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Effect of thyroid hormone on oxidative stress in cells from patients with mtDNA defects
Author(s) -
Menzies Keir J.,
Hood David A.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a817
Subject(s) - mitochondrial biogenesis , tfam , mitochondrial dna , oxidative stress , mitochondrion , biology , mitochondrial disease , reactive oxygen species , oxidative phosphorylation , mitochondrial ros , microbiology and biotechnology , medicine , endocrinology , chemistry , biochemistry , gene
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 (T 3 ) induces mitochondrial biogenesis and enhances the ability of cells to generate ATP. To evaluate the role of T 3 ‐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 tRNA leu 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 Ca 2+ 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 T 3 treatment, in normal and patient cells, mitochondrial mass did not change, but ROS production was decreased by 30–40%, cytoplasmic Ca 2+ 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 T 3 ‐treated patient and normal cells. T 3 also restored the levels of MnSOD to normal values in patient cells and increased MnSOD by 25% in control cells. These results suggest that T 3 acts to reduce cellular oxidative stress, which may help attenuate ROS‐mediated macromolecular damage. Supported by CIHR.