Regulation of succinate-fueled mitochondrial respiration in liver and skeletal muscle of hibernating thirteen-lined ground squirrels

Abstract

SUMMARYHibernating ground squirrels (Ictidomys tridecemlineatus) alternate between two distinct metabolic states throughout winter: torpor, during which metabolic rate (MR) and body temperature (T b ) are considerably suppressed, and interbout euthermia (IBE), during which MR and T b briefly return to euthermic levels. Previous studies showed suppression of succinate-fuelled respiration during torpor in liver and skeletal muscle mitochondria; however, these studies used only a single, saturating succinate concentration. Therefore, they could not address whether mitochondrial metabolic suppression occurs under physiological substrate concentrations or whether differences in the kinetics of mitochondrial responses to changing substrate concentration might also contribute to mitochondrial metabolic regulation during torpor. The present study confirmed that succinate oxidation is reduced during torpor in liver and skeletal muscle at 37 and 10°C over a 100-fold range of succinate concentrations. At 37°C, this suppression resulted from inhibition of succinate dehydrogenase (SDH), which had a greater affinity for oxaloacetate (an SDH inhibitor) during torpor. At 10°C, SDH was not inhibited, suggesting that SDH inhibition initiates but does not maintain mitochondrial suppression during torpor. Moreover, in both liver and skeletal muscle, mitochondria from torpid animals maintained relatively higher respiration rates at low succinate concentrations, which reduces the extent of energy savings that can be achieved during torpor, but may also maintain mitochondrial oxidative capacity above some lower critical threshold, thereby preventing cellular and/or mitochondrial injury during torpor and facilitating rapid recruitment of oxidative capacity during arousal.

Metabolic Flexibility: Hibernation, Torpor, and Estivation

“…Mitochondria isolated from the liver of torpid 13-lined ground squirrels exhibit state 3 respiration rates (near maximal respiration in the presence of saturating substrate and ADP) that are up to 70% lower than those from animals in IBE or summer euthermia (39,200). A similar, if less extreme, pattern is seen in liver mitochondria of Djungarian hamsters (40,167) and mice (42) that undergo daily torpor.…”

Kinetic parameters of respiration in rat permeabilized hepatocytes upon Са2+ in various concentrations in medium and prolonged Influence of taurine

“…Kinetic analysis of the succinate oxidation in hepatocytes mitochon dria was carried out upon low temperatures [2], hypoxia [12], immobilization stress [22], and upon the various physiological states [3]. Brown has revealed that the substrate oxi dation kinetics is modified during hibernation and it provides the metabolism regulation by mitochondria [3]. Priority use of succinate compared to the other substrates was noted in most works [2,3,18,19].…”

“…Brown has revealed that the substrate oxi dation kinetics is modified during hibernation and it provides the metabolism regulation by mitochondria [3]. Priority use of succinate compared to the other substrates was noted in most works [2,3,18,19]. Its oxidation rate is much higher in comparison with other sub strates of tricarboxylic acid cycle and the power of transmembrane potential generation is so large that supplies the maximal ADP phosphorylation intensity.…”

“…Succinate is usually applied at saturating concentrations in the researches, but making clear of its oxidation kinetics with different substrate concentrations gives an opportunity to reveal the interest ing regularities. In particular, in experiments with hibernating animals, higher respiration rate indexes were received upon lower succinate concentration than in condition of satu rating succinate content [3]. It is considered to maintenance of provide energy processes intensity at sufficient level during hibernation, preserve cell and mitochondria against damage and give a chance to turn into active state quickly.…”

Are long chain acyl CoAs responsible for suppression of mitochondrial metabolism in hibernating 13-lined ground squirrels?

“…However, despite this reversal, torpid respiration still remained four-fold lower than euthermic rates, indicating that inhibition of SDH by oxaloacetate does not account for the majority of suppression seen in torpor. Additionally, Brown et al (2013) found that while SDH activity was suppressed in torpor at 37°C, it was not suppressed when measured at 10°C, suggesting that SDH may contribute in the initiation of suppression, but does not maintain it. Finally, in both liver and skeletal muscle, torpid mitochondria have a greater affinity for succinate than euthermic mitochondria .…”