Grant: Project Grant

Mitochondria are energy producing structures that serve as the "powerhouse of the cell". However, mitochondria also have important non-energetic functions. Mitochondria regulate the rate of cell division (through effects on the cell cycle) and eliminate abnormal cells (through a quality control process called apoptosis). The regulation of cell division and apoptosis by mitochondria relates to their ability to undergo highly regulated cycles of joining together (called fusion) and dividing (called fission). We discovered that increased rates of mitochondrial fission permit rapid cell growth and inhibit apoptosis in conditions like cancer and pulmonary arterial hypertension (PAH). PAH is a fatal disease that causes shortness of breath and reduces exercise capacity. PAH leads to death in 50% of patients within 5 years of diagnosis. Our prior work shows that increased mitochondrial fission, due to activation of an enzyme called Drp1, contributes to a cancer-like behaviour of PAH pulmonary artery smooth muscle cells (PASMC), allowing these cells to grow too rapidly and ultimately block blood vessels. This proposal focuses on a new discovery related to how fission occurs. We find that after Drp1 narrows the mitochondrion, a large GTPase, Dynamin 2 (DNM2), completes the division process. Interestingly, DNM2 levels are elevated in PAH patients due to loss of its regulatory microRNAs and activation of its transcription factor, STAT3. We show that inhibiting DNM2 prevents fission, normalizes rates of cell division and apoptosis, and regresses PAH in male rats. We will define DNM2's role in fission, the basis for the pathway being more important in males, and how its expression is regulated. In addition to these fundamental discoveries, this research has therapeutic implications because we assess whether inhibiting DNM2 could be a new PAH therapy. This is impactful as PAH remains lethal, and current therapies are vasodilators that do not target PAH's cancer-like phenotype.