Fine-tuning Metabolic Switches


Cells get the energy for most of their activities in the form of adenosine triphosphate (ATP), which is generated through the breakdown of glucose and lipid molecules. Partial breakdown of a single glucose molecule through glycolysis yields 2 ATP molecules; and when glycolysis is followed by pyruvate decarboxylation and the tricarboxcylic acid (TCA) cycle, a cell can eke out between 30 and 38 ATP molecules per molecule of glucose. Lipids are another potent energy source that, after some preliminary processing, can also be metabolized through the TCA cycle. Disruptions to metabolic conditions (such as changes in environmental oxygen availability) are dangerous to many organisms, because while glycolysis can occur in the absence of oxygen the TCA cycle cannot. Glycolysis isn’t sufficient to meet the long-term energy needs of, for example, the adult human heart, which consumes large amounts of ATP for each of the more than 6 billion beats it undergoes in the average lifetime. But fine-tuning of the glycolytic pathway can be critical to meet cells’ energy needs in certain scenarios, as a pair of papers published in this month’s PLOS Biology demonstrate. A paper by a multinational team of researchers headed by Ross Breckenridge and Timothy Mohun at the MRC-London investigates a metabolic switch that occurs in the hearts of neonates. The second paper, by Tobias Eckle, Holger Eltzschig, and colleagues at the University of Colorado, Denver, looks at the metabolic changes that accompany acute lung injury. Although the research teams had different aims and were studying different tissues and biological problems, the efforts of both groups have highlighted how the regulation of metabolic responses can affect clinical outcomes. In point of fact, glycolysis can suffice for the energy needs of some tissues; it’s been known for some time that the fetal heart relies exclusively on glycolysis in the lowoxygen environment of the womb. In the heart, therefore, oxidative pathways only come into play after birth. How do heart cells pull off this metabolic switch? We now have a much better grip on this process thanks to the paper by Breckenridge et al. Breckenridge and colleagues were interested in a protein called Hand1, a transcription factor that is abundantly expressed in embryonic but not adult cardiomyocytes. If Hand1’s expression changes around the time of birth, the group reasoned, then it’s possible Hand1 might be involved in the observed metabolic switch. Indeed, they found that Hand1 levels drop dramatically soon after birth, because Hand1’s expression is turned on by a protein called hypoxiainducible factor-1a (HIF1a). And HIF1a, as its name implies, is expressed only under low oxygen conditions. To see how Hand1 expression impacts heart metabolic pathways, the researchers used microarray analyses to compare gene expression patterns in normal hearts to the patterns in hearts of mice that overexpress Hand1. They showed that Hand1 specifically represses the expression of proteins involved in lipid metabolism and in the mitochondrial TCA cycle, often by directly binding to and repressing the genes’ promoters. After birth it’s important for the neonatal heart to turn off Hand1 expression so that the tissue can start using the more efficient oxidative metabolic pathways (Figure 1). Consequently, mice overexpressing Hand1 exhibit respiratory distress and high death rates soon after birth; they are relying on glycolysis, which by itself can’t generate enough energy for the adult organ’s metabolic needs. But that’s not to say that Hand1 finds no use in adult life; in fact, the authors note that Hand1—and therefore glycolytic metabolism—is re-expressed in the hearts of adults undergoing heart

DOI: 10.1371/journal.pbio.1001664

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@inproceedings{Sedwick2013FinetuningMS, title={Fine-tuning Metabolic Switches}, author={Caitlin Sedwick}, booktitle={PLoS biology}, year={2013} }