Danchen Wu, Queen’s University
Supervisor: Stephen Archer, Queen’s University
Pulmonary arterial hypertension (PAH) is a pathological state characterized by elevated pulmonary arterial pressure (PAP) and increased pulmonary vascular resistance (PVR). PAH patients share similar pulmonary vascular pathology in spite of diverse etiologic triggers. In PAH, increases in both proliferation and apoptosis- resistance in pulmonary arterial smooth muscle cell (PASMC) contribute to pulmonary vascular obstruction. The resulting increase in PVR and vascular stiffness leads to death from right ventricular failure.
PASMC mitochondria are continuously dividing (fission), joining together (fusion), and moving throughout the cell (motility). These activities are in aggregate referred to as mitochondrial dynamics. Previous studies from our lab revealed increased fission and decreased fusion contribute to PASMC proliferation and apoptosis resistance and showed that inhibiting fission or augmenting fusion can reduce proliferation, increase apoptosis and regress experimental PAH.
While the role of fission and fusion in PAH is established, the contribution of mitochondrial motility to the PAH phenotype is unknown. Motor proteins (kinesins) convey mitochondria along microtubules by binding a Miro-Milton protein complex (appendix figure). Miro proteins are conserved GTPases located on the outer mitochondrial membrane (OMM). Milton is a cytosolic protein which binds both Miro and kinesin heavy chain (KHC). Miro has a calcium-binding EF hand domain that senses increased cytosolic calcium ([Ca2+]C), causing conformational changes in Miro that alter its interaction within the mitochondrial transport complex. Preliminary studies from our lab reveal elevated [Ca2+]C and increased mitochondrial motility in human PAH PASMCs (Data unpublished). This is consistent with studies of cerebral arterial SMC, which showed that cell proliferation was associated with increased mitochondrial motility. However, the role of increased mitochondrial motility and the potential impact of pathological elevation of [Ca2+]C on mitochondrial motility in PAH are unknown.
Hypothesis: Deficiency in Miro’s expression and/or calcium sensing mechanism increases mitochondrial motility in PAH PASMC and contributes to a hyperproliferative state.
Goals: We will compare the mitochondrial motility in PAH PASMCs (from patients and rats with monocrotaline-induced pulmonary hypertension, MCT-PH) model versus their respective normal controls. We will also investigate the relationship between elevated [Ca2+]C and altered mitochondrial motility in PAH.
Relevance: This project focuses on revealing pathogenesis and finding new therapeutic target for pulmonary hypertension, which is encouraged by Vascular Network.