Drp1 promotes vascular smooth muscle cell death via adverse mitochondrial dynamics

Vascular smooth muscle cell (vSMC) death has been linked to the pathogenesis of various vascular diseases. Although mitochondrial dynamics play an important role in cellular homeostasis, excessive mitochondrial fission in response to pathological stimuli has been identified to promote cell death. Regulating mitochondrial fission may provide a promising therapeutic target in degenerative vascular diseases associated with the loss of medial vSMCs. Inhibition of Drp1, a GTPase that catalyzes mitochondrial fission and is the main inducer of pathological mitochondrial fragmentation, using mitochondrial division inhibitor 1 (mdivi-1) ameliorated staurosporine (STS)-induced cell death in the vSMCs. mdivi-1 also promoted vSMC proliferation. The assessment of mitochondrial morphology exhibited significantly elongated mitochondrial networks, mean branch length, and mitochondrial footprint in mdivi-1-treated vSMCs, indicating reduced mitochondrial fragmentation. Inhibitory effects of mdivi-1 on fission were exerted by reduced Drp1 phosphorylation at Serine 616. The evaluation of mitochondrial function demonstrated significantly increased mitochondrial permeability transition pore opening and reduced metabolic potential represented by OCR and ECAR in the STS-challenged vSMCs. mdivi-1 prevented STS-induced mitochondrial morphological and functional changes. Mdivi-1-mediated improved mitochondrial structural integrity was associated with reduced mitophagy and decreased levels of cell death-related proteins. These findings suggested that inhibition of mitochondrial fission provides a potential therapeutic target to augment vSMCs mitochondrial structure and function in degenerative vascular diseases associated with loss of vSMCs.