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Combined Metabolome and Transcriptome Analysis Reveals Key Components of Complete Desiccation Tolerance in an Anhydrobiotic Insect

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Combined Metabolome and Transcriptome Analysis Reveals Key Components of Complete Desiccation Tolerance in an Anhydrobiotic Insect Combined metabolome and transcriptome analysis reveals key components of complete desiccation tolerance in an anhydrobiotic insect Alina Ryabovaa,1, Richard Cornetteb,1, Alexander Cherkasova,c, Masahiko Watanabeb,2, Takashi Okudad, Elena Shagimardanovaa, Takahiro Kikawada (黄川田 隆洋)b,e,3, and Oleg Guseva,f,g,3 aInstitute of Fundamental Medicine and Biology, Kazan Federal University, 420012 Kazan, Russia; bAnhydrobiosis Research Group, Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, 305-8634 Ibaraki, Japan; cCenter of Life Sciences, Skolkovo Institute of Science and Technology, 143028 Moscow, Russia; dNEMLI PROJECT LLC, Tsuchiura, 300-0023 Ibaraki, Japan; eGraduate School of Frontier Sciences, The University of Tokyo, Kashiwa, 277-8561 Chiba, Japan; fRIKEN Cluster for Science, Technology and Innovation Hub, RIKEN, 351-0198 Yokohama, Japan; and gRIKEN Center for Integrative Medical Sciences, RIKEN, 351-0198 Yokohama, Japan Edited by David L. Denlinger, The Ohio State University, Columbus, OH, and approved July 6, 2020 (received for review February 27, 2020) Some organisms have evolved a survival strategy to withstand physiology within a couple of hours of rehydration. Anhy- severe dehydration in an ametabolic state, called anhydrobiosis. drobiosis is a natural phase in their life cycle, such that larvae can The only known example of anhydrobiosis among insects is successfully withstand a series of desiccation–rehydration events. observed in larvae of the chironomid Polypedilum vanderplanki. To enter into anhydrobiosis, it is necessary for larvae to follow an Recent studies have led to a better understanding of the molecular appropriately slow desiccation regime that normally takes about mechanisms underlying anhydrobiosis and the action of specific 48 h (3). Once in the anhydrobiotic state, P. vanderplanki larvae are protective proteins. However, gene regulation alone cannot ex- able not only to survive almost complete desiccation for over 17 y plain the rapid biochemical reactions and independent metabolic but they also show outstanding cross-tolerance to various abiotic changes that are expected to sustain anhydrobiosis. For this rea- stresses, including extreme temperature fluctuation, hypoxia, high son, we conducted a comprehensive comparative metabolome– hydrostatic pressure, exposure to toxic chemicals, vacuum, and ul- transcriptome analysis in the larvae. We showed that anhydrobi- traviolet and different types of ionizing or electromagnetic radiation BIOCHEMISTRY otic larvae adopt a unique metabolic strategy to cope with com- – plete desiccation and, in particular, to allow recovery after (4 7). rehydration. We argue that trehalose, previously known for its Over the last decade, investigations of P. vanderplanki larvae anhydroprotective properties, plays additional vital roles, provid- have resulted in an improved understanding of the machinery of ing both the principal source of energy and also the restoration of anhydrobiosis, which acts at various physiological levels in the antioxidant potential via the pentose phosphate pathway during organism. In particular, unique clusters of paralogous genes in- the early stages of rehydration. Thus, larval viability might be di- cluding late embryogenesis abundant (LEA) proteins, thio- rectly dependent on the total amount of carbohydrate (glycogen redoxins, protein-repair methyltransferases, or hemoglobins, and trehalose). Furthermore, in the anhydrobiotic state, energy is stored as accumulated citrate and adenosine monophosphate, Significance allowing rapid reactivation of the citric acid cycle and mitochon- drial activity immediately after rehydration, before glycolysis is Anhydrobiosis is a reversible ametabolic state that occurs in fully functional. Other specific adaptations to desiccation include response to severe desiccation. The largest anhydrobiotic ani- potential antioxidants (e.g., ophthalmic acid) and measures to mal known is the larva of the African chironomid Polypedilum avoid the accumulation of toxic waste metabolites by converting vanderplanki. Here, we investigated how the metabolism of these to stable and inert counterparts (e.g., xanthurenic acid and larvae changes during the desiccation–rehydration cycle and allantoin). Finally, we confirmed that these metabolic adaptations how simple biochemical processes determine viability of the correlate with unique organization and expression of the chironomid. Major findings suggest that, in addition to its corresponding enzyme genes. known anhydroprotectant role, trehalose acts as a major source of energy for rehydration. Citrate