Bioenergetic Aspects of Mitochondrial Actions of Thyroid Hormones

Abstract

Much is known, but there is also much more to discover, about the actions that thyroid hormones (TH) exert on metabolism. Indeed, despite the fact that thyroid hormones are recognized as one of the most important regulators of metabolic rate, much remains to be clarified on which mechanisms control/regulate these actions. Given their actions on energy metabolism and that mitochondria are the main cellular site where metabolic transformations take place, these organelles have been the subject of extensive investigations. In relatively recent times, new knowledge concerning both thyroid hormones (such as the mechanisms of action, the existence of metabolically active TH derivatives) and the mechanisms of energy transduction such as (among others) dynamics, respiratory chain organization in supercomplexes and cristes organization, have opened new pathways of investigation in the field of the control of energy metabolism and of the mechanisms of action of TH at cellular level. In this review, we highlight the knowledge and approaches about the complex relationship between TH, including some of their derivatives, and the mitochondrial respiratory chain.

Keywords: bioenergetics; iodothyronines; mitochondrial proteomics.

Figure 1

Schematic summary of the main cellular pathways through which TH regulate mitochondrial functions. TH (T4/T3) move from outside the plasma membrane into the cytoplasm (trough passive diffusion or active transport) or bind to surface receptor such as integrin αvb3. In the cytoplasm, deiodination allows the conversion of T4 into T3 by DIO1 or DIO2 action, and T3 can bind to cytosolic proteins (i.e., cytosolic TH receptors, TR). These can signal through transduction pathways involving Mitogen-Activated Protein Kinases (MAPKs), Protein C (PKC), Protein Kinase B (AKT), and phosphoinositide 3-kinase (PI3-K)-AKT, similar to those activated by integrins. All these may result in gene transcription. Direct transcriptional regulation by T3/TR requires TREs (early expression (early)). Late T3-dependent transcription (late expression (late)) requires some intermediate factors [(e.g., Nuclear Respiratory Factor 1 (NRF-1), Nuclear Respiratory Factor 2 (NRF-2), Peroxisome Proliferator-Activated Recepto (PPAR)γ, and transcriptional coactivators such as Peroxisome Proliferator-Activated Receptor Gamma Coactivator (PGC)-1α and PGC-1β) which can also enter the mitochondrion to modulate mitochondrial biogenesis, oxygen consumption, and gene expression. An important role is played by the nuclear-encoded transcription factor mitochondrial Transcription Factor A (mtTFA), a key modulator of mtDNA stabilization. Mitochondria contain two N-terminally truncated forms of the TRα1 receptor isoform, with molecular weights of 43 (p43) and 28 kDa (p28), with p43 now considered a T3-dependent transcription factor of the mitochondrial genome (adapted from [26]).

Figure 2

Nongenomic actions of T3 and its endogenous metabolites, T2 and T1AM, on mitochondrial respiratory chain. Cross-section of a mitochondrion (mt), with a schematic view of OXPHOS. I = Complex I; II = Complex II; III = Complex III; IV = Complex IV; V = Complex V. Arrows indicate the so far identified molecular targets of the three molecules. T3, through p43, affects mitochondrial transcription and protein synthesis and the overall activity of the OXPHOS. T2, like T3, is able to modulate the OXPHOS and to directly stimulate Complex IV (COX) activity, likely specifically binding the Va subunit. T1AM was demonstrated to modulate Complex V kinetic properties and to partially block Complex III. Mitochondrial actions of T3 mediated by p28 largely remain unknown (?).