# Molecular mechanisms and treatment of cardiomyopathy in Barth Syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $394,688

## Abstract

PROJECT SUMMARY
Mutations in tafazzin (Taz, also known as G4.5) cause Barth syndrome (BTHS, MIM 302060), a life-threatening
disorder disrupting metabolism of the mitochondrial-specific phospholipid cardiolipin (CL). Cardiomyopathy is
the major clinical feature in BTHS, highlighting the importance of Taz and the CL metabolism pathway in
cardiomyocytes (CMs). Taz encodes a mitochondrial phospholipid-lysophospholipid transacylase, which is
essential for CL remodeling to achieve the characteristic fatty acid composition of mature CL. Mutations in Taz
found in BTHS patients result in low total CL concentrations, abnormal CL fatty acyl composition, and elevated
monolyso-CL (MLCL) to CL ratios. However, little is known as to the detailed molecular mechanisms by which
Taz deficiency and consequent CL abnormalities lead to the progression of cardiomyopathy. Thus far, there is
no curative therapy for BTHS. Although it has been established that Taz deficiency causes BTHS, lack of a
Taz knockout mouse model has hindered studies of molecular pathology and developments of therapeutic
approaches for BTHS. To elucidate the molecular pathogenic mechanism of BTHS cardiomyopathy, and to
identify potential targets for therapeutic intervention, we have generated Taz CM-specific knockout (cKO) mice
and observed dilated cardiomyopathy (DCM) phenotypes, as well as mitochondrial malformations and
dysfunction in Taz cKO mice. Our data strongly suggest a critical role of Taz and CL in cardiac and
mitochondrial function. Our Taz cKO mouse provides us with a unique model to investigate the molecular basis
for and potential therapeutic approaches to BTHS. Studies in cultured cells suggest that linoleic acid (LA)
supplementation increases mature CL levels in Taz-deficient cells by increasing incorporation of linoleoyl
groups into de novo synthesized CL and also ameliorating the increase in MLCL. Inhibition of the mitochondrial
phospholipase A2 (PLA2) by bromoenol lactone (BEL) also ameliorates increased MLCL in Taz-deficient cells
by blocking generation of MLCL from nascent CL. However, these potential therapeutic approaches have not
been studied in an in vivo mammalian model of BTHS. Moreover, no study has explored if a combination of LA
supplementation and BEL treatment can act synergistically to ameliorate BTHS. Accordingly, our hypothesis is
that Taz-mediated CL remodeling is essential to maintain mitochondrial homeostasis and CM function, and that
linoleic acid (LA) and/or bromoenol lactone (BEL) treatment will provide beneficial effects to ameliorate BTHS
cardiomyopathy. Our specific aims are: (1) To investigate the role and molecular mechanisms by which Taz-
mediated CL remodeling is required in maintaining CM mitochondrial homeostasis and normal cardiac function
by histological, physiological, biochemical, and molecular analyses of Taz cKO mice; and (2) To assess
therapeutic effects of linoleic acid (LA) and mitochondrial PLA2 inhibitor bromoenol lactone (BEL), as sing...

## Key facts

- **NIH application ID:** 10181507
- **Project number:** 1R01HL157115-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Xi Fang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,688
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10181507

## Citation

> US National Institutes of Health, RePORTER application 10181507, Molecular mechanisms and treatment of cardiomyopathy in Barth Syndrome (1R01HL157115-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10181507. Licensed CC0.

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