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Saks, Valdur; Veksler, Vladimir; Кузнецов, А. В.; Kay, Laurence; Sikk, Peeter; Tiivel, Toomas; Tranqui, L.; Olivares, José; Winkler, Kirstin; Wiedemann, Falk R.; Kunz, Wolfram S.

doi:10.1023/a:1006834912257

Cited by 301 publications

(121 citation statements)

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“…Phosphorylation of these CK substrates occurs in microcompartments formed by mtCK and ANT (see below) (35). Because we did not add external adenine nucleotides, phosphorylation must occur via internally available ATP inside mitochondria, suggesting continuous cycling of internal ADP and ATP between matrix and intermembrane space mediated by ANT, if Cr or CyCr are present.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the Mitochondrial Permeability Transition by Creatine Kinase Substrates

Dolder

Walzel²,

Speer

et al. 2003

Journal of Biological Chemistry

199

120

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Mitochondria from transgenic mice, expressing enzymatically active mitochondrial creatine kinase in liver, were analyzed for opening of the permeability transition pore in the absence and presence of creatine kinase substrates but with no external adenine nucleotides added. In mitochondria from these transgenic mice, cyclosporin A-inhibited pore opening was delayed by creatine or cyclocreatine but not by ␤-guanidinopropionic acid. This observation correlated with the ability of these substrates to stimulate state 3 respiration in the presence of extramitochondrial ATP. The dependence of transition pore opening on calcium and magnesium concentration was studied in the presence and absence of creatine. If mitochondrial creatine kinase activity decreased (i.e. by omitting magnesium from the medium), protection of permeability transition pore opening by creatine or cyclocreatine was no longer seen. Likewise, when creatine kinase was added externally to liver mitochondria from wild-type mice that do not express mitochondrial creatine kinase in liver, no protective effect on pore opening by creatine and its analog was observed. All these findings indicate that mitochondrial creatine kinase activity located within the intermembrane and intercristae space, in conjunction with its tight functional coupling to oxidative phosphorylation, via the adenine nucleotide translocase, can modulate mitochondrial permeability transition in the presence of creatine. These results are of relevance for the design of creatine analogs for cell protection as potential adjuvant therapeutic tools against neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Inhibition of the Mitochondrial Permeability Transition by Creatine Kinase Substrates

Dolder

Walzel²,

Speer

et al. 2003

Journal of Biological Chemistry

199

120

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show abstract

“…Nucleotide permeability is controlled by VDAC, which is normally in a low conductance state that is poorly permeable to ATP (2,34,50), and energy transfers between mitochondria and cytosol are mediated instead by Cr and creatine phosphate (55). Octamers of Mi-CK bridge the IMS between outer membrane VDAC and inner membrane ATP/ADP translocator (62).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart

Santos

Kowaltowski

Laclau

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

203

141

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. Mechanisms by which opening the mitochondrial ATP-sensitive K ϩ channel protects the ischemic heart. Am J Physiol Heart Circ Physiol 283: H284-H295, 2002. First published February 14, 2002 10.1152/ajpheart. 00034.2002-Diazoxide opening of the mitochondrial ATPsensitive K ϩ (mitoKATP) channel protects the heart against ischemia-reperfusion injury by unknown mechanisms. We investigated the mechanisms by which mitoKATP channel opening may act as an end effector of cardioprotection in the perfused rat heart model, in permeabilized fibers, and in rat heart mitochondria. We show that diazoxide pretreatment preserves the normal low outer membrane permeability to nucleotides and cytochrome c and that these beneficial effects are abolished by the mitoKATP channel inhibitor 5-hydroxydecanoate. We hypothesize that an open mitoK ATP channel during ischemia maintains the tight structure of the intermembrane space that is required to preserve the normal low outer membrane permeability to ADP and ATP. This hypothesis is supported by findings in mitochondria showing that small decreases in intermembrane space volume, induced by either osmotic swelling or diazoxide, increased the half-saturation constant for ADP stimulation of respiration and sharply reduced ATP hydrolysis. These effects are proposed to lead to preservation of adenine nucleotides during ischemia and efficient energy transfer upon reperfusion. mitochondria; metabolism; creatine kinase; membrane transport; cytochrome c; ischemic preconditioning THERE IS NOW GENERAL AGREEMENT that the mitochondrial ATP-sensitive K ϩ (mitoK ATP ) channel plays a pivotal role in cardioprotection against ischemia-reperfusion injury (16,17,20,21,36,64); however, little is known about the mechanism of this protection. It has been proposed that mitoK ATP channel opening triggers protection by increasing the generation of reactive oxygen species (ROS) (13, 47), and this effect has now been demonstrated by several laboratories (10,13,44,57). We proposed that the mitoK ATP channel is also an end effector of protection (16), and many studies have confirmed that the mitoK ATP channel is required to be open during the ischemic phase (11,46,58,59,64). Thus the mitoK ATP channel is both a trigger and an end effector of cardioprotection, and these two roles are temporally and mechanistically distinct.We have previously suggested that cardioprotection by mitoK ATP channel opening is due in part to volume regulation, which serves to preserve the structurefunction of the intermembrane space (IMS) and the low permeability of the outer membrane to nucleotides (31). Nucleotide transport across the outer membrane occurs primarily through the voltage-dependent anion channel (VDAC) (2, 34, 49, 50). We hypothesize that VDAC permeability to nucleotides is regulated in part by IMS volume, which in turn is regulated by K ϩ flux across the inner membrane.This study focuses on the end effector mechanisms by which an open mitoK ATP channel protects the heart during ischemia and reperfusion. We show, in sapon...

