Elsevier

Vascular Pharmacology

Volume 52, Issues 3–4, March–April 2010, Pages 120-130
Vascular Pharmacology

Review
Thyroid hormone and myocardial mitochondrial biogenesis

https://doi.org/10.1016/j.vph.2009.10.008Get rights and content

Abstract

Mitochondria have been central in the development of some of the most important ideas in modern biology. Since the discovery that mitochondria have its own DNA and specific mutations and deletions were found in association with neuromuscular and heart diseases, as well as in aging, an extraordinary number of publications have followed, and the term mitochondrial medicine was coined. Recently, it has been found that thyroid hormone (TH) stimulates cardiac mitochondrial biogenesis increasing myocardial mitochondrial mass, mitochondrial respiration, oxidative phosphorylation (OXPHOS), enzyme activities, mitochondrial protein synthesis (by stimulation in a T3-dependent manner), cytochrome, phospholipid and mtDNA content. Also, TH therapy may modulate cardiac mitochondrial protein-import apparatus. To identify the sequence of events, molecules and signaling pathways that is activated by TH affecting mitochondrial structure, biogenesis and function further research is warranted.

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

References (97)

  • J.M. Hernandez et al.

    Gene struc-ture of the human mitochondrial outer membrane receptor Tom20 and evolutionary study of its family of processed pseudogenes

    Gene

    (1999)
  • N. Kenmochi et al.

    The human mitochondrial ribosomal protein genes: mapping of 54 genes to the chromosomes and implications for human disorders

    Genomics

    (2001)
  • M.P. King et al.

    Post-transcriptional regulation of the steady-state levels of mitochondrial tRNAs in HeLa cells

    J. Biol. Chem.

    (1993)
  • E.C. Koc et al.

    Identification of mammalian mitochondrial translational initiation factor 3 and examination of its role in initiation complex formation with natural mRNAs

    J. Biol. Chem.

    (2002)
  • J.A. Korhonen et al.

    Twinkle has 5' -> 3' DNA helicase activity and is specifically stimulated by mitochondrial single-stranded DNA-binding protein

    J. Biol. Chem.

    (2003)
  • B. Li et al.

    Respiratory uncoupling induces delta-aminolevulinate synthase expression through a nuclear respiratory factor-1-dependent mechanism in HeLa cells

    J. Biol. Chem.

    (1999)
  • J. Ma et al.

    Cloning and sequence analysis of the cDNA for bovine mitochondrial translational initiation factor 2

    Biochim. Biophys. Acta

    (1995)
  • J. Marín-García et al.

    Understanding the impact of mitochondrial defects in cardiovascular disease: a review

    J. Card. Fail.

    (2002)
  • D.E. Matthews et al.

    Protein composition of the bovine mitochondrial ribo-some

    J. Biol. Chem.

    (1982)
  • C.T. Moraes

    What regulates mitochondrial DNA copy number in animal cells?

    Trends Genet.

    (2001)
  • B.D. Nelson et al.

    The role of thy-roid hormone and promoter diversity in the regulation of nuclear encoded mitochondrial proteins

    Biochim. Biophys. Acta

    (1995)
  • T.W. O'Brien

    Evolution of a protein-rich mitochondrial ribosome: Implications for human genetic disease

    Gene

    (2002)
  • C. Pantos et al.

    Thyroid hormone and “cardiac metamorphosis”: potential therapeutic implications

    Pharmacol. Ther.

    (2008)
  • G. Paradies et al.

    Enhanced cytochrome oxidase activity and modification of lipids in heart mitochondria from hyperthyroid rats

    Biochim. Biophys. Acta

    (1994)
  • P.A. Ropp et al.

    Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma

    Genomics

    (1996)
  • R.C. Scarpulla

    Nuclear activators and coactivators in mammalian mitochondrial biogenesis

    Biochim. Biophys. Acta

    (2002)
  • K. Scheller et al.

    Localization of glucocorticoid hormone receptors in mitochondria of human cells

    Eur. J. Cell Biol.

    (2000)
  • G.L. Schieber et al.

    Site of synthesis of the pro-teins of mammalian mitochondrial ribosomes. Evidence from cultured bovine cells

    J. Biol. Chem.

    (1985)
  • E. Schleiff et al.

