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. 2015 Aug 29;53:4728–4744. doi: 10.1007/s12035-015-9399-4

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© The Author(s) 2015

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Fig. 2 — Substrate-specific and respiratory-chain-complex-limited rates as well as non-phosphorylating rates of respiration of brain mitochondria isolated from control (C57BL/6J) and mtNOD mice brains. Rates of respiration as well as ratios were measured as described in ‘Methods’. The complex II-dependent rates of state 3 respiration in the presence of glutamate/malate were significantly increased in 200-day-old mtNOD mice as compared to controls (b; e for detail), and also to young (100 days) controls (a, number sign indicates significant difference to 200-day-old mitochondria in b). In the presence of α-ketoglutarate (KG)/malate, the rates of complex II-dependent respiration are clearly lower as compared to those with glutamate and are not affected by mtNOD polymorphisms or age (e). No differences are detectable in other complexes of the electron transport chain (a, b). The rates of state 3_glu/mal coefficient are stimulated by Ca²⁺ to about 163 % without age- or polymorphism-related changes (c), whereas the state 3_KG/mal coefficient (d) increased only about 34 %. Nonetheless, the mtNOD polymorphisms enhanced the Ca²⁺ activated state 3_KG/mal coefficient in 100-day-old animals significantly by 11 % indicating an increased activity of α-ketoglutarate dehydrogenase [28]. After Ca²⁺-addition to the system, cytosolic Ca²⁺ activates the mitochondrial glutamate uptake via aralar, the glutamate aspartate carrier as part of the malate aspartate shuttle. This mechanism is responsible for pyruvate supply to mitochondria. In contrast, Ca²⁺ can after its uptake by mitochondria modulate the activity intramitochondrial dehydrogenases [57]. Different modes of non-phosphorylating respiration were determined for complex I- and complex II-dependent substrates. After inhibition of the adenine nucleotide carrier with atractyloside, the non-phosphorylating respiration with succinate as substrate was smaller in old controls (C57BL/6J) compared old mtNOD mice and to young control mice (f). The state 4_glu/mal/pyr respiration, in the presence of 75 nM adenine nucleotides (mainly ADP), showed no changes due to age and polymorphism (g). The rates of non-phosphorylating respiration without added adenine nucleotides revealed no changes caused by age and polymorphism (h). Additionally, respiratory control ratios (RCR) were calculated for complex I-dependent respiration (i) and complex II-dependent respiration (j). No changes are observable in complex I-dependent respiration, whereas old control mitochondria show significantly greater RCR_{suc/atractyloside} values as compared to young controls in complex II-dependent respiration (j). Data is presented as means ± SD (n ≥ 11), *, #p ≤ 0.05; **p ≤ 0.01; ***p < 0.001 (one-way ANOVA followed by Sidak’s multiple comparison test and Kruskal-Wallis test followed by Dunn’s multiple comparison test, respectively)