title: Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome.
abstract: 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.
authors.affiliation: Department of Biochemistry II, University Medical Center Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Dudek
authors.forename: I-Fen
authors.initials: IF
authors.lastname: Cheng
authors.forename: Martina
authors.initials: M
authors.lastname: Balleininger
authors.forename: Frédéric M
authors.initials: FM
authors.lastname: Vaz
authors.forename: Katrin
authors.initials: K
authors.lastname: Streckfuss-Bömeke
authors.forename: Daniela
authors.initials: D
authors.lastname: Hübscher
authors.forename: Milena
authors.initials: M
authors.lastname: Vukotic
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Peter
authors.initials: P
authors.lastname: Rehling
authors.forename: Kaomei
authors.initials: K
authors.lastname: Guan
mesh_terms: D000818:Animals; D056889:Barth Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002308:Cardiolipins / Q000096:biosynthesis / Q000378:metabolism*; D004579:Electron Transport; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice
chemical_list: D002308:Cardiolipins