    Expression, purification, and in vitro characterization of the human outer mitochondrial membrane receptor human translocase of the outer mitochondrial membrane 20

    Arch. Biochem. Biophys.

    (1999)
  • P. Schonfeld et al.

    Long-chain fatty acid-promoted swelling of mitochondria: further evidence for the protonophoric effect of fatty acids in the inner mitochondrial membrane

    FEBS Lett.

    (2000)
  • R.A. Schultz et al.

    Differential expression of mitochondrial DNA replication factors in mammalian tissues

    J. Biol. Chem.

    (1998)
  • D. Seiden et al.

    Oxygen diffusion distance in thyroxine-induced hypertrophic rabbit myocardium

    J. Mol. Cell. Cardiol.

    (1988)
  • O. Spirina et al.

    Heart-specific splice-variant of a human mitochondrial ribosomal protein (mRNA processing; tissue specific splicing)

    Gene

    (2000)
  • H. Suzuki et al.

    Human nuclear and mitochondrial Mt element-binding proteins to regulatory regions of the nuclear respiratory genes and to the mitochondrial promoter region

    Biochem. Biophys. Res. Commun.

    (1995)
  • J.E. Sylvester et al.

    Mitochondrial ribosomal proteins: candidate genes for mitochondrial disease

    Genet. Med.

    (2004)
  • M. Uldry et al.

    Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation

    Cell Metab.

    (2006)
  • T.W. Wong et al.

    Isolation and characterization of a DNA primase from human mitochondria

    J. Biol. Chem.

    (1985)
  • V.L. Woriax et al.

    Cloning and sequence analysis and expression of mammalian mitochondrial protein synthesis elongation factor Tu

    Biochim. Biophys. Acta

    (1995)
  • C. Wrutniak et al.

    A 43-kDa protein related to c-erb A a1 is located in the mitochondrial matrix of rat liver

    J. Biol. Chem.

    (1995)
  • Z. Wu et al.

    Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1

    Cell

    (1999)
  • H. Xin et al.

    Cloning and expression of mitochondrial translational elongation factor Ts from bovine and human liver

    J. Biol. Chem.

    (1995)
  • P.J. Adhihetty et al.

    Effect of chronic contractile activity on SS and IMF mitochondrial apoptotic susceptibility in skeletal muscle

    Am. J. Physiol.: Endocrinol. Metab.

    (2007)
  • M. Albring et al.

    Association of a protein structure of probable membrane derivation with HeLa cell mitochondrial DNA near its origin of replication

    Proc. Natl. Acad. Sci. U. S. A.

    (1977)
  • S. Anderson et al.

    Sequence and organization of human mitochondrial genome

    Nature

    (1981)
  • B.H. Annex et al.

    Mitochondrial DNA structure and expression in specialized subtypes of mammalian striated muscle

    Mol. Cell. Biol.

    (1990)
  • G. Attardi et al.

    Biogenesis of mitochondria

    Annu. Rev. Cell Biol.

    (1988)
  • P. Barbe et al.

    Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes

    FASEB J.

    (2001)
  • P.M. Barger et al.

    Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth

    J. Clin. Invest.

    (2000)
  • Cited by (47)

    • Role of thyroid hormones-induced oxidative stress on cardiovascular physiology

      2022, Biochimica et Biophysica Acta - General Subjects
    • Thyroid hormone protects cardiomyocytes from H<inf>2</inf>O<inf>2</inf>-induced oxidative stress via the PI3K-AKT signaling pathway

      2019, Experimental Cell Research
      Citation Excerpt :

      The PI3K/AKT cardioprotection pathway is known to inhibit apoptosis by maintaining mitochondrial function and modulating the activities of the Bcl-2 family proteins, caspase 9 and caspase 3 [15]. The biologically active thyroid hormone (TH) triiodothyronine (T3) is considered a major regulator of cardiovascular function, including the regulation of contractile and calcium-handling protein expression, mitochondrial function, and ion channels in cardiac myocytes [8–10]. Severe heart diseases, including myocardial infarction and heart failure, are often accompanied by altered TH metabolism [11].

    • Underlying mechanism of the contractile dysfunction in atrophied ventricular myocytes from a murine model of hypothyroidism

      2018, Cell Calcium
      Citation 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 Dermatology
      Citation 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).

    View all citing articles on Scopus
    View full text