The atypical cadherin Fat1 regulates mitochondrial activity to control vascular smooth muscle cell growth

Abstract

In response to vascular injury, vascular smooth muscle cells (SMCs) undergo phenotypic switching, with enhanced cell cycle entry and migration, and loss of contractile protein expression. Previously, we found that the atypical cadherin Fatl is upregulated in SMCs after vascular injury. In cultured SMCs, Fatl is induced by growth factor stimulation, but limits SMC proliferation. Recently, we found that Fatl intracellular domain (ICD) species accumulate in SMC mitochondria and associates with proteins critical for metabolism, including Complex I subunits. The factors governing and significance of mitochondrial activity during SMC response to vascular injury are unclear. We hypothesized that Fatl regulates mitochondria) activity to control SMC growth. In cultured SMCs, loss of Fatl (Fat1KO) increased mitochondrial oxygen consumption rate, maximal respiratory capacity, and oxygen consumed for ATP production. Reactive oxygen species (ROS) was also increased in Fat1KO SMCs. This enhancement in mitochondrial respiration in the absence of Fatl was not associated with changes in overall mitochondrial morphology, mass, or dynamics. Mitochondrial specific targeting of Fatl ICD was sufficient to suppress respiration, and mitochondrial Complex I activity was elevated in Fat1KO cells, suggesting that Fatl can inhibit intrinsic mitochondrial respiratory activity. Fat1KO SMCs exhibited enhanced growth, which was opposed by adding Rotenone to inhibit Complex I function. In a mouse model of vascular injury, SMC Fatl deletion caused early and exuberant medial hyperplasia and neointimal expansion. We also found higher neointimal cell proliferation and ROS production in Fatl -deleted vessels after injury. In conclusion, we show that the atypical cadherin Fatl communicates with mitochondrial Complex I to repress energy and ROS production, acting as a molecular "brake" on mitochondrial activity to suppress SMC growth after vascular injury. This novel mechanism could serve as an effective target in the treatment of hyperproliferative vascular diseases.