Hypoxic naked mole–rat brains use microRNA to coordinate hypometabolic fuels and neuroprotective defenses

Abstract

Naked mole–rats are among the mammalian champions of hypoxia tolerance. They evolved adaptations centered around reducing metabolic rate to overcome the challenges experienced in their underground burrows. In this study, we used next‐generation sequencing to investigate one of the factors likely supporting hypoxia tolerance in naked mole–rat brains, posttranscriptional microRNAs (miRNAs). Of the 212 conserved miRNAs identified using small RNA sequencing, 18 displayed significant differential expression during hypoxia. Bioinformatic enrichment revealed that hypoxia‐mediated miRNAs were suppressing energy expensive processes including de novo protein translation and cellular proliferation. This suppression occurred alongside the activation of neuroprotective and neuroinflammatory pathways, and the induction of central signal transduction pathways including HIF‐1α and NFκB via miR‐335, miR‐101, and miR‐155. MiRNAs also coordinated anaerobic glycolytic fuel sources, where hypoxia‐upregulated miR‐365 likely suppressed protein levels of ketohexokinase, the enzyme responsible for catalyzing the first committed step of fructose catabolism. This was further supported by a hypoxia‐mediated reduction in glucose transporter 5 proteins that import fructose into the cell. Yet, messenger RNA and protein levels of lactate dehydrogenase, which converts pyruvate to lactate in the absence of oxygen, were elevated during hypoxia. Together, this demonstrated the induction of anaerobic glycolysis despite a lack of reliance on fructose as the primary fuel source, suggesting that hypoxic brains are metabolically different than anoxic naked mole–rat brains that were previously found to shift to fructose‐based glycolysis. Our findings contribute to the growing body of oxygen‐responsive miRNAs “OxymiRs“ that facilitate natural miRNA‐mediated mechanisms for successful hypoxic exposures.

Feline microRNAome in ovary and testis: Exploration of in-silico miRNA-mRNA networks involved in gonadal function and cellular stress response

“…In our study, we identified changes in expression of several miRNAs in response to vitrification stress that have also been reported to be involved in the strategies of stress-tolerant animals. Like this, miR-335 has been shown to regulate hypoxiainducible transcription factor 1 in brains of hypoxic naked mole rats (Li et al, 2015;Hadj-Moussa et al, 2021), while in our study it was upregulated in ovarian tissues after vitrification and warming. A study on hibernating grey mouse lemurs reported increased expression of miRNAs miR-92a and miR-193b during torpor, which was related to regulation of p53 signaling and mTOR pathway (Li et al, 2017;Biggar et al, 2018;Zhang et al, 2020).…”

MicroRNA Cues from Nature: A Roadmap to Decipher and Combat Challenges in Human Health and Disease?

“…For example, miR-24 that was upregulated in the brain is known to be involved in hypoxia-induced reduction of cytochrome c, a mitochondrial protein involved in inducing apoptosis [ 67 ]. Another study showed that downregulation of miR-335 that regulates the hypoxia-inducible transcription factor-1 (HIF-1) in brains of hypoxic naked mole rats can activate genes involved in glycolysis under low oxygen availability [ 68 , 69 ]. Furthermore, the study showed an upregulation of miR-155 in mole rat brain that targets HIF-1α and also induce the expression of NF-κB transcription factor that is involved in antioxidant defense, DNA damage repair, and the inflammatory response.…”

“…Furthermore, the study showed an upregulation of miR-155 in mole rat brain that targets HIF-1α and also induce the expression of NF-κB transcription factor that is involved in antioxidant defense, DNA damage repair, and the inflammatory response. NF-κB induction can maintain miR-155 levels during hypoxic stress suggesting stringent regulation at a posttranscriptional level by players in the cell stress response machinery [ 69 , 70 ]. A study of hibernating grey mouse lemurs ( Microcebus murinus ) from Madagascar also showed miRNA action in regulating genes involved in cellular defense systems.…”

Low Cancer Incidence in Naked Mole-Rats May Be Related to Their Inability to Express the Warburg Effect

“…The increase in blood glucose levels may also partly be explained by decreased glucose consumption during hypometabolic states ( Pamenter et al, 2019a ). In the brain, and following acute in vivo hypoxic exposure, mild acidification is observed, lactate dehydrogenase (LDH) protein expression increases, and the expression of SREP2, a key regulator of fatty acid synthesis, decreases ( Hadj-Moussa et al, 2021b ), all consistent with increased glycolytic throughput in this tissue. Finally, NMRs have large cardiac glycogen stores relative to C57/BL5 mice ( Faulkes et al, 2019 ), suggesting this organ is primed for sustained glycolytic metabolism.…”