MicroRNAs are small non-coding RNA (18-24 nt long) that fine-tune gene expression at the post-transcriptional level. With the advent of "multi-omics" analysis and sequencing approaches, they have now been implicated in every facet of basic molecular networks, including metabolism, homeostasis, and cell survival to aid cellular machinery in adapting to changing environmental cues. Many animals must endure harsh environmental conditions in nature, including cold/freezing temperatures, oxygen limitation (anoxia/hypoxia), and food or water scarcity, often requiring them to revamp their metabolic organization, frequently on a seasonal or life stage basis. MicroRNAs are important regulatory molecules in such processes, just as they are now well-known to be involved in many human responses to stress or disease. The present review outlines the role of miRNAs in natural animal models of environmental stress and adaptation including torpor/hibernation, anoxia/hypoxia tolerance, and freeze tolerance. We also discuss putative medical applications of advances in miRNA biology including organ preservation for transplant, inflammation, ageing, metabolic disorders (e.g., obesity), mitochondrial dysfunction (mitoMirs) as well as specialized miRNA subgroups respective to low temperature (CryomiRs) and low oxygen (OxymiRs). The review also covers differential regulation of conserved and novel miRNAs involved at cell, tissue, and stress specific levels across multiple species and their roles in survival. Ultimately, the species-specific comparison and conserved miRNA responses seen in evolutionarily disparate animal species can help us to understand the complex miRNA network involved in regulating and reorganizing metabolism to achieve diverse outcomes, not just in nature, but in human health and disease.

The sea cucumber (Apostichopus japonicus) has become a good model organism for studying environmentally induced aestivation in marine invertebrates. We hypothesized that mechanisms that arrest energy-expensive cell cycle activity would contribute significantly to establishing the hypometabolic state during aestivation. Cyclin A is a core and particularly interesting cell cycle regulator that functions in both the S phase and in mitosis. In the present study, negative relationships between miR-200-3p and AjCA expressions were detected at both the transcriptional and the translational levels during aestivation in A. japonicus. Dual-luciferase reporter assays confirmed the targeted location of the miR-200-3p binding site within the AjCA gene transcript. Furthermore, gain- and loss-of-function experiments were conducted in vivo with sea cucumbers to verify the interaction between miR-200-3p and AjCA in intestine tissue by qRT-PCR and Western blotting. The results show that the overexpression of miR-200-3p mimics suppressed AjCA transcript levels and translated protein production, whereas transfection with a miR-200-3p inhibitor enhanced both AjCA mRNA and AjCA protein in A. japonicus intestine. Our findings suggested a potential mechanism that reversibly arrests cell cycle progression during aestivation, which may center on miR-200-3p inhibitory control over the translation of cyclin A mRNA transcripts.

The insulin-IGF-1 signaling (IIS) pathway is conserved throughout multicellular organisms and regulates many traits, including aging, reproduction, feeding, metabolism, stress resistance, and growth. Here, we present evidence of a survival-sustaining role for IIS in a subset of gut cells in Drosophila melanogaster, namely the intestinal stem cells (ISCs) and progenitor cells. Using RNAi to knockdown the insulin receptor, we found that inhibition of IIS in ISCs statistically shortened the lifespan of experimental flies compared with non-knockdown controls, and also shortened their survival under starvation or malnutrition conditions. These flies also showed decreased reproduction and feeding, and had lower amounts of glycogen and glucose in the body. In addition, increased expression was observed for the Drosophila transcripts for the insulin-like peptides dilp2, dilp5, and dilp6. This may reflect increased insulin signaling in peripheral tissues supported by up-regulation of the target of the brain insulin gene (tobi). In contrast, activation of IIS (via knockdown of the insulin pathway inhibitor PTEN) in intestinal stem and progenitor cells decreased fly resistance to malnutrition, potentially by affecting adipokinetic hormone signaling. Finally, Pten knockdown to enhance IIS also activated JAK-STAT signaling in gut tissue by up-regulation of upd2, upd3, and soc36 genes, as well as genes encoding the EGF receptor ligands spitz and vein. These results clearly demonstrate that manipulating insulin levels may be used to modulate various fly traits, which are important determinants of organismal survival.