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Fatty acid oxidation disorders unfortunately can result in the sudden unexplained death of infants. Mitochondrial trifunctional protein (MTP) deficiency is one such disease where long-chain fatty acids cannot be fully oxidized through beta-oxidation which, can lead to cardiac arrythmias in an infant. Furthermore, mothers who are carrying an MTP deficient fetus have a prevalence for pregnancy complications, especially AFLP, acute fatty liver of pregnancy and HELLP syndrome. To better understand the etiology of the potential pro-arrhythmic state the MTP deficient infants may enter, we developed an in vitro model of MTP deficiency in cardiomyocytes to elucidate the underpinning molecular mechanism of this disease. Using CRISPR/Cas9, we developed MTP deficient mutant and knockout pluripotent stem cell lines. Furthermore, we generated patient derived induced pluripotent stem cell lines harboring a so-called founder mutation, the most commonly identified alteration in MTP in the population. Upon differentiating these mutant stem cells into cardiomyocytes and then challenging with fatty acids, we observed pro-arrhythmic behavior, depressed mitochondrial energetics, and elevated hydroxylated long-chain fatty acids, all perhaps expected phenotypes due to MTP deficiency. However, unexpectedly, we also identified an inability of these disease cardiomyocytes to generate mature cardiolipin. Cardiolipin is a key pillar of the powerhouse of life, mitochondria. For the first time this disease-in-a-dish model revealed the key culprit for the dramatic MTP mutant mitochondrial defects and identified potentially a second role for the enzyme HADHA in MTP. HADHA is required for the biosynthesis of functional cardiolipin and therefore healthy mitochondria. However, in the disease, defective cardiolipin results in mitochondrial abnormalities and cardiac arrythmias in infants. These studies reveal an important target for sudden infant death syndrome therapy. With this foundational work on an in vitro model of MTP deficiency and potential avenues for therapy, the next important task is to extend this model to address fetal-maternal interactions towards better governing maternal health.

Using Mitochondrial Trifunctional Protein Deficiency to Understand Maternal Health