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

Abstract

Mitochondrial DNA (mtDNA) mutations contribute to the development of various disease states and are characterized by low ATP production in patient cells. In contrast, thyroid hormone (T3) induces mitochondrial biogenesis and enhances the ability of cells to generate ATP. To evaluate the role of T3-mediated mitochondrial biogenesis in patients with mtDNA mutations, three primary fibroblast cell lines with mtDNA mutations were evaluated, including a patient with Leigh’s syndrome, one with a tRNAleu mutation and another with an ATP6 mutation. Compared to normal cells, patient fibroblasts displayed similar levels of mitochondrial mass, a 1.6-fold elevation in reactive oxygen species (ROS) production, a 1.7-fold elevation in cytoplasmic Ca2+ levels and a 10% lower mitochondrial membrane potential. Patient cells also exhibited 25% reduction in cytochrome c oxidase (COX) activity and MnSOD levels compared to normal cells. Following T3 treatment, in normal and patient cells, mitochondrial mass did not change, but ROS production was decreased by 30–40%, cytoplasmic Ca2+ levels were reduced by 20% and COX activity was increased by 10–20%. There was no significant change in the expression of the mitochondrial biogenesis regulator PGC-1, but a 20% increase in Tfam levels was evident in both T3-treated patient and normal cells. T3 also restored the levels of MnSOD to normal values in patient cells and increased MnSOD by 25% in control cells. These results suggest that T3 acts to reduce cellular oxidative stress, which may help attenuate ROS-mediated macromolecular damage. Supported by CIHR.