Mechanism of cardiolipin remodeling by TAFAZZIN

David Stokes, PhD, New York University

2024 Development Award, $75,000 over two years

Barth Syndrome results from a defect in TAFAZZIN, which is a protein in mitochondria responsible for producing a special lipid called cardiolipin. When TAFAZZIN is defective, abnormal forms of cardiolipin are produced, the morphology of mitochondria is severely disrupted, and protein complexes responsible for making cellular energy are not able to assemble, giving rise to the symptoms that underly Barth syndrome. Despite this general understanding how Barth syndrome occurs, we lack fundamental understanding about the structure and function of TAFAZZIN. This project aims to develop a better understanding of this protein molecule. We propose to use a form of imaging called electron microscopy to take pictures of TAFAZZIN in order to evaluate its architecture, its interaction with cardiolipin, and related lipid molecules, as well as its interaction with the specialized membranes that compose mitochondria. Although tools of electron microscopy have improved dramatically in recent years, TAFAZZIN itself is still too small to be imaged with good resolution. Therefore, we have designed various molecules called chimeras that make TAFAZZIN bigger and that will allow us to assemble a complex that is favorable for imaging via electron microscopy. Thus, the goals of this proposal are to use bacteria to make these protein complexes and assess their functionality in producing cardiolipin as well as their suitability for electron microscopy. The best candidate will then be used for generating high-resolution images, initially in isolation and later in association with partner molecules and the membrane surface itself. In this way, we hope to contribute to understanding the mechanism of TAFAZZIN and its ability to produce the appropriate kind of cardiolipin for robust mitochondrial function. Although this work will not lead directly to a cure for Barth Syndrome, fundamental understanding of the structure and function of TAFAZZIN will be valuable in developing strategies to fight this disease.

This co-funded project was made possible by generous contributions from our affiliates Barth Syndrome Foundation of Canada and Barth Italia.