Thyroid hormone in the frontier of cell protection, survival and functional recovery LUIS A. VIDELA 1 *, VIRGINIA FERNÁNDEZ 1 , PAMELA CORNEJO 2 , ROMINA VARGAS 1 , IVÁN CASTILLO 3 1 Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile, 2 School of Medical Technology, Faculty of Health and Odontology, Diego Portales University, Santiago, Chile, and 3 School of Medicine, Faculty of Medicine, Catholic University of Maule, Talca, Chile Thyroid hormone (TH) exerts important actions on cellular energy metabolism, accelerating O 2 consumption with consequent reactive oxygen species (ROS) generation and redox signalling affording cell protection, a response that is contributed by redox-independent mechanisms. These processes underlie genomic and non-genomic pathways, which are integrated and exhibit hierarchical organisation. ROS production led to the activation of the redox- sensitive transcription factors nuclear factor-κB, signal transducer and activator of transcription 3, activating protein 1 and nuclear factor erythroid 2-related factor 2, promoting cell protection and survival by TH. These features involve enhancement in the homeostatic potential including antioxidant, antiapoptotic, antiinflammatory and cell proliferation responses, besides higher detoxification capabilities and energy supply through AMP- activated protein kinase upregulation. The above aspects constitute the molecular basis for TH-induced preconditioning of the liver that exerts protection against ischemia-reperfusion injury, a strategy also observed in extrahepatic organs of experimental animals and with other types of injury, which awaits application in the clinical setting. Noteworthy, re-adjusting TH to normal levels results in several beneficial effects; for example, it lengthens the cold storage time of organs for transplantation from brain-dead donors; allows a superior neurological outcome in infants of <28 weeks of gestation; reduces the cognitive side-effects of lithium and improves electroconvulsive therapy in patients with bipolar disorders. Thyroid hormone (TH) coordinates short-term and long-term energy requirements by regulating metabolic processes essential for normal growth, development and maintenance of cellular functions (Ref. 1). Thyroid gland produces and releases the prohormone thyroxin (T 4 ) into circulation, a process that is regulated by thyrotropin releasing hormone and thyroid stimulat- ing hormone. T 4 is further taken up into cells and trans- formed into the active form triiodothyronine (T 3 ) by iodothyronine deiodinases D1 and D2, which are dif- ferentially expressed in mammalian tissues (Ref. 2). As a key metabolic regulator, T 3 is considered a hor- metic agent, which is able to induce physiological (i.e. calorigenic effect), beneficial (i.e. organ protec- tion) responses in the low-concentration range, whereas potentially harmful responses are triggered at high-concentration ranges (i.e. thyrotoxicosis) (Refs 3, 4, 5). Recently, Mourouzis et al. have drawn attention that T 3 or T 4 play a critical role for the repair after injury in several organs in the experimental setting (Ref. 6). Studies by our group have demonstrated that the in vivo administration of a single dose of T 3 (0.1 mg/kg; 20 μg/animal) to rats affords protection against liver injury induced by1 h ischemia/20 h reper- fusion protocol (Ref. 7), representing an example of pharmacological preconditioning (PC) that might have clinical application. In general terms, organ PC refers to the development of an increased tolerance to injuring stimuli, which is induced by previous maneu- vers triggering beneficial molecular and functional changes (Ref. 8). In addition to the PC action of THs against organ injury, restoring normal TH levels in spe- cific cases has resulted in several beneficial effects, which include (i) the T 3 -dependent preservation of liver regenerative capacity and antiinflammatory responses after partial hepatectomy in the rat when combined with methylprednisolone (Ref. 9); (ii) the improvement induced by T 4 in mental, motor and neurological outcomes in infant <28 weeks of gesta- tion, which exhibit lower plasma TH levels than in term-born infants (Ref. 10); (iii) the diminution in the cognitive side effects of lithium and electroconvulsive therapy by T 3 administration to patients with bipolar disorders (Ref. 11); and (iv) the higher number of organs being functionally acceptable and in the early and intermediate graft survival found in brain-dead donors (Ref. 12). However, because of discrepancies observed in the benefits of routine TH administration in brain-dead potential organ donors, additional large- scale, prospective, multicentre, doubled-blind and Expert Reviews in Molecular Medicine, Vol. 17; e10; 1 of 12. © Cambridge University Press, 2015 doi:10.1017/erm.2015.8