Mitochondrial Bioenergetics During Ischemia and Reperfusion

Abstract

During ischemia and reperfusion (I/R) mitochondria suffer a deficiency to supply the cardiomyocyte with chemical energy, but also contribute to the cytosolic ionic alterations especially of Ca. Their free calcium concentration ([Ca]m) mainly depends on mitochondrial entrance through the uniporter (UCam) and extrusion in exchange with Na (mNCX) driven by the electrochemical gradient (ΔΨm). Cardiac energetic is frequently estimated by the oxygen consumption, which determines metabolism coupled to ATP production and to the maintaining of ΔΨm. Nevertheless, a better estimation of heart energy consumption is the total heat release associated to ATP hydrolysis, metabolism, and binding reactions, which is measurable either in the presence or the absence of oxygenation or perfusion. Consequently, a mechano-calorimetrical approach on isolated hearts gives a tool to evaluate muscle economy. The mitochondrial role during I/R depends on the injury degree. We investigated the role of the mitochondrial Ca transporters in the energetic of hearts stunned by a model of no-flow I/R in rat hearts. This chapter explores an integrated view of previous and new results which give evidences to the mitochondrial role in cardiac stunning by ischemia o hypoxia, and the influence of thyroid alterations and cardioprotective strategies, such as cardioplegic solutions (high K-low Ca, pyruvate) and the phytoestrogen genistein in both sex. Rat ventricles were perfused in a flow-calorimeter at either 30 °C or 37 °C to continuously measure the left ventricular pressure (LVP) and total heat rate (Ht). A pharmacological treatment was done before exposing to no-flow I and R. The post-ischemic contractile (PICR as %) and energetical (Ht) recovery and muscle economy (Eco: P/Ht) were determined during stunning. The functional interaction between mitochondria (Mit) and sarcoplasmic reticulum (SR) was evaluated with selective mitochondrial inhibitors in hearts reperfused with Krebs-10 mM caffeine-36 mM Na. The caffeine induced contracture (CIC) was due to SR Ca release, while relaxation mainly depends on mitochondrial Ca uptake since neither SL-NCX nor SERCA are functional under this media. The ratio of area-under-curves over ischemic values (AUC-ΔHt/AUC-ΔLVP) estimates the energetical consumption (EC) to maintain CIC. Relaxation of CIC was accelerated by inhibition of mNCX or by adding the aerobic substrate pyruvate, while both increased EC. Contrarily, relaxation was slowed by cardioplegia (high K-low Ca Krebs) and by inhibition of UCam. Thus, Mit regulate the cytosolic [Ca] and SR Ca content. Both, hyperthyroidism (HpT) and hypothyroidism (HypoT) reduced the peak of CIC but increased EC, in spite of improving PICR. Both, CIC and PICR in HpT were also sensitive to inhibition of mNCX or UCam, suggesting that Mit contribute to regulate the SR store and Ca release. The interaction between mitochondria and SR and the energetic consequences were also analyzed for the effects of genistein in hearts exposed to I/R, and for the hypoxia/reoxygenation process. Ou...

Ginsenoside Rg1 Ameliorates Rat Myocardial Ischemia-Reperfusion Injury by Modulating Energy Metabolism Pathways

“…Given the potential of Rg1 to abolish the no reflow in the reperfusion phase, this mechanism is certainly a contributor in this respect, although the cause and effect relation between its effect on improving MBF and energy metabolism remains an open question. Another mechanism is to modulate the activity and/or expression of mitochondria respiratory chain Complexes, the machinery for synthesis of ATP (Consolini et al, 2017 ). The results from the present study demonstrated that this mechanism contributes indeed to the energy improving role of Rg1 in myocardial I/R injury, as evidenced by the increase in the activity of these Complexes by Rg1 pretreatment.…”

Measuring biological aging in humans: A quest

“…Importantly, very little is known about how environmental stresses are sensed and encoded into epigenetic changes the quantification of characterization of morphological changes using microscopy imaging techniques (Coggan, 1995;Hughes et al, 2015). Many of these indexes have been associated with aging and increased risk of chronic conditions (Consolini et al, 2017;Gonzalez-Freire et al, 2018). Several assays are available for measuring ROS generation, antioxidant defense, and oxidative damage to macromolecules in blood, cells, and tissues (Dikalov & Harrison, 2014;Starkov, 2010).…”

“…In humans, mitochondrial metabolic function is often studied in vitro in skeletal muscle by respirometry in permeabilized muscle fibers obtained through biopsies, as well as in vivo by phosphorous magnetic resonance spectroscopy (P 31 MRS) (Lanza & Nair, ). Using both methods, it has been demonstrated that the degree of oxidative phosphorylation declines with aging in humans in the heart, skeletal muscle, and other tissues (Coen et al, ; Consolini, Ragone, Bonazzola, & Colareda, ; Fabbri et al, ; Gonzalez‐Freire et al, ; Holloway et al, ). Reduced mitochondrial function is associated with mobility decline in older persons, while the effect is mediated by a reduction of muscle strength (Zane et al, ).…”

“…Muscle biopsies are invasive but safe and allow for a variety of measurements—including direct mitochondrial respiration—as well as a wide range of biochemical assays that target different components of the energetic and biogenesis machinery, and the quantification of characterization of morphological changes using microscopy imaging techniques (Coggan, ; Hughes et al, ). Many of these indexes have been associated with aging and increased risk of chronic conditions (Consolini et al, ; Gonzalez‐Freire et al, ). Several assays are available for measuring ROS generation, antioxidant defense, and oxidative damage to macromolecules in blood, cells, and tissues (Dikalov & Harrison, ; Starkov, ).…”

Reduced β2-glycoproteinI Alleviated Rat Myocardial Ischemia/Reperfusion Injury via Mitochondrial Protection and Inhibition of Apoptosis

“…Previous studies have demonstrated that the lack of ATP production is the basis for myocardial I/R injury, and the sharp increase of reactive oxygen species (ROS) along with the intracellular calcium overload are the central parts of I/R injury. In addition, I/R injury involves in many other factors such as apoptosis, mitochondrial permeability transition, in ammation, and so on [6][7][8].…”