Mitochondrial Ca2+/Calmodulin-dependent kinase ii (CaMKII) regulates smooth muscle cell migration and neointimal formation via mitochondrial Ca2+ uptake and mobility

Clinically relevant coronary artery disease can present acutely as a heart attack or chest pain, which is caused by complete obstruction of the artery and poor oxygenation of heart tissue. A common and effective treatment for heart attacks is intra-arterial intervention that can restore blood flow. However, this procedure is often followed by a complication known as restenosis, which is due to an overgrowth of cells into the artery leading to decreased blood flow, known as neointimal hyperplasia. Attempts to prevent this complication have focused on the role of the vascular smooth muscle cell, which is able to proliferate and migrate into the lumen of the artery and eventually obstruct blood flow. The work of this thesis has characterized the importance of a cellular organelle, the mitochondria, on smooth muscle cell migration and neointimal hyperplasia. Mitochondria are intracellular organelles that are responsible for generating the necessary cellular energy for basic cellular processes; however they additionally are able to regulate intracellular Ca²⁺, an important molecule in smooth muscle cell behavior. In this study, we identify a novel regulator of mitochondrial Ca²⁺ in smooth muscle cells, the Ca²⁺/Calmodulin dependent kinase II (CaMKII). Our work distinguishes CaMKII as a regulator of mitochondrial Ca²⁺ uptake and cell migration. Our data demonstrate that mitochondrial ability to move within the cell and deliver energy to drive processes necessary for migration is dependent on the mitochondria’s ability to take up Ca²⁺. Ultimately, we have highlighted the importance of mitochondrial function in promoting cell migration and neointimal hyperplasia.