Abnormal mitochondria is associated with aortic aneurysm in a mouse model of Marfan Syndrome

Abstract

Aortic aneurysms, or the pathogenic remodeling and stiffening of the aorta extracellular matrix (ECM), are usually undetectable until excessive expansion, dissection, or rupture occurs. The understanding of the molecular mechanisms of aneurysm and dissection remains incomplete, but heritable syndromes such as Marfan Syndrome (MFS), where genetic mutations result in aneurysm phenotypes, offer models to discover functional pathways. Recent work in our lab and others have identified a potential association between reduced mitochondrial regulators, such as PGC1alpha, mitochondrial content, and aneurysm. These associations have not been fully described to date in a model of classical MFS driven by Fibrillin-1 (FBN1) mutation. We hypothesized that mitochondrial content and integrity would be disrupted in the MFS aorta and isolated MFS smooth muscle cell models. Western blot for several key mitochondrial proteins associated with oxidative phosphorylation (NDUFB8, SDHB, UQCRC2, MTCO1, ATP5A) demonstrated significant reduction in the aortic root of MFS mice compared to wild type (WT) mice. Consistent with these in vivo findings, we observed a reduced total quantity of mitochondria relative to total cell volume in isolated primary MFS relative to WT ascending aortic smooth muscle cells. Furthermore, analysis of mitochondrial morphology revealed that MFS primary lines have more fragmented mitochondrial networks than WT lines, indicating abnormal structural regulation of mitochondrial networks in MFS. Through these initial studies we have found indicators of potential dysfunction in the networks of MFS mitochondria. Future work will elucidate the functional consequences of these abnormalities and decipher their potential role in the pathogenesis of aneurysm progression in MFS.