Thyroid hormones act as master regulators of cellular metabolism. Thereby, the biologically active triiodothyronine (T3) induces the expression of genes to enhance mitochondrial metabolic function. Notably, Ca²⁺ ions are necessary for the activity of dehydrogenases of the tricarboxylic acid cycle and, thus, mitochondrial respiration. We investigated whether treating HeLa cells with T3 causes alterations in mitochondrial Ca²⁺ ([Ca²⁺]_mito) levels. Real-time measurements by fluorescence microscopy revealed that treatment with T3 for 3 h induces a significant increase in basal [Ca²⁺]_mito levels and [Ca²⁺]_mito uptake upon the depletion of the endoplasmic reticulum (ER) Ca²⁺ store, while cytosolic Ca²⁺ levels remained unchanged. T3 incubation was found to upregulate mRNA expression levels of uncoupling proteins 2 and 3 (UCP2, UCP3) and of protein arginine methyltransferase 1 (PRMT1). Live-cell imaging revealed that T3-induced enhancement of mitochondrial Ca²⁺ uptake depends on the mitochondrial Ca²⁺ uniporter (MCU), UCP2, and PRMT1 that are essential for increased mitochondrial ATP ([ATP]_mito) production after T3 treatment. Besides, increased [Ca²⁺]_mito and [ATP]_mito levels correlated with enhanced production of reactive oxygen species (ROS) in mitochondria. Notably, ROS scavenging causes mitochondrial Ca²⁺ elevation and outplays the impact of T3 on [Ca²⁺]_mito homeostasis. Based on these results, we assume that thyroid hormones adjust [Ca²⁺]_mito homeostasis by modulating the UCP2- and PRMT1-balanced [Ca²⁺]_mito uptake via MCU in case of physiological ROS levels to convey their impact on mitochondrial ATP and ROS production.

Angelo Jarc

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