Thyroid hormone and gene expression in the regulation of mitochondrial respiratory function

Abstract

Thyroid hormone has a profound effect on cellular respiration. Abnormally high levels of this hormone accelerate respiration in conjunction with a general increase in metabolism while pathologically low amounts cause low levels of respiration with a general slowing of metabolic activity. The affect on respiration is primarily the result of changes in the expression of respiratory genes and modulation of inner membrane structure. This review focuses on the regulation of respiratory gene expression by thyroid hormone. Respiratory genes are encoded in both the nucleus and the mitochondrion, the products of which are required in stoichiometric amounts for proper assembly of the respiratory chain. Thyroid hormone influences the expression of a number of nuclear encoded respiratory genes at the level of mRNA and enhances expression of mitochondrially encoded respiratory genes. Therefore, thyroid hormone appears to affect gene regulation in two different cell compartments. The current evidence for a direct thyroid hormone/thyroid receptor regulation of these respiratory genes and possible indirect pathway(s) mediating the thyroid effect is discussed.

Thyroid hormone action in mitochondria

“…It remains to be established what is the contribution of direct mechanisms involving the c-Erb A nuclear receptors, and of indirect ones mediated by the induction of transcription factors responding to T3, such as nuclear respiratory factor 1, whose RE has been identified in several nuclear respiratory genes (for review see Pillar & Seitz 1997). However, recent data discussed below have raised the possibility that a direct mitochondrial pathway could also be involved in this delayed T3 influence.…”

“…Moreover, T3 stimulation of mt-TFA expression (Garstka et al 1994) is probably a major mechanism involved in mitochondriogenesis as this factor stimulates mitochondrial genome expression and replication. The expression of several nuclear genes encoding mitochondrial proteins is T3-regulated, as shown for -F1ATPase, ANT, cytochrome c1, mt-TFA, UCPs and several sub-units of the respiratory chain (for review see Pillar & Seitz 1997). In addition, improvement in the mitochondrial import of nuclear-encoded proteins has been observed in cardiac muscle cells (Craig et al 1998), in agreement with the study of Schneider & Hood (2000) indicating that mt-heat shock protein 70 expression, a chaperone involved in import, is increased by thyroid hormone.…”

Effect of thyroid hormone on mitochondrial properties and oxidative stress in cells from patients with mtDNA defects

“…This leads to the upregulation of multiple nuclear-encoded respiratory genes, thereby altering the activity of the mitochondrial electron transport chain (42). The mechanisms of mitochondrial biogenesis involve the upregulation of nuclear-encoded mitochondrial transcription factor A (Tfam), a protein that binds mtDNA to regulate its transcription (33), as well as peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣), a master regulator of mitochondrial biogenesis. T 3 has been shown to increase the expression of both Tfam and PGC-1␣ in a tissuespecific manner (14,16).…”

Characterization of human liver thermostable phenol sulfotransferase (SULT1A1) allozymes with 3,3',5-triiodothyronine as the substrate

“…Thyroid hormones including T 4 , rT 3 , and 3,5-T 2 mediate several extranuclear (nongenomic) actions at the cell membrane and cytoskeleton, such as the regulation of actin polymerization in glial cells to control cell surface availability of the type II 5 -deiodinase (Davis & Davis 1996, Leonard & Farwell 1997. In addition, 3,3 -T 2 and 3,5-T 2 have been reported to act through nonnuclear pathways to enhance mitochondrial respiration and thus resting metabolism (Lanni et al 1996, Moreno et al 1997, Pillar & Seitz 1997. Both SULT1A1*1 and SULT1A1*2 preferentially sulfoconjugated 3,3 -T 2 .…”