Dr Senka Ljubojevic-Holzer earned a PhD in Molecular Medicine at the Medical University of Graz (Austria). After graduation, she was granted a ‘Hertha Firnberg’ fellowship for exceptional young female scientists (2013–17) from the Austrian Science Fund. The project investigating subcellular ion homeostasis and excitation-transcription coupling was allocated at the University of California Davis (USA) and the Medical niversity of Graz (Austria). Dr Ljubojevic-Holzer will continue her research in the field of myocardial remodelling in hypertrophy and heart failure within the frame of senior post-doctoral fellowship ‘Elise Richter’, which she was granted last year (2017–20).
Commentary on ‘Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat’ by Park et al., Science, 2017.1
At low levels of oxygen (hypoxia), the stressed heart makes a variety of adjustments to maintain the supply of oxygen and nutrients to metabolically active tissues. These adjustments involve rapid and slower responses, such as coronary vasodilatation and altered patterns of gene expression, respectively.2 In an oxygen-deprived atmosphere (anoxia), however, survival depends on immediate rewiring of cellular metabolism to win time until the oxygen supply is stored.3 Under anoxia, the energy-carrying molecule adenosine triphosphate (ATP) can only be produced by anaerobic metabolism, a process that yields <10% of oxidative ATP production. Due to the high energy demand of the heart, its stock of ATP is depleted within minutes under anoxic conditions, causing the loss of ionic gradients, cell membrane excitability and contractility of cardiomyocytes. Consequently, humans, like most mammals, can survive for no more than few minutes when deprived of oxygen due to myocardial and brain ischaemia, two major causes of death worldwide.
Park et al. recently identified a rare example of anoxia tolerance among mammals—the naked mole–rat (Heterocephalus glaber).1 Residing in their subterranean burrow systems, naked mole-rats developed the ability to cope with an atmosphere of extremely low oxygen and high carbon dioxide. The authors showed that naked mole-rats can tolerate an atmosphere of 5% oxygen for 5 h without apparent detrimental effects, whereas mice (Mus musculus) died in <15 min. During anoxia, both mice and naked mole-rats rapidly lost consciousness. However, while mice could not be resuscitated even when re-exposed to ambient air (21% oxygen) within one minute of the anoxia initiation, the naked mole-rats fully recovered after 18 min of anoxia. Insights into the molecular basis of naked mole-rats’ adaptation to anoxia was provided by metabolomic profiles of blood and tissues, which revealed surprisingly high concentrations of sugars fructose and sucrose. Using metabolic flux of the stable isotope 13C6-D-fructose, Park et al. discovered that naked mole-rats substitute fructose for glucose as a substrate for anaerobic metabolism in the heart and brain. A switch to fructose has the advantage of bypassing a rate-limiting step of glycolysis, which is regulated by phosphofructokinase and subjected to feedback inhibition by ATP, low pH, and citrate. By entering the pathway downstream of phosphofructokinase, fructose catabolism is independent of cellular energy status.
Naked mole-rat’s innovative metabolic pathway, relevant for survival under anoxic conditions, required the recruitment of fructose transporters and enzymes in the heart, as they are typically only expressed in the kidney and liver. Fructose enters glycolysis after phosphorylation by ketohexokinase (KHK) and is converted to fructose-1-phosphate. This central fructose-metabolizing enzyme exists in two isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose than KHK-A,4 and is expressed primarily in the liver and kidney, thus restricting fructose metabolism almost exclusively to these organs. Interestingly, Park et al. found that both KHK isoforms were markedly up-regulated in naked mole–rat heart and brain tissue as compared with mice.
In the heart, oxygen (un)availability influences gene expression by several mechanisms; one of them is the regulation of gene transcription by the hypoxia-inducible factor 1α (HIF-1α).5 In the context of acute myocardial hypoxia or ischemia, HIF-1α mediates adaptive transcriptional regulation of an extensive repertoire of genes, including those involved in cardiomyocyte growth, myocardial angiogenesis and metabolic reprogramming.6 Mirtschink et al.7 showed that the critical component of hypoxia-induced, HIF-1α-driven, metabolic reprogramming in cardiomyocytes is the coordinated enhancement of both glucose and fructose uptake and flux. Specifically, myocardial hypoxia was shown to stimulate fructose metabolism in human and mouse hearts through HIF-1α-mediated splice switching of KHK-A to KHK-C. The increase in KHK-C expression was accompanied by a transcriptional induction of the fructose-specific transporter GLUT5, further signifying enhanced fructose metabolism in hypoxic cardiomyocytes. Consequently, activation of fructose metabolism by HIF-1α emerged as a central component of hypoxia-driven metabolic programs used to enhance biosynthetic capacity and survival of stressed myocardium.8
In contrast, a switch to fructose metabolism under hypoxia has also been associated with cancer malignancy, metabolic syndrome, and heart failure,7,9,10 and constitutive HIF-1α activation in mice was shown to cause cardiac hypertrophy and impaired contractility of the heart.11 Furthermore, excessive increase in fructose intake due to the consumption of artificially sweetened beverages and foods brought fructose metabolism in focus of current research and shed light on its adverse effects on metabolism and cardiovascular function. Fructose overload in drinking water or chow showed superiority over glucose and starch for the induction of metabolic syndrome in animal models, leading to an array of hemodynamic, structural and functional cardiovascular alterations.12 It is thus essential to understand under which conditions HIF-1α-stimulated fructose metabolism con tributes to adaptive vs. maladaptive remodeling and how naked mole-rats utilize fructose metabolism with no apparent physiological drawbacks.
Future research will have to give answers to yet two major questions. First, what is the source of fructose in metabolically active organs and does fructose intake plays a role in hypoxic-induced fructolysis? An initial clue was provided by Mirtschink et al.7 when they detected [3H] radiolabel derived from [3H]fructose in the RNA, DNA and protein fractions of cardiomyocytes in a KHK-C-dependent manner, suggesting that exogenous fructose contributes significantly to the metabolic effects mediated by KHK-C. Secondly, what solution have the naked mole-rats evolved in response to the problem of lactate clearance, the end product of accelerated anaerobic pathways for ATP production? Anoxia-tolerant fishes solved this problem by converting lactate to ethanol which diffuses from the gills into the water, while turtles can buffer excess lactate and hydrogen ions in the blood by releasing calcium carbonate from their shells,3 but neither of these unusual mechanisms is available to mammals. These are some lessons from marine mammals who display extreme tolerance for low pH in their blood and active muscles.
To date, biomedical science has had a limited success in counteracting deleterious effects of ischemia/hypoxia in humans. Existence of a mammalian model for studying anoxia tolerance has high medical relevance, as insights into the naked mole-rat’s previously unknown metabolic capacities may help in designing new strategies against anoxic tissue damage caused by ischemic heart disease or stroke.13
Conflict of interest: none declared.
