When it comes to generating energy, the glycolytic pathway might seem a touch anachronistic. Compared to super-charged mitochondrial energetics,glycolysis produces a fraction of the ATP that mitochondria can churn out. So why have sophisticated, oxygen-fuelled organisms retained glycolysis's energetic carthorse? One reason is that our tissues are continually on the verge of running out of oxygen explains Keith Webster. Biological tissues are constantly at risk from the oxidising toxins liberated by each breath we take,so aerobic organisms have struck a finely balanced deal; limiting tissue oxygen levels so that they are sufficient to sustain the ATP lifeline, but no more. At times of high activity, the precarious balance can tip. When oxygen levels fail to keep pace with voracious mitochondrial consumption rates,tissues become hypoxic and glycolysis steps in to supplement a potentially life-threatening energy deficit. Webster is fascinated by the finely tuned cellular mechanisms that protect aerobic life from hypoxia. In a review published in this issue of the J. Exp. Biol. he takes us on a journey through time, from the anaerobic primordial swamp where glycolysis first evolved, introducing us to the key stages in the system's development that culminated in hypoxia's current role in glycolytic regulation(p. 2911).
Webster describes how glycolysis was first harnessed by anaerobic prokaryotes almost 6 billion years ago. But as the oxygen level rose, `it exerted massive selection pressures' he explains, driving prokaryotes to develop oxidative metabolism, and oxygen-sensitive switches, to regulate the expression of key metabolic genes as oxygen levels fluctuate. `The rudimentary components of hypoxia-regulated glycolytic gene expression may have been in place extremely early in evolution' explains Webster, ready for activation when the first eukaryotic organisms appeared two billion years later.
Progressing to eukaryotic gene regulation, Webster describes how eukaryotes evolved a series of DNA elements that regulate a suite of hypoxia-tolerant genes in yeast and plants. One of the simplest eukaryotes, the humble baker's yeast, regulates the expression of a few essential hypoxia tolerance genes through a transcriptional DNA element called the `low oxygen response element'. But as Webster points out, this element doesn't appear to regulate glycolytic genes. We have to wait until plants appear before the first anaerobic response elements in glycolytic enzymes are found, and the small weed, Arabidopsis thaliana, might prove to be the final link to mammalian hypoxia regulation. Arabidopsis has a glycolytic regulatory element that is identical to a transcriptional regulator in mammalian genes,the hypoxia responsive element (HRE), which turns up in more than eight mammalian glycolytic genes that are regulated by a set of hypoxia responsive transcription factors, including HIF-1α.
But hypoxia isn't just a mild metabolic inconvenience. It's at the root of many major diseases in the West, claiming countless victims to heart failure,coronary heart disease and stroke. Understanding how tissues regulate gene expression during hypoxia could eventually help clinicians develop gene and cell-based therapies that `switch on during disease to prevent the permanent damage that often results from oxygen deprivation' says Webster.
