T3-induced enhancement of mitochondrial Ca2+ uptake as a boost for mitochondrial metabolism

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.

Automated summary

Thyroid hormones regulate mitochondrial Ca2+ uptake, leading to increased energy metabolism and reactive oxygen species production.