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Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2020)

Cardiolipin, the signature phospholipid of mitochondria, is crucial for mitochondrial function and architecture in the heart. Defects in cardiolipin remodeling processes and metabolism lead to cardiomyopathy, as seen in patients with Barth Syndrome (BTHS). Tafazzin is a major acyltransferase in CL remodeling that transfers linoleoyl groups to monolyso-CL until the final symmetric acyl composition is achieved. Mutations in Taz that result in BTHS cause inefficient transacylation between phosphoplipid-lysophospholipids, leading to cardiomyopathy. However, little is known as to the detailed molecular mechanisms by which Taz deficiency and consequent CL absnormalities lead to the progression of cardiomyopathy. In our present study, we found that loss of Tafazzin results in increased levels of cardiac stress markers, Anf and Bnp. Histological analysis demonstrated that mice with Taz deletions had thinner left ventricular walls and dilated left ventricular chambers relative to the control mice. Echocardiography analysis also showed that loss of Tafazzin causes decreased cardiac function. Together, these observations suggest that deletion of Tafazzin in cardiomyocytes results in dilated cardiomyopathy as seen in Barth Syndrome.

    Cover page: Deletion of Tafazzin in Cardiomyocytes Results in Dilated Cardiomyopathy
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2021)

    Background

    Cardiomyopathy is a major clinical feature in Barth syndrome (BTHS), an X-linked mitochondrial lipid disorder caused by mutations in Tafazzin (TAZ), encoding a mitochondrial acyltransferase required for cardiolipin remodeling. Despite recent description of a mouse model of BTHS cardiomyopathy, an in-depth analysis of specific lipid abnormalities and mitochondrial form and function in an in vivo BTHS cardiomyopathy model is lacking.

    Methods

    We performed in-depth assessment of cardiac function, cardiolipin species profiles, and mitochondrial structure and function in our newly generated Taz cardiomyocyte-specific knockout mice and Cre-negative control mice (n≥3 per group).

    Results

    Taz cardiomyocyte-specific knockout mice recapitulate typical features of BTHS and mitochondrial cardiomyopathy. Fewer than 5% of cardiomyocyte-specific knockout mice exhibited lethality before 2 months of age, with significantly enlarged hearts. More than 80% of cardiomyocyte-specific knockout displayed ventricular dilation at 16 weeks of age and survived until 50 weeks of age. Full parameter analysis of cardiac cardiolipin profiles demonstrated lower total cardiolipin concentration, abnormal cardiolipin fatty acyl composition, and elevated monolysocardiolipin to cardiolipin ratios in Taz cardiomyocyte-specific knockout, relative to controls. Mitochondrial contact site and cristae organizing system and F1F0-ATP synthase complexes, required for cristae morphogenesis, were abnormal, resulting in onion-shaped mitochondria. Organization of high molecular weight respiratory chain supercomplexes was also impaired. In keeping with observed mitochondrial abnormalities, seahorse experiments demonstrated impaired mitochondrial respiration capacity.

    Conclusions

    Our mouse model mirrors multiple physiological and biochemical aspects of BTHS cardiomyopathy. Our results give important insights into the underlying cause of BTHS cardiomyopathy and provide a framework for testing therapeutic approaches to BTHS cardiomyopathy, or other mitochondrial-related cardiomyopathies.
      Cover page: Cardiolipin Remodeling Defects Impair Mitochondrial Architecture and Function in a Murine Model of Barth Syndrome Cardiomyopathy
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