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Cardiolipin targeting remediates mitochondrial defects in cellular models of TAFAZZIN deficiency and clinical findings in individuals with Barth Syndrome

Barth Syndrome is a rare X-linked genetic disorder caused by pathogenic variants in TAFAZZIN. TAFAZZIN encodes for an enzyme involved in the remodeling of cardiolipin, a phospholipid localized to the inner mitochondrial membrane. Cardiolipin has a characteristic structure consisting of two phosphatidic acid groups connected by a glycerol backbone to form a dimeric structure. Deficient TAFAZZIN function results in an elevation of the remodeling intermediate, monolysocardiolipin, and a decrease in remodeled cardiolipin. In a paper entitled “Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules”, Anzmann et al.(2021) used shotgun proteomics to characterize effects of TAFAZZIN deficiency on mitochondrial function in a new CRISPR-edited TAFAZZIN-deficient HEK293 cell model. Anzmann et al. identified abnormalities in expression, assembly, and function of Complex I of the mitochondrial respiratory chain and dysfunction of the PARL-PGAM5 mitochondrial stress-response pathway. PARL, a rhomboid protease associated with the inner mitochondrial membrane, was found to have increased expression in the TAFAZZIN-deficient cells, which correlated with increased processing of the downstream target PGAM5, both at baseline and in response to mitochondrial stress. Moreover, these defects were partially remediated via targeting of cardiolipin metabolism with bromoenol lactone, which inhibits cardiolipin deacylation, and targeting of cardiolipin stability with SS-31 (elamipretide), a tetrapeptide shown to selectively bind to cardiolipin and stabilize cristae morphology among other effects.

From a clinical perspective Barth Syndrome is characterized by childhood-onset cardiomyopathy, neutropenia, skeletal muscle defects and growth defects. The clinical applications of targeting cardiolipin in TAFAZZIN deficiency were shown by Thompson et al. (2021) in a recent paper entitled “A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Thompson et al. (2021) demonstrated that after 36 weeks of treatment with elamipretide, patients had improvements in muscle strength, exercise tolerance and some cardiac parameters. Thus, on both cellular and clinical levels, modification of cardiolipin can remediate some of the effects of TAFAZZIN deficiency.


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2021