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The not so secret passage of cellular respiration holds key to survival without water

Urvashi Bhattacharyya

Ball and stick model of the trehalose molecule
Ball and stick model of the trehalose molecule   (Photo: By Ben Mills - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=10829390)

“Water is life’s mater and matrix, mother and medium. There is no life without water,” noted Albert Szent-Gyorgyi, a Hungarian American physiologist who received the Nobel Prize in 1937 for discovering Vitamin C. While generally true, many small organisms like nematodes, tardigrades, plant seeds, fungal spores and yeast cells have devised clever ways of staying alive for extended periods of time under limited water availability. This strategy to tolerate desiccation is called anhydrobiosis. 

Animals evade desiccation by changing their metabolic state and by accumulation of disaccharides (a compound of 2 sugar molecules), such as sucrose and trehalose. Trehalose is postulated to stabilise dry membranes and macromolecules either by replacing water or forming glasses-like state in the cell. During periods of starvation, organisms like worms and yeasts enter this state, with the necessary requirement of trehalose production. A recent study published in eLife, not only explores the mechanism of trehalose generation in these animals, but also re-addresses the role of a metabolic pathway called the glyoxylate shunt, long thought to be non-essential. This pathway, first discovered by Hans Kornberg and Hans Krebs in 1957, provides an alternate route of metabolism involving conversion of fats or acetic acid to produce sugars. It is a part of the citric acid or Krebs cycle, (named after its discoverer, Hans Krebs) that constitutes the main energy producing pathway in cells. The recent study was a collaboration between Sunil Laxman from National Centre for Biological Sciences and researchers from Max Planck Institute of Molecular Cell Biology and Genetics, Germany.

“We were looking at the question of how and why trehalose is recruited during periods of desiccation”, says Laxman. The researchers used two model organisms—C. elegans (worms) and S. cerevisiae (yeast cells)—to find their answers. The worm passes through 4 developmental stages to mature into an adult form. It retains the capacity of changing to hypo-metabolic state under harsh conditions such as high temperature or low water levels. This state of the larvae, known the dauer state, was particularly suited to study mechanisms of desiccation tolerance. The researchers verified that these larvae indeed had lowered respiration rates along with higher levels of trehalose compared to larvae in the third stage of morphogenesis (L3 stage). They also identified the mechanism of trehalose production as a part of glyoxylate shunt cycle through radioactive labelling of acetate, an intermediate compound of both the glyoxylate and Krebs cycles. Dauer larvae had higher amounts of labelled trehalose, while L3 stage larvae had higher amounts of radio-labeled metabolites such amino acids, nucleotides and sugars. Enzymes responsible for switching to trehalose production were also found in higher numbers in the dauer larvae. Thus it was likely that during periods of desiccation, these larvae switched to production of sugar compounds using the sugar producing glyoxylate shunt. 

Sunil clarifies further, “Under desiccation, the glyoxylate shunt forces cells to divert from one pathway to another, and make sugars through bypassing glucose breakdown. It is quite a clever way to generate trehalose and avoid damage to the cellular membranes at the same time.” 

The researchers further confirmed these results using manipulations such as heat shock, mutants lacking essential enzymes to generate trehalose, and finding similar results in yeast cells. They dissected the whereabouts of this process in mitochondria, otherwise known as the powerhouse of the cell. “It opens up other fundamental questions about coordination of these processes between different cellular organelles,” observes Sunil.

The study has real life implications in situations of drought. Plants that have a conserved glyoxylate cycle, can be redirected to generate trehalose instead of withering away. Engineered mammalian cells can be conditioned to desiccation with better chances of adapting to stressful environments. It is amusing to wonder what Albert Szent-Gyorgyi, also one of the pioneer contributors of Krebs cycle, would make of tardigrades that have the ability to survive even in space. The fictional Ian Malcolm of Jurassic Park, might of course remark, “Life, uh, finds a way.”