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Altered Fibroblast Glutamine Metabolism Is Linked to the Severity of Cardiac Dysfunction in DCMA, a Mitochondrial
Melissa A King1, Katherine C Heger1, Marija Drikic1
1Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Abstract:
The dilated cardiomyopathy with ataxia (DCMA) syndrome is a rare mitochondrial disorder caused by mutations in the poorly understood DNAJC19 gene. Cardiac involvement in DCMA ranges from mild conduction abnormalities to early severe myocardial dysfunction. Although evidence suggests that DCMA is linked to abnormalities in mitochondrial function, the molecular underpinnings of this condition are unclear, and there is no way to predict which patients will develop life-threatening disease. To address this, we developed a metabolic flux assay for assessing the metabolic function of mitochondria in fibroblasts derived from DCMA patients. Using this approach, we discovered that DCMA fibroblasts have elevated glutamine uptake, increased glutamate and ammonium secretion, and elevated lactate production. Moreover, we observed that these cellular perturbations were closely correlated with cardiac dysfunction in a blinded cohort of patient cell lines. These findings suggest that glutamine catabolism is abnormal in DCMA and may serve as a predictor of clinical progression.
Insights
Dilated cardiomyopathy with ataxia (DCMA) is a mitochondrial disorder. DCMA fibroblasts show abnormal glutamine metabolism, which correlates with cardiac dysfunction and may predict disease severity.
Area of Science:
- Mitochondrial biology
- Cardiovascular genetics
- Metabolic disorders
Background:
- Dilated cardiomyopathy with ataxia (DCMA) syndrome is a rare mitochondrial disorder linked to DNAJC19 gene mutations.
- Cardiac dysfunction in DCMA varies, and the molecular basis for disease severity is unknown.
- Current understanding of mitochondrial dysfunction in DCMA is limited, hindering prediction of clinical outcomes.
Purpose of the Study:
- To investigate the metabolic function of mitochondria in DCMA patient-derived fibroblasts.
- To identify metabolic alterations associated with DCMA.
- To explore potential biomarkers for predicting cardiac dysfunction in DCMA.
Main Methods:
- Development of a metabolic flux assay for assessing mitochondrial function in patient fibroblasts.
- Analysis of nutrient uptake and metabolite secretion in DCMA fibroblasts.
- Correlation of cellular metabolic profiles with cardiac dysfunction in a blinded patient cohort.
Main Results:
- DCMA fibroblasts exhibit significantly elevated glutamine uptake.
- Increased secretion of glutamate and ammonium was observed in DCMA fibroblasts.
- Elevated lactate production and correlation of these metabolic changes with cardiac dysfunction were noted.
Conclusions:
- Glutamine catabolism is demonstrably abnormal in DCMA.
- Metabolic perturbations in DCMA fibroblasts correlate with clinical cardiac phenotype.
- Aberrant glutamine metabolism may serve as a predictive biomarker for DCMA progression.
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