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“…It should be noted that, when mitochondrial function is measured in isolated mitochondria, the organelle is susceptible to structural disruption (Hepple 2014;Picard et al 2011b), which can exaggerate the magnitude of age-related impairments in mitochondrial function compared with saponin-permeabilized fiber bundles (Picard et al 2011c). This latter in vitro approach does not disrupt organelle structure (Saks et al 1998). …”

Section: R a F Tmentioning

confidence: 99%

Heterogeneous effects of old age on human muscle oxidative capacity in vivo: a systematic review and meta-analysis

Fitzgerald

Christie

Kent

2016

Appl. Physiol. Nutr. Metab.

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https://mc06.manuscriptcentral.com/apnm-pubs Applied Physiology, Nutrition, and Metabolism D r a f t 2 ABSTRACTDespite intensive efforts to understand the extent to which skeletal muscle mitochondrial capacity changes in older humans, the answer to this important question remains unclear. To determine what the preponderance of evidence from in vivo studies suggests, we conducted a systematic review and meta-analysis of the effects of age on muscle oxidative capacity as measured noninvasively by magnetic resonance spectroscopy. A secondary aim was to examine potential moderators contributing to differences in results across studies, including: muscle group, physical activity status, and sex. Candidate papers were identified from PubMed searches (n=3,561 papers) and the reference lists of relevant papers. Standardized effects (Hedges' g) were calculated for age and each moderator using data from the 22 studies that met the inclusion criteria (n=28 effects). Effects were coded as positive when older (≥55 years) adults had higher muscle oxidative capacity than younger (20-45 years) adults. The overall effect of age on oxidative capacity was positive (g=0.171, p<0.001), indicating modestly greater oxidative capacity in old. Notably, there was significant heterogeneity in this result (Q=245.8, p<0.001; I 2 ~70-90%). Muscle group, physical activity, and sex were all significant moderators of oxidative capacity (p≤0.029). This analysis indicates that the current body of literature does not support a de facto decrease of in vivo muscle oxidative capacity in old age. The heterogeneity of study results and identification of significant moderators provide clarity regarding apparent discrepancies in the literature, and indicate the importance of accounting for these variables when examining purported age-related differences in muscle oxidative capacity.

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Cited by 301 publications

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Inhibition of the Mitochondrial Permeability Transition by Creatine Kinase Substrates

Inhibition of the Mitochondrial Permeability Transition by Creatine Kinase Substrates

Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart

Heterogeneous effects of old age on human muscle oxidative capacity in vivo: a systematic review and meta-analysis

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Cited by 301 publications

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Inhibition of the Mitochondrial Permeability Transition by Creatine Kinase Substrates

Inhibition of the Mitochondrial Permeability Transition by Creatine Kinase Substrates

Mechanisms by which opening the mitochondrial ATP- sensitive K+channel protects the ischemic heart

Heterogeneous effects of old age on human muscle oxidative capacity in vivo: a systematic review and meta-analysis

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Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart