ReviewThyroid hormone and myocardial mitochondrial biogenesis
Graphical Abstract
Introduction
Thyroid hormone (TH) is a key regulator of metabolism in a plurality of organs including the heart, and changes in the thyroid status are associated with profound abnormalities in the biochemical and also in the physiological functioning of cardiac muscle. Physiological stimulation of skeletal and cardiac muscle occurs in response to increased contractile activity by physical exercise (Chow et al., 2007), electrical stimuli (Adhihetty et al., 2007), long-term cold exposure (Klingenspor, 2003), caloric restriction (Civitarese et al., 2007), and also in response to TH exposure. Notably, through TH action increased mitochondrial biogenesis will also occur. In this regard, the interactions between nucleus and mitochondria for a coordinated regulation of gene expression have been recognized as having a large, subtle, and rich interrelationship that gradually is being deciphered. This relationship is considered to be a two-way dialogue or cross-talk between the mitochondrial and the nucleus genomes, allowing an integration of responses to extracellular and intracellular stimuli and signals, such as exposure to TH. Furthermore, coordinated increases in both mitochondrial and nuclear gene expression have been found in patients with primary mitochondrial diseases related to OXPHOS defects, including mitochondrial cardiomyopathy (Heddi et al., 1999, Marín-García and Goldenthal, 2002). Understanding the stimuli, signals, and transducers that govern mitochondrial biogenesis pathways may have critical significance in the treatment of cardiovascular disorders. In this review we will analyze TH-induced changes that may occur in mitochondria function and biogenesis, how TH stimuli regulate these multi-faceted organelles, and how these mitochondrial changes may affect cardiac hypertrophy.
Section snippets
Mitochondrial genome
The mitochondrial genome encodes 13 peptide subunits, while the remaining peptide subunits of the respiratory complexes are encoded by the nuclear genome. The latter also encodes the entire complement of proteins involved in mtDNA replication and transcription, protein components of mitochondrial ribosomes and multiple structural and transport proteins of the mitochondrial membranes. These nuclear-encoded proteins are synthesized on the cytosolic ribosomes, targeted to mitochondria, and
Replication
The replication cycle of mtDNA begins with the initiation of the leading H-strand synthesis (Fig. 1) at the replication origin (OH) with an RNA primer transcribed from the light strand promoter (LSP) (Shadel and Clayton, 1997). The synthesis of this primer requires both an mtRNA polymerase and the mitochondrial transcription factor (mtTFA). The RNA primer exists as a stable and persistent RNA:DNA hybrid (also known as an R-loop), which is formed during transcription at human OH (Xu and Clayton,
Mitochondrial ribosomes
Translation of mitochondrial mRNAs occurs exclusively on mitochondrial ribosomes. The rRNA of mitochondrial ribosomes is encoded by mtDNA, while the ribosomal proteins are entirely encoded by nuclear DNA (Schieber and O'Brien, 1985). The ribosomes present in mammalian mitochondria have a lower sedimentation coefficient (i.e. 55 S) than cytoplasmic ribosomes and are composed of small (28 S) and large (39 S) subunits. They are characterized by a significantly lower percentage of rRNA, compared to
Nuclear regulatory proteins and coordination of transcriptional events
Mitochondria have been estimated to contain more than 1000 polypeptides, and most of them are nuclear-DNA-encoded. With a limited (but essential) contribution of 13 proteins, 2 ribosomal rRNAs, and 22 tRNAs, mitochondria are obviously not self-supporting organelles. The entire complement of enzymes and regulatory factors required for mtDNA replication and repair, transcription, RNA processing, and translation is encoded by nuclear DNA. In addition, the large network of enzymes involved in
Hormones affecting both mitochondrial and nuclear transcription
A number of nuclear and mitochondrial-encoded genes exhibit a similar pattern of transcriptional regulation in cardiac tissue (Wiesner et al., 1994). However, the analysis of transcript and peptide levels, of both nuclear and mtDNA-encoded enzyme subunits, assessed in response to physiological transition (e.g. TH treatment and cell-growth activation), have revealed a more complex pattern of transcriptional regulation of nuclear genes encoding mitochondrial proteins, indicating multiple
Mitochondria import and assembly of proteins
The translocation of proteins into mitochondria (as with other organelles such as the chloroplast and peroxisome) is post-translational. Translocation occurs at mitochondrial “contact” sites joining outer and inner membranes. Signal sequences (signal peptides 20 to 80 residues long) on the imported proteins are a prerequisite for their efficient translocation into the mitochondrial matrix; a second signal (normally composed of hydrophobic residues) is required for insertion into the inner
Thyroid hormone and myocardial hypertrophy
TH is a key regulator of metabolism in tissues such as heart and liver, and changes in thyroid status have been associated with profound alterations in their biochemical and physiological functioning. In the heart hyperthyroidism is associated with increased metabolic rate, augmented cardiac muscle contractility and structural hypertrophy; thus, cardiac hypertrophy, and therefore remodeling is the usual response to TH. Also, models of cardiac hypertrophy have shown TH-induced increases in total
Specific TH-induced mitochondrial biogenesis
TH has a dramatic effect on mitochondrial biogenesis through TH receptor-dependent regulation of gene expression in the mitochondrial and nuclear genome. Treatment with TH will result in augmented myocardial mitochondrial proliferation (Zak et al., 1980) mitochondrial respiration and OXPHOS enzyme activities, mitochondrial protein synthesis, and cytochrome content. Furthermore, treatment with TH sharply increases myocardial oxygen consumption that parallels the increase in mitochondrial
Conclusions
TH induces cardiac hypertrophy and increases mitochondrial biogenesis. One way that this is achieved is by the programmatic activation of nuclear gene expression (via the thyroxin-receptor, which upon binding thyroxin [e.g. T3] translocates into the nucleus and acts as a transcription factor). This receptor-ligand complex binds to DNA as either homodimeric or heterodimeric complexes; the major heterodimeric partners include the nuclear receptors RXRα and PPARα. Among the many genes
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2019, International Journal of CardiologyUnderlying mechanism of the contractile dysfunction in atrophied ventricular myocytes from a murine model of hypothyroidism
2018, Cell CalciumCitation Excerpt :Nevertheless, it is known that long term Hypo leads to cardiac chambers dilatation, and further remodeling includes myocyte elongation [12], therefore, alterations in T-tubules and other structures (e.g. SR and mitochondria [79]), cannot be excluded as contributors to HF development. T3 upregulates the expression of nuclear and mitochondrial genes for proteins of the Krebs cycle, substrate utilization, electron chain transport and numerous transcription factors, and thereby enhance myocardial metabolism, oxidative capacity, and mitochondrial biogenesis [26,27]. In Hypo, a decrease in mitochondrial biogenesis should impact myocyte oxidative capacity, and in combination with a decrease in energy reserve, via the creatine kinase transfer system [30], could diminish ATP supply.
Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis
2016, Journal of Investigative DermatologyCitation Excerpt :To assess whether any expression changes in these parameters altered also the intraepidermal mitochondrial oxidative phosphorylation, we asked whether THs modified the activity of complex I, the initial step of the mitochondrial respiratory chain (Chandel and Jeffs, 2015; Hirst, 2013; Scheffler, 2008) and of complex II and IV. Finally, because THs stimulate mitochondrial biogenesis in several human cell types (Cioffi et al., 2013; Lee et al., 2012; Marin-Garcia, 2010) and human hair follicles (Vidali et al., 2014), we used transmission electron microscopy to determine whether this also occurred in human epidermis ex vivo. Increased mitochondrial activity may exert both beneficial and deleterious effects; the latter include the promotion of aging-associated pathways by enhancing reactive oxygen species (ROS) production and subsequent DNA damage (Bratic and Larsson, 2013; Kozieł et al., 2011; Swerdlow, 2016).