Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome

A publication (2013 | journal article; research paper) of the University of Göttingen

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​Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome​
Dudek, J. ; Cheng, I.-F. ; Balleininger, M.; Vaz, F. M.; Streckfuss-Bömeke, K. ; Hübscher, D.   & Vukotic, M.  et al.​ (2013) 
Stem Cell Research11(2) pp. 806​-819​.​

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Dudek, Jan 
Cheng, I-Fen 
Balleininger, Martina
Vaz, Frederic M.
Streckfuss-Bömeke, Katrin 
Hübscher, Daniela 
Vukotic, Milena 
Wanders, Ronald J. A.
Rehling, Peter 
Guan, Kaomei 
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 mitochondria( 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. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.
Issue Date
Stem Cell Research 
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | A04: Patienten-spezifische induzierte pluripotente Stammzellen zur funktionellen Untersuchung von Ryanodinrezeptor-Mutationen 
SFB 1002 | A06: Molekulare Grundlagen mitochondrialer Kardiomyopathien 
Working Group
RG Guan (Application of patient-specific induced pluripotent stem cells in disease modelling) 
RG Rehling (Mitochondrial Protein Biogenesis) 



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