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CELLULAR AND MITOCHONDRIAL METABOLISM

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

¹School of Kinesiology and Health Science, ²Department of Biology, and the ³Muscle Health Research Centre, York University, Toronto; and ⁴The Hospital for Sick Children, Toronto, Ontario, Canada

Submitted 12 September 2007 ; accepted in final form 17 November 2008

Mitochondrial (mt)DNA mutations contribute to various disease states characterized by low ATP production. In contrast, thyroid hormone [3,3',5-triiodothyronine (T₃)] induces mitochondrial biogenesis and enhances ATP generation within cells. To evaluate the role of T₃-mediated mitochondrial biogenesis in patients with mtDNA mutations, three fibroblast cell lines with mtDNA mutations were evaluated, including two patients with Leigh's syndrome and one with hypertrophic cardiomyopathy. Compared with control cells, patient fibroblasts displayed similar levels of mitochondrial mass, peroxisome proliferator-activated receptor- coactivator-1 (PGC-1), mitochondrial transcription factor A (Tfam), and uncoupling protein 2 (UCP2) protein expression. However, patient cells exhibited a 1.6-fold elevation in ROS production, a 1.7-fold elevation in cytoplasmic Ca²⁺ levels, a 1.2-fold elevation in mitochondrial membrane potential, and 30% less complex V activity compared with control cells. Patient cells also displayed 20–25% reductions in both cytochrome c oxidase (COX) activity and MnSOD protein levels compared with control cells. After T₃ treatment of patient cells, ROS production was decreased by 40%, cytoplasmic Ca²⁺ was reduced by 20%, COX activity was increased by 1.3-fold, and ATP levels were elevated by 1.6-fold, despite the absence of a change in mitochondrial mass. There were no significant alterations in the protein expression of PGC-1, Tfam, or UCP2 in either T₃-treated patient or control cells. However, T₃ restored the mitochondrial membrane potential, complex V activity, and levels of MnSOD to normal values in patient cells and elevated MnSOD levels by 21% in control cells. These results suggest that T₃ acts to reduce cellular oxidative stress, which may help attenuate ROS-mediated damage, along with improving mitochondrial function and energy status in cells with mtDNA defects.

reactive oxygen species; mitochondrial biogenesis; cytoplasmic calcium; mitochondrial disease; 3,3',5-triiodothyronine; mitochondrial DNA