Mitochondrial (mt)DNA mutations contribute to various disease states 
characterized by low ATP production. In contrast, thyroid hormone 
[3,3',5-triiodothyronine (T(3))] induces mitochondrial biogenesis and enhances 
ATP generation within cells. To evaluate the role of T(3)-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-gamma coactivator-1alpha (PGC-1alpha), 
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 T(3) 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-1alpha, Tfam, or UCP2 in either T(3)-treated 
patient or control cells. However, T(3) 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 T(3) 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.