MIRO1 controls energy production and proliferation of vascular smooth muscle cells.

Background: The outer mitochondrial Rho GTPase 1, MIRO1, mediates mitochondrial motility within cells, but implications for vascular smooth muscle cell (VSMC) physiology and its roles in vascular diseases, such as neointima formation following vascular injury are widely unknown. Methods: Carotid ligation was performed in an in vivo model of selective Miro1 deletion in smooth muscle cells. VSMC proliferation during the cell cycle and molecular mechanisms of smooth muscle cell proliferation were explored in cultured aortic VSMCs by imaging mitochondrial positioning and cristae structure and assessing the effects on ATP production, metabolic function and interactions with components of the electron transport chain (ETC). MIRO1 expression was analyzed in human coronary arteries, and its function was assessed via knockdown in human coronary artery VSMCs. Results: Results revealed strong MIRO1 expression in VSMCs within human atherosclerotic plaques. MIRO1 facilitated VSMC proliferation and neointima formation by regulating mitochondrial positioning and PDGF-stimulated ATP production and respiration, critical for cell-cycle progression at G1/S. Deletion of Miro1 disrupted mitochondrial cristae structure, diminished ETC complex I activity, and impaired super complex formation. Notably, restoring MIRO1 function with a mutant lacking EF hands, which are essential for mitochondrial mobility, only partially rescued these effects. MIRO1 knockdown in human coronary artery VSMCs confirmed its pivotal role in mitochondrial function and VSMC proliferation. Conclusions: This study highlights two key mechanisms by which MIRO1 regulates VSMC proliferation. First, it maintains ATP synthesis by preserving mitochondrial cristae integrity. Second, its Ca