Barth syndrome cells display widespread remodeling of mitochondrial complexes without affecting metabolic flux distribution

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Chatzispyrou, Iliana A.¹  Guerrero-Castillo, Sergio²  Held, Ntsiki M.¹  Ruiter, Jos P. N.¹  Denis, Simone W.¹  Ijlst, Lodewijk¹  Wanders, Ronald J.¹  van Weeghel, Michel¹  Ferdinandusse, Sacha¹  Vaz, Frederic M.¹  Brandt, Ulrich²  Houtkooper, Riekelt H.¹ 

[1] Univ Amsterdam, Amsterdam Gastroenterol & Metab, Amsterdam Cardiovasc Sci, Lab Genet Metab Dis,Amsterdam UMC, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Dept Pediat, Radboud Inst Mol Life Sci, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands

关键词: Barth syndrome;    Tafazzin;    Mitochondria;    Complexome profiling;    Metabolomics;    Respiratory chain Supercomplex;    MICOS complex;    2-Oxoglutarate dehydrogenase complex;   

DOI  :  10.1016/j.bbadis.2018.08.041

来源: Elsevier

【 摘 要 】

Barth syndrome (BTHS) is a rare X-linked disorder that is characterized by cardiac and skeletal myopathy, neutropenia and growth abnormalities. The disease is caused by mutations in the tafazzin (TAZ) gene encoding an enzyme involved in the acyl chain remodeling of the mitochondria] phospholipid cardiolipin (CL). Biochemically, this leads to decreased levels of mature CL and accumulation of the intermediate monolysocardiolipin (MLCL). At a cellular level, this causes mitochondrial fragmentation and reduced stability of the respiratory chain supercomplexes. However, the exact mechanism through which tafazzin deficiency leads to disease development remains unclear. We therefore aimed to elucidate the pathways affected in BTHS cells by employing proteomic and metabolic profiling assays. Complexome profiling of patient skin fibroblasts revealed significant effects for about 200 different mitochondrial proteins. Prominently, we found a specific destabilization of higher order oxidative phosphorylation (OXPHOS) supercomplexes, as well as changes in complexes involved in cristae organization and CL trafficking. Moreover, the key metabolic complexes 2-oxoglutarate dehydrogenase (OGDH) and branched-chain ketoacid dehydrogenase (BCKD) were profoundly destabilized in BTHS patient samples. Surprisingly, metabolic flux distribution assays using stable isotope tracer-based meta-bolomics did not show reduced flux through the TCA cycle. Overall, insights from analyzing the impact of TAZ mutations on the mitochondria] complexome provided a better understanding of the resulting functional and structural consequences and thus the pathological mechanisms leading to Barth syndrome.

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