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The mechanism by which thyroid hormone exerts its manifold actions has been a source of fascination to investigators for many years. In a review of this subject published over 30 years ago, Wolf and Wolf cited some 358 references (1). Ideas ranged from a proposal that thyroid hormones acted by chelating copper, to suggestions that thyroid hormones interacted directly with individual enzymes.
A very popular theory held that the hormones exerted a direct and immediate effect on mitochondria (2–4). The profound effects of thyroid hormone on mitochondrial enzymes made this hypothesis particularly appealing. Hyperthyroidism was in fact perceived as an example of generalized mitochondrial dysfunction (5). Shortly after the publication of the review by Wolf and Wolf, Tata et al. proposed that thyroid hormone might function by augmenting the expression of nuclear target genes (6). These prescient inferences were based on time-course studies in hypothyroid rats treated with
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