Hypometabolic Responses to Chronic Hypoxia: A Potential Role for Membrane Lipids

Abstract

Metabolic suppression is an essential strategy to cope with chronic hypoxia. This review examines the physiological processes used to survive in low oxygen environments. It proposes a novel mechanism-the remodeling of membrane lipids-to suppress ATP use and production. Temperature (homeoviscous adaptation), diet (natural doping in migrant birds) and body mass (membrane pacemaker of metabolism) have an impact on the lipid composition of membranes, which, in turn, modulates metabolic capacity. Vertebrate champions of hypoxia tolerance show extensive changes in membrane lipids upon in vivo exposure to low oxygen. These changes and those observed in hibernating mammals can promote the downregulation of ion pumps (major ATP consumers), ion channels, mitochondrial respiration capacity (state 3, proton leak, cytochrome c oxidase), and energy metabolism (β-oxidation and glycolysis). A common membrane signal regulating the joint inhibition of ion pumps and channels could be an exquisite way to preserve the balance between ATP supply and demand in hypometabolic states. Membrane remodeling together with more traditional mechanisms could work in concert to cause metabolic suppression.

Keywords: Na+/K+-ATPase; cholesterol; energy metabolism; fatty acids; hypometabolism; hypoxia tolerance; low oxygen stress; membrane remodeling; metabolic suppression; mitochondrial respiration; phospholipids.

Figure 1

Relative membrane cholesterol in the tissues of normoxic controls and hypoxia-acclimated animals for two hypoxia-tolerant vertebrates: the goldfish [14] and the naked-mole rat [15]. Values are means ± SEM (n = 9–16 per treatment). * p < 0.05, ** p < 0.01, *** p < 0.001 indicate significant effects of hypoxia.

Figure 2

Percent docosahexaenoic acid (n-3 22:6) in membrane phospholipids in the tissues of normoxic controls and hypoxia-acclimated animals for two hypoxia-tolerant vertebrates: the goldfish [14] and the naked-mole rat [15]. Values are means ± SEM (n = 9–14 per treatment). * p < 0.05, *** p < 0.001 indicate significant effects of hypoxia.

Figure 3

Remodeling of membrane lipids is a proposed new mechanism to promote metabolic suppression in chronic hypoxia. Prolonged in vivo exposure to low oxygen alters the relative abundance of membrane cholesterol, n-3 polyunsaturated fatty acids (PUFA), and possibly mitochondrial cardiolipin in ways that downregulate ion pumps such as Na⁺/K⁺-ATPase (a major ATP consumer), ion channels, and possibly mitochondrial respiration capacity [state 3 (OXPHOS in the presence of substrates and ADP) and LEAK (proton leak)]. Chronic hypoxia also causes a general reduction in cytochrome c oxidase (COX) indicating a decrease in mitochondrial density. The observed changes in membrane composition are known to modulate metabolic pathways of energy metabolism such as β-oxidation (downregulation) and glycolysis (up or downregulation). Reduction of flux through the ATP-ADP cycle can also be induced by previously characterized mechanisms that involve post-translational/post-transcriptional modifications [11], 5′-AMP-activated protein kinase (AMPK) [12] or epigenetic changes [13]. Membrane remodeling and established mechanisms work in concert to cause metabolic suppression.