CKB mRNA accumulation during postnatal development was temporally delayed. Analysis of myocyte enhancer factor (MEF)-2 and Sp1, factors known to initiate or sustain CKB transcription in tissues other than brain, revealed that MEF-2 in cerebellum was low at week 1 but increased 3.5-fold by week 7, while Sp1 remained unchanged. The increase in CKB protein during cerebellar postnatal development was coincident with that of the ubiquitous mitochondrial CK protein and mRNA, indicating that a functional phosphocreatine energy shuttle probably exists for efficient ATP regeneration in the cerebellum. This should be beneficial for the many energy-demanding requirements during cerebellar development, as indicated by the observed temporal co-expression of CKB with myelin basic protein, which is involved in axon myelination by oligodendrocytes.

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Réus, Gislaine Z., Roberto B. Stringari, Gislaine T. Rezin, Daiane B. Fraga, Juliana F. Daufenbach, Giselli Scaini, Joana Benedet, Natália Rochi, Emílio L. Streck, and João Quevedo. "Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain." Journal of Neural Transmission 119, no. 4 (September 28, 2011): 481–91. http://dx.doi.org/10.1007/s00702-011-0718-2.

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Gonçalves, Cinara Ludvig, Giselli Scaini, Gislaine Tezza Rezin, Isabela Casagrande Jeremias, Gisele Daiane Bez, Juliana Felipe Daufenbach, Lara Mezari Gomes, Gabriela Kozuchovski Ferreira, Alexandra Ioppi Zugno, and Emilio Luiz Streck. "Effects of acute administration of mazindol on brain energy metabolism in adult mice." Acta Neuropsychiatrica 26, no. 3 (September 19, 2013): 146–54. http://dx.doi.org/10.1017/neu.2013.43.

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ObjectivesMazindol is a sympathomimetic amine, widely used as an anorectic agent in the treatment of obesity. This drug causes psychostimulant effects because of its pharmacological profile similar to amphetamine, acting like a monoamine reuptake inhibitor. However, the mechanisms underlying the action of mazindol are still not clearly understood.MethodsSwiss mice received a single acute administration of mazindol (0.25, 1.25 and 2.5 mg/kg, ip) or saline. After 2 h, the animals were killed by decapitation; the brain was removed and used for the evaluation of activities of mitochondrial respiratory chain complexes, Krebs cycle enzymes and creatine kinase.ResultsAcute administration of mazindol decreased complex I activity only in the hippocampus. Complex IV activity was increased in the cerebellum (2.5 mg/kg) and cerebral cortex (0.25 mg/kg). Citrate synthase activity was increased in the cerebellum (1.25 mg/kg) and cerebral cortex (1.25 mg/kg), and creatine kinase activity was increased in the cerebellum (1.25 mg/kg).ConclusionWe suggest that the inhibition of complex I in the hippocampus only and activation of complex IV, citrate synthase and creatine kinase occurs because of a stimulus effect of mazindol in the central nervous system, which causes a direct impairment on energy metabolism.

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Wyss, M., J. Schlegel, P. James, H. M. Eppenberger, and T. Wallimann. "Mitochondrial creatine kinase from chicken brain. Purification, biophysical characterization, and generation of heterodimeric and heterooctameric molecules with subunits of other creatine kinase isoenzymes." Journal of Biological Chemistry 265, no. 26 (September 1990): 15900–15908. http://dx.doi.org/10.1016/s0021-9258(18)55484-3.

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Journal articles on the topic 'Creatine, brain, mitochondria'

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