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Cell Stress Response Impacts Energy Use in the Heart

Article title: Activation of the integrated stress response rewires the cardiac metabolism in Barth syndrome

Authors: Ilona Kutschka, Edoardo Bertero, Christina Wasmus, Ke Xiao, Lifeng Yang,  Xinyu Chen, Yasuhiro Oshima, Marcus Fischer, Manuela Erk, Berkan Arslan, Lin Alhasan, Daria Grosser, Katharina J. Ermer, Alexander Nickel, Michael Kohlhaas, Hanna Eberl, Sabine Rebs, Katrin Streckfuss-Bömeke, Werner Schmitz, Peter Rehling, Thomas Thum, Takahiro Higuchi, Joshua Rabinowitz, Christoph Maack, and Jan Dudek

Journal: Basic Research in Cardiology (Link to Article)


Barth syndrome is a disease caused by changes in TAFAZZIN, a protein important for heart and skeletal muscle function and a strong immune system. Research on Barth syndrome has shown that TAFAZZIN mutations lead to problems in the mitochondria, which are tiny, specialized structures in cells responsible for making energy. When mitochondria do not function properly, they can produce high levels of toxic byproducts called reactive oxygen species (e.g. hydrogen peroxide). The heart is one of the most energy-demanding organs in the human body but in Barth syndrome patients, the heart has trouble making enough energy and also makes higher than normal levels of reactive oxygen species. In research, mouse models are sometimes used to better understand a disease. There are a few different mouse models for Barth syndrome and important differences in energy production and reactive oxygen species accumulation have been observed between the models. Mice without Tafazzin have high levels of reactive oxygen species while mice with lower than normal levels of Tafazzin do not. One focus in Barth syndrome research is understanding how the heart responds to stress under these different conditions.


In a recent paper from Dr. Jan Dudek’s lab (University Clinic Würzburg, Germany), his team set out to investigate this important question in mice with lower than normal Tafazzin expression as well as human cellular models of Barth syndrome. The team undertook a series of elegant biochemistry experiments—that is, experiments looking at the smaller building blocks of a cell and how they work with each other—to look at the different steps making energy in mitochondria and found several key changes. The turnover of fats, which is normally the most important energy source for the heart, was strongly reduced in these mice and cells which activated the “integrated stress response” in cells. By activating the integrated stress response, the cells dramatically changed how the heart produced energy. The turnover of amino acids (building blocks for proteins) was increased and allowed cells to guard against over-producing reactive oxygen species. Understanding how the heart protects itself from damage due to dysfunctional mitochondria may help identify new ways to intervene in Barth syndrome patients in the future.

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