Abstract Body: Background. Friedreich Ataxia (FA) is an autosomal recessive neurodegenerative disease resulting from a mutation within the frataxin gene and heart failure is the most common cause of early mortality in this population. Hypertrophic cardiomyopathy (CM) secondary to FA results from massive mitochondrial accumulation rather than overexpression of contractile proteins. There is limited understanding of the molecular signaling pathways driving the development of CM to inform clinical management of this disease. To address this knowledge gap, we utilized mass spectrometry to examine differences in the cardiac proteomics between FA, other neuromuscular-associated CM, and non-ischemic CM (NICM).
Hypothesis. We hypothesized that the proteome in FA-CM would be enriched for differences in mitochondrial pathways when compared to other neuromuscular CM.
Methods. Left ventricular tissue was obtained at either the time heart transplant or left ventricular assist device placement from FA (n=1), Duchenne muscular dystrophy (DMD) (n=1), Danon disease (DD) patients (n=1), or NICM (n=1) to serve as a control. Proteomic profiling was performed on cardiac tissues and samples were run in technical triplicates. Data was processed using FragPipe-Analyst to determine differential expression analysis and Ingenuity Pathway Analysis was used to assess pathway enrichment across conditions.
Results. Our principal component analysis revealed 3 subgroups; NICM and DMD were similar, and DD was the most different. Downregulated proteins in FA vs. NICM were related to mitochondrial function and mitochondrial protein import pathways. Upregulated proteins were related to the sirtuin signaling, mitochondrial cristae formation, and complex III and IV assembly.
Conclusion. In conclusion, our proteomic analysis supports a defect in mitochondrial function underlying cardiomyopathy in FA. This supports the need for developing therapies targeting mitochondrial dysfunction for this group of patients.