Metabolic adaptation to chronic hypoxia in cardiac mitochondria

Abstract

Chronic hypoxia decreases cardiomyocyte respiration, yet the mitochondrial mechanisms remain largely unknown. We investigated the mitochondrial metabolic pathways and enzymes that were decreased following in vivo hypoxia, and questioned whether hypoxic adaptation was protective for the mitochondria. Wistar rats were housed in hypoxia (7 days acclimatisation and 14 days at 11% oxygen), while control rats were housed in normoxia. Chronic exposure to physiological hypoxia increased haematocrit and cardiac vascular endothelial growth factor, in the absence of weight loss and changes in cardiac mass. In both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria isolated from hypoxic hearts, state 3 respiration rates with fatty acid were decreased by 17-18%, and with pyruvate were decreased by 29-15%, respectively. State 3 respiration rates with electron transport chain (ETC) substrates were decreased only in hypoxic SSM, not in hypoxic IFM. SSM from hypoxic hearts had decreased activities of ETC complexes I, II and IV, which were associated with decreased reactive oxygen species generation and protection against mitochondrial permeability transition pore (MPTP) opening. In contrast, IFM from hypoxic hearts had decreased activity of the Krebs cycle enzyme, aconitase, which did not modify ROS production or MPTP opening. In conclusion, cardiac mitochondrial respiration was decreased following chronic hypoxia, associated with downregulation of different pathways in the two mitochondrial populations, determined by their subcellular location. Hypoxic adaptation was not deleterious for the mitochondria, in fact, SSM acquired increased protection against oxidative damage under the oxygen-limited conditions.

Tissue-specific changes in fatty acid oxidation in hypoxic heart and skeletal muscle

“…Curiously, CS activity was normal in both tissues at both durations of hypoxia, however, aconitase activity was more than 50% lower in hypoxic cardiac muscle at both time points, in agreement with a recent finding in the cardiac mitochondria of chronically hypoxic rats (15). Previous studies in lung (43), skeletal muscle (55), brain (5), and nerve cells (53) have indicated that aconitase is particularly susceptible to ROS-mediated inhibition, as are other TCA cycle enzymes such as isocitrate dehydrogenase (28).…”

“…Alternatively, aconitase has also been shown to undergo reversible modulation by frataxin, an iron-binding protein (40). Previous reports on rat cardiac tissue indicate that total aconitase protein concentration does not change after 2 wk of hypoxia and propose that it is a posttranslational modification that decreases aconitase activity (15). Hypoxic tissues produce ROS as a result of attenuated electron flow through the ETS when oxygen, the final electron acceptor, is limited (33).…”

“…In cardiac muscle there was an increased reliance on electron entry into the ETS via complex I after 7 days of hypoxia. Hypoxia induces a loss of complex I levels in some tissues including skeletal muscle, and this is thought to prevent the production of damaging levels of ROS (15,29). In these mice, however, an increase in electron flux through complex I in chronic hypoxia may be necessary to maintain myocardial ATP production, though this could also theoretically increase ROS production.…”

Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies

“…Hypoxia has been shown to decrease mitochondrial respiration in the cardiomyocyte, which is associated with cellular dysfunction (50). Nevertheless, literature addressing mitochondrial subpopulation differences in hypoxic models remains scarce (45). Using a rat model of chronic hypoxia (11% oxygen exposure for 14 days), Heather et al (45) observed a decrease in state 3 respiration rates of both SSM and IFM when using fatty acid and pyruvate as substrates.…”

Protein Lysine Acetylated/Deacetylated Enzymes and the Metabolism-Related Diseases

“…Another example was that in endothelial cells of mice lower limbs, the formation of cardiovascular induced by ischemia was inhibited when Sirt1 was silenced. Instead, the genes of vascular endothelial growth factor (VEFG) and its receptor 2 (VEFGR2) and nitric oxide synthase were expressed while resveratrol activated Sirt1 [41]. According to above experiments, Sirt1 induces angiogenesis probably by inhibiting forkhead box class O family transcription factor (FoxO1), an essential negative regulatory factor in vascular differentiation.…”