Lost in translation: miRNAs and mRNAs in ischemic preconditioning and ischemia/reperfusion injury

• The cell in preparation for a rainy day may see fit to store some RNA.
• Messages encoding oxphos ’zymes that may come in handy in sunnier times.
• To survive the storm of nutrient loss or preparing to withstand the winter frost hibernators conserve their energy and meet their needs with autophagy.
• But in fuel nadir and near energy-less, they nevertheless start mito-biogenesis expecting that they’ll soon emerge from winter burrow or feel reperfusion surge.

Ischemic stress involves nutrient deprivation, hypoxia, acidosis, and altered levels of various ions and metabolites. Reperfusion, which abruptly alters these parameters, is a second stress to already stressed cells. Ischemic preconditioning, in which brief ischemia alternates with reperfusion to elicit a protective response to ischemia/reperfusion (I/R) injury, revealed the existence of a highly conserved, cell-autonomous, and nearly ubiquitous program. While we often assume that evolutionary selection is irrelevant with respect to myocardial infarctions—which generally occur long after reproduction—the program of ischemia tolerance may date back much further, to hibernating squirrels, turtles, and estivating frogs and snails (extremophiles), which must survive by entering a hypometabolic state. This relationship is further strengthened by the presence of similar signaling pathways and regulatory mechanisms such as mRNA localization and miRNA regulation. These parallels may offer new insights into the myocardial response to I/R injury. This review will explore some of the recent advances in our understanding of autophagy and mitochondrial turnover in the setting of I/R injury, and related findings drawn from research on hibernating extremophiles.