A Novel Association Between Glutamine Metabolism and Clinical Progression in DCMA, A Mitochondrial Cardiomyopathy

Abstract

The Dilated Cardiomyopathy with Ataxia Syndrome (DCMA) is a severe mitochondrial disorder with a high rate of mortality. DCMA is caused by mutations in the poorly characterized DNAJC19 gene which cause a variety of clinical characteristics including elevated 3-methylglutaconic and 3-methylglutaric acids. How these mutations elicit the complex disease presentation is unclear. For this thesis, I developed a fibroblast-based model to study DCMA mitochondrial metabolism. Using stable isotope labeling and metabolomics, I demonstrate that DCMA may be linked to alterations in glutamine catabolism and propose a new model for DCMA involving an inability to import glutamate into the mitochondria. Furthermore, I show that the metabolic phenotype correlates with patient clinical progression. This novel finding could allow clinicians to predict DCMA patient outcomes. This thesis paves the way to reclassifying DCMA as a disorder of glutamine metabolism, and may guide more effective diagnostics for preventing the early death of affected children.