Mitochondrial Dysfunction: A New Hallmark in Hereditable Thoracic Aortic Aneurysm Development

Abstract

Thoracic aortic aneurysms (TAAs) pose a significant health burden due to their asymptomatic progression, often culminating in life-threatening aortic rupture, and due to the lack of effective pharmacological treatments. Risk factors include elevated hemodynamic stress on the ascending aorta, frequently associated with hypertension and hereditary genetic mutations. Among the hereditary causes, Marfan syndrome is the most prevalent, characterized as a connective tissue disorder driven by FBN1 mutations that lead to life-threatening thoracic aortic ruptures. Similarly, mutations affecting the TGF-β pathway underlie Loeys-Dietz syndrome, while mutations in genes encoding extracellular or contractile apparatus proteins, such as ACTA2, are linked to non-syndromic familial TAA. Despite differences in genetic origin, these hereditary conditions share central pathophysiological features, including aortic medial degeneration, smooth muscle cell dysfunction, and extracellular remodeling, which collectively weaken the aortic wall. Recent evidence highlights mitochondrial dysfunction as a crucial contributor to aneurysm formation in Marfan syndrome. Disruption of the extracellular matrix-mitochondrial homeostasis axis exacerbates aortic wall remodeling, further promoting aneurysm development. Beyond its structural role in maintaining vascular integrity, the ECM plays a pivotal role in supporting mitochondrial function. This intricate relationship between extracellular matrix integrity and mitochondrial homeostasis reveals a novel dimension of TAA pathophysiology, extending beyond established paradigms of extracellular matrix remodeling and smooth muscle cell dysfunction. This review summarizes mitochondrial dysfunction as a potential unifying mechanism in hereditary TAA and explores how understanding mitochondrial dysfunction, in conjunction with established mechanisms of TAA pathogenesis, opens new avenues for developing targeted treatments to address these life-threatening conditions. Mitochondrial boosters could represent a new clinical opportunity for patients with hereditary TAA.

Keywords: Marfan; aneurysm; connective tissue; mitochondria; smooth muscle cells; vascular pathology.

Figure 1

Thoracic aortic aneurysm dynamics caused by mitochondrial dysfunction [10,39,103]. NR: Nicotinamide Riboside.; NAD: Nicotinamide Adenine Riboside; Tfam: Transcription factor A mitochondrial.; MFS: Marfan Syndrome; VSMCs: Vascular Smooth muscle cells; MYLK: Myosin light chain Kinase; Acta2: Actin alpha 2; PRKG1: Protein Kinase CGMP-Dependent 1; LDS: Loews-Dietz Syndrome; CL: cutis laxa syndrome; ECM: Extracellular Matrix; MYH11: Myosin heavy chain 11 (Smooth muscle specific); SMAD3:Mothers against decapentaplegic homolog 3; Pgc1a: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha.

Figure 2

Schematic representation of the thoracic aortic aneurysm mechanism.