TY - JOUR
T1 - Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome
AU - Dudek, Jan
AU - Cheng, I.-Fen
AU - Balleininger, Martina
AU - Vaz, Frédéric M.
AU - Streckfuss-Bömeke, Katrin
AU - Hübscher, Daniela
AU - Vukotic, Milena
AU - Wanders, Ronald J. A.
AU - Rehling, Peter
AU - Guan, Kaomei
PY - 2013
Y1 - 2013
N2 - Barth syndrome (BTHS) patients carrying mutations in tafazzin (TAZ1), which is involved in the final maturation of cardiolipin, present with dilated cardiomyopathy, skeletal myopathy, growth retardation and neutropenia. To study how mitochondrial function is impaired in BTHS patients, we generated induced pluripotent stem cells (iPSCs) to develop a novel and relevant human model system for BTHS. BTHS-iPSCs generated from dermal fibroblasts of three patients with different mutations in TAZ1 expressed pluripotency markers, and were able to differentiate into cells derived from all three germ layers both in vitro and in vivo. We used these cells to study the impact of tafazzin deficiency on mitochondrial oxidative phosphorylation. We found an impaired remodeling of cardiolipin, a dramatic decrease in basal oxygen consumption rate and in the maximal respiratory capacity in BTHS-iPSCs. Simultaneous measurement of extra-cellular acidification rate allowed us a thorough assessment of the metabolic deficiency in BTHS patients. Blue native gel analyses revealed that decreased respiration coincided with dramatic structural changes in respiratory chain supercomplexes leading to a massive increase in generation of reactive oxygen species. Our data demonstrate that BTHS-iPSCs are capable of modeling BTHS by recapitulating the disease phenotype and thus are important tools for studying the disease mechanism
AB - Barth syndrome (BTHS) patients carrying mutations in tafazzin (TAZ1), which is involved in the final maturation of cardiolipin, present with dilated cardiomyopathy, skeletal myopathy, growth retardation and neutropenia. To study how mitochondrial function is impaired in BTHS patients, we generated induced pluripotent stem cells (iPSCs) to develop a novel and relevant human model system for BTHS. BTHS-iPSCs generated from dermal fibroblasts of three patients with different mutations in TAZ1 expressed pluripotency markers, and were able to differentiate into cells derived from all three germ layers both in vitro and in vivo. We used these cells to study the impact of tafazzin deficiency on mitochondrial oxidative phosphorylation. We found an impaired remodeling of cardiolipin, a dramatic decrease in basal oxygen consumption rate and in the maximal respiratory capacity in BTHS-iPSCs. Simultaneous measurement of extra-cellular acidification rate allowed us a thorough assessment of the metabolic deficiency in BTHS patients. Blue native gel analyses revealed that decreased respiration coincided with dramatic structural changes in respiratory chain supercomplexes leading to a massive increase in generation of reactive oxygen species. Our data demonstrate that BTHS-iPSCs are capable of modeling BTHS by recapitulating the disease phenotype and thus are important tools for studying the disease mechanism
U2 - https://doi.org/10.1016/j.scr.2013.05.005
DO - https://doi.org/10.1016/j.scr.2013.05.005
M3 - Article
C2 - 23792436
SN - 1873-5061
VL - 11
SP - 806
EP - 819
JO - Stem Cell Research
JF - Stem Cell Research
IS - 2
ER -