Abstract 1046: Miro1 Promotes Mitochondria ER Contact Sites Formation In Vascular Smooth Muscle Cells During G1/s
Arteriosclerosis, thrombosis, and vascular biology, Vol.44(Suppl_1)
05/2024
: 10.1161/atvb.44.suppl_1.1046
Abstract only Vascular smooth muscle cell (VSMC) proliferation plays a key role in vascular disorders including atherosclerosis. Mitochondria promote VSMC proliferation by mitochondrial Ca 2+ regulation, ROS and ATP production. Mitochondria-ER contact sites (MERCS) promote signal transduction to mitochondria. MIRO1, an outer mitochondrial membrane GTPase, drives intracellular mitochondrial mobility. In drosophila, MIRO1 controls MERCS formation. However, it is unknown whether this interaction promotes key cellular eukaryotic phenotypes, such as proliferation. Here, we tested whether MIRO1 promotes VSMC proliferation by modulating MERCS and mitochondrial Ca 2+ entry. MIRO1 deletion decreased neointima formation in vivo, and abolished VSMC proliferation and G1/S transition in vitro. In WT VSMCs, proximity ligation assays (PLA) and split-GFP imaging revealed that MERCS formation increased in G1/S phase along with recruitment of MIRO1. MIRO1 deletion abolished cell cycle-dependent regulation of MERCS while increasing the expression of MERCS proteins GRP75 and IP3R. MIRO1 deletion also blocked increases in baseline mitochondrial [Ca 2+ ] by mitoPericam imaging and decreases in ER [Ca 2+ ] by CEPIA-ER in G1/S phase. Additionally, the mitochondrial membrane potential (TMRM) and mitochondrial respiration significantly increased at G1/S in WT VSMCs but not in MIRO1-/- cells. In WT VSMCs, pyruvate dehydrogenase activity increased G1/S phase while cytosolic ATP levels (ATP sensor) were increased. In MIRO1-/- cells, both parameters did not change. These data demonstrate that MERCS formation and mitochondrial [Ca 2+ ] increases during the cell cycle and is controlled by MIRO1. Furthermore, MIRO1 deletion decreases cellular ATP levels in VSMCs. In conclusion, we propose that MIRO1 controls MERCS and increased mitochondrial [Ca 2+ ] that drives metabolic activity and proliferation.
- Abstract 1046: Miro1 Promotes Mitochondria ER Contact Sites Formation In Vascular Smooth Muscle Cells During G1/s
- Benney Endoni - University of IowaOlha Koval - University of IowaLan Qian - University of IowaIsabella M Grumbach - University of Iowa, Carver College of Medicine
- Abstract
- Arteriosclerosis, thrombosis, and vascular biology, Vol.44(Suppl_1)
- 10.1161/atvb.44.suppl_1.1046
- 1079-5642
- 1524-4636
- English
- 05/2024
- Cardiovascular Medicine; Internal Medicine; Radiation Oncology
- 9984691559402771
2