Abstract
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 mitochondrial 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 metabolomics did not show reduced flux through the TCA cycle. Overall, insights from analyzing the impact of TAZ mutations on the mitochondrial complexome provided a better understanding of the resulting functional and structural consequences and thus the pathological mechanisms leading to Barth syndrome.
Highlights
Barth syndrome (BTHS) is a rare inherited X-linked disorder mainly characterized by cardiomyopathy, skeletal myopathy, neutropenia, 3methylglutaconic aciduria and growth retardation with abnormal mitochondria [1,2,3,4]
Of 2769 proteins identified in total, 1238 were considered as mitochondrial based on different criteria
We aimed to obtain a more detailed understanding of the molecular mechanisms underlying BTHS by comprehensively assessing the changes resulting from mutations in the TAZ gene at the level of the mitochondrial complexome and by linking the observed alterations to metabolic flux distribution in BTHS patient cells
Summary
Barth syndrome (BTHS) is a rare inherited X-linked disorder mainly characterized by cardiomyopathy, skeletal myopathy, neutropenia, 3methylglutaconic aciduria and growth retardation with abnormal mitochondria [1,2,3,4]. The genetic cause of BTHS has been identified in the X-linked tafazzin (TAZ) gene, previously known as G4.5 [6,7], where pathogenic mutations spreading across all its 11 exons have been described [8]. The TAZ gene encodes the enzyme tafazzin, a mitochondrial acyltransferase involved in the remodeling of the phospholipid cardiolipin (CL) [9,10,11]. CL is considered the ‘signature’ phospholipid of mitochondria, as it is highly abundant in the organelle's membranes, comprising 10–15% of total lipid content in the inner mitochondrial membrane
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