Cardiac‐specific succinate dehydrogenase deficiency in Barth syndrome

Abstract

Barth syndrome (BTHS) is a cardiomyopathy caused by the loss of tafazzin, a mitochondrial acyltransferase involved in the maturation of the glycerophospholipid cardiolipin. It has remained enigmatic as to why a systemic loss of cardiolipin leads to cardiomyopathy. Using a genetic ablation of tafazzin function in the BTHS mouse model, we identified severe structural changes in respiratory chain supercomplexes at a pre‐onset stage of the disease. This reorganization of supercomplexes was specific to cardiac tissue and could be recapitulated in cardiomyocytes derived from BTHS patients. Moreover, our analyses demonstrate a cardiac‐specific loss of succinate dehydrogenase (SDH), an enzyme linking the respiratory chain with the tricarboxylic acid cycle. As a similar defect of SDH is apparent in patient cell‐derived cardiomyocytes, we conclude that these defects represent a molecular basis for the cardiac pathology in Barth syndrome.

Biosynthesis, remodeling and turnover of mitochondrial cardiolipin

“…It has been established that CL deficiency can be responsible for the instability of cristae membrane supercomplexes [85]. Indeed, the abundance of such supercomplexes was found to be low in BTHS [45, 86, 87]. However, new data from our laboratory suggest that supercomplex instability may be the cause rather than the effect of CL deficiency in BTHS.…”

Shaping the mitochondrial inner membrane in health and disease

“…Depletion of either one causes mitochondrial dysfunction and atypical cristae architecture , and depletion of both cardiolipin and phosphatidylethanolamine is lethal . In humans, decreased cardiolipin levels and aberrant cardiolipin species, resulting from mutant variants of the cardiolipin remodelling enzyme tafazzin, cause Barth syndrome, a cardiomyopathy with muscle weakness (Table ) .…”

Metabolic Alterations in Inherited Cardiomyopathies

“…The increased MLCL/CL ratio is used as a diagnostic marker for BTHS [147]. Different cell and animal models including yeast, lymphoblasts, Drosophila, Caenorhabditis elegans, Trypanosoma, mouse, and induced stem cell (iPSC)-derived cardiomyocytes have been designed to study the impact of CL deficiency on cellular physiology [148][149][150][151][152][153][154][155]. The defect in CL biogenesis in BTHS causes structural and functional changes in mitochondria that have a profound impact on cellular metabolism and physiology [149,156,157].…”

“…A role for CL in proton transport has been recently proposed also for complex IV [171]. In cellular models of BTHS, including patient-derived iPSC, oxygen consumption at the respiratory chain is reduced, reflecting the impaired activity of individual respiratory chain complexes and diminished energetic coupling between complexes [148,154,156].…”