and adenosine anhydrobiosis | metabolome | desiccation tolerance | Polypedilum monophosphate, accumulated in the dry state, allow rapid re- vanderplanki | transcriptome sumption of metabolism during the recovery phase. Finally, metabolic waste is stored as stable or nontoxic compounds ater molecules form a universal substrate for all processes such as allantoin, xanthurenic acid, or ophthalmic acid that may Winside living cells and maintain the conformation of also act as antioxidants. membranes and biomolecules. Severe dehydration leads to damage of cellular structures and can be lethal. If an organism Author contributions: R.C., T.O., T.K., and O.G. designed research; A.R., R.C., A.C., M.W., and E.S. performed research; A.R. and A.C. analyzed data; and A.R., R.C., T.K., and O.G. cannot escape a dangerous environment it must adapt to any wrote the paper. extreme conditions it might experience. One such adaptation is The authors declare no competing interest. anhydrobiosis, which is the ametabolic state that occurs in some This article is a PNAS Direct Submission. organisms in response to drought (1). Anhydrobiosis is common This open access article is distributed under Creative Commons Attribution-NonCommercial- for the majority of plant seeds (1) and microorganisms but is also NoDerivatives License 4.0 (CC BY-NC-ND). observed among a limited number of microscopic invertebrates 1A.R. and R.C. contributed equally to this work. (2). The largest anhydrobiotic animal and the only insect is “the 2 ” Deceased January 19, 2007. Polypedilum vanderplanki 3 sleeping chironomid (Diptera, Chi- To whom correspondence may be addressed. Email: [email protected] or oleg. ronomidae), whose larvae inhabit ephemeral rock pools in [email protected]. semiarid regions of western Africa. The larvae can survive almost This article contains supporting information online at https://www.pnas.org/lookup/suppl/ complete water loss (up to 97% of total body mass) by entering doi:10.1073/pnas.2003650117/-/DCSupplemental. into the anhydrobiotic state but can reestablish normal First published July 28, 2020. www.pnas.org/cgi/doi/10.1073/pnas.2003650117 PNAS | August 11, 2020 | vol. 117 | no. 32 | 19209–19220 Downloaded by guest on September 28, 2021 which are strongly responsive to the onset of desiccation, have The PCA loadings revealed that metabolites with high positive been identified in the P. vanderplanki genome (8). Comparative PC1 values demonstrate a significant increase in concentration genome analysis showed that the congeneric species, Polypedilum during at least one of the stages of anhydrobiosis (Fig. 1B). nubifer, which is sensitive to desiccation, and other insects, such Differences in PC2 loadings allowed the identification of three as mosquitoes of the Anopheles and Aedes genera, lack corre- major patterns of change in metabolite content: 1) accumulation sponding gene clusters (9). At the biochemical level, several during desiccation, 2) accumulation during rehydration, and 3) groups of biomolecules, including LEA proteins, various anti- accumulation during both stages of anhydrobiosis. For each of oxidants, and heat-shock proteins, act coordinately as anhy- these groups, an average pattern of change was determined droprotectants (4, 6, 10). Trehalose is also a core determinant of (Fig. 1C). The metabolites with the 10 highest loadings for each desiccation tolerance in P. vanderplanki larvae, and its accumu- group are also shown; these are likely to be important for dis- lation may reflect the readiness of larvae to undergo anhy- criminating between the groups. Among these are trehalose-6- drobiosis (11). In P. vanderplanki, as in other anhydrobiotes, this phosphate (T6P), a precursor of a compound (i.e., trehalose) disaccharide possesses a number of anhydroprotectant features; with known anhydroprotective properties; intermediates of the for example, it adjusts osmotic potential in cells, protects mem- glutathione (GSH) pathway (gamma-aminobutyric acid, gamma- branes, and stabilizes macromolecules by formation of glass-like glutamylcysteine, and ophthalmic acid); neuroactive intermedi- structures in the cytoplasm (12–14). ates of the tryptophan degradation pathway (kynurenine [KYN] However, despite considerable knowledge of the transcrip- and kynurenic acid [KA]); and AMP, whose accumulation is tional activity relating to anhydrobiosis, little is known about the typical of P. vanderplanki larvae during anhydrobiosis. associated nonenzymatic biochemical processes and metabolic perturbations. In the final stages of desiccation and the initial Role of Trehalose in Anhydrobiosis: An Optimal Energy Resource for a stages of rehydration there can be no enzyme activity (because Rapid Resumption of Metabolism. Metabolic profiling of P. van- water level is extremely low) and consequently homeostasis and derplanki larvae revealed significant perturbations in
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