Correcting mitochondrial defects in Barth syndrome models by targeting phosphatidylethanolamine metabolism
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abstract
Barth syndrome (BTHS) is a severely debilitating X-linked genetic disorder characterized by cardiomyopathy, skeletal muscle myopathy, neutropenia, growth-delay, and exercise intolerance for which currently no treatment exists. The primary defect in BTHS is caused by the loss of function of cardiolipin (CL) remodeling enzyme tafazzin, which results in elevation of monolysocardiolipin (MLCL) and a decrease in CL. Apart from alterations in CL species, there are also perturbations in another structurally similar mitochondrial phospholipid, phosphatidylethanolamine (PE). The downstream consequences of the altered mitochondrial phospholipid composition include destabilization of the mitochondrial respiratory chain (MRC) supercomplexes and an increased oxidative stress. Thus, mitochondrial membrane phospholipid composition is an obvious target for correcting the pathophysiology associated with BTHS. While CL metabolism has been the focus of BTHS research, alterations in PE have been ignored. The increase in PE levels in yeast and murine BTHS models suggests a compensatory response to make up for the lack of CL. This idea is supported by previous studies showing overlapping functions of PE and CL, owing to their similar biophysical properties. Based on these observations, we hypothesize that stimulating PE biosynthesis in BTHS cells could compensate for CL deficiency. In support of this hypothesis we have recently shown that stimulation of PE biosynthesis by ethanolamine (Etn) supplementation can alleviate respiratory defects of CL deficient taz1 knockout cells, a yeast model of BTHS. In the proposed research, we will determine the mechanism of Etn dependent rescue of taz1 knockout cells by measuring mitochondrial bioenergetic parameters that are perturbed in taz1 knockout cells and test the general applicability of this 'Etn supplementation' strategy in higher eukaryotes including BTHS patient cells and Drosophila model of BTHS. (AHA Program: Grant-in-Aid)
