TY - JOUR
T1 - Patient-derived fibroblasts indicate oxidative stress status and may justify antioxidant therapy in OXPHOS disorders
AU - Voets, A. M.
AU - Lindsey, P. J.
AU - Vanherle, Sabina J V
AU - Timmer, E. D.
AU - Esseling, J. J.
AU - Koopman, Werner J. H.
AU - Willems, P. H. G. M.
AU - Schoonderwoerd, G. C.
AU - De Groote, P.
AU - the Poll, B.T.
AU - de Coo, Irenaeus F M
AU - Smeets, H. J. M.
PY - 2012/11
Y1 - 2012/11
N2 - Oxidative phosphorylation disorders are often associated with increased oxidative stress and antioxidant therapy is frequently given as treatment. However, the role of oxidative stress in oxidative phosphorylation disorders or patients is far from clear and consequently the preventive or therapeutic effect of antioxidants is highly anecdotic. Therefore, we performed a systematic study of a panel of oxidative stress parameters (reactive oxygen species levels, damage and defense) in fibroblasts of twelve well-characterized oxidative phosphorylation patients with a defect in the POLG1 gene, in the mitochondrial DNA-encoded tRNA-Leu gene (m.3243A>G or m.3302A>G) and in one of the mitochondrial DNA-encoded NADH dehydrogenase complex 1 (Cl) subunits. All except two cell lines (one POLG1 and one tRNA-Leu) showed increased reactive oxygen species levels compared with controls, but only four (two Cl and two tRNA-Leu) cell lines provided evidence for increased oxidative protein damage. The absence of a correlation between reactive oxygen species levels and oxidative protein damage implies differences in damage prevention or correction. This was investigated by gene expression studies, which showed adaptive and compensating changes involving antioxidants and the unfolded protein response, especially in the POLG1 group. This study indicated that patients display individual responses and that detailed analysis of fibroblasts enables the identification of patients that potentially benefit from antioxidant therapy. Furthermore, the fibroblast model can also be used to search for and test novel, more specific antioxidants or explore ways to stimulate compensatory mechanisms.
AB - Oxidative phosphorylation disorders are often associated with increased oxidative stress and antioxidant therapy is frequently given as treatment. However, the role of oxidative stress in oxidative phosphorylation disorders or patients is far from clear and consequently the preventive or therapeutic effect of antioxidants is highly anecdotic. Therefore, we performed a systematic study of a panel of oxidative stress parameters (reactive oxygen species levels, damage and defense) in fibroblasts of twelve well-characterized oxidative phosphorylation patients with a defect in the POLG1 gene, in the mitochondrial DNA-encoded tRNA-Leu gene (m.3243A>G or m.3302A>G) and in one of the mitochondrial DNA-encoded NADH dehydrogenase complex 1 (Cl) subunits. All except two cell lines (one POLG1 and one tRNA-Leu) showed increased reactive oxygen species levels compared with controls, but only four (two Cl and two tRNA-Leu) cell lines provided evidence for increased oxidative protein damage. The absence of a correlation between reactive oxygen species levels and oxidative protein damage implies differences in damage prevention or correction. This was investigated by gene expression studies, which showed adaptive and compensating changes involving antioxidants and the unfolded protein response, especially in the POLG1 group. This study indicated that patients display individual responses and that detailed analysis of fibroblasts enables the identification of patients that potentially benefit from antioxidant therapy. Furthermore, the fibroblast model can also be used to search for and test novel, more specific antioxidants or explore ways to stimulate compensatory mechanisms.
KW - Oxidative stress
KW - POLG1
KW - Cl deficiency
KW - MELAS
KW - ROS
KW - Protein carbonyls
U2 - 10.1016/j.bbabio.2012.07.001
DO - 10.1016/j.bbabio.2012.07.001
M3 - Article
C2 - 22796146
SN - 0005-2728
VL - 1817
SP - 1971
EP - 1978
JO - Biochimica et Biophysica Acta-bioenergetics
JF - Biochimica et Biophysica Acta-bioenergetics
IS - 11
ER -