In SKI SMCs, stimulation of AMPK by metformin or 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), or inhibition of Drp1 with mitochondrial division inhibitor 1 (Mdivi-1), restored mitochondrial homeostasis, mitigated excessive matrix metalloproteinase 2 and SMC apoptosis, thereby preserved SMC function. In vivo administration of metformin and Mdivi-1 both ameliorated atherosclerosis triggered by SERCA2 dysfunction and particularly enhanced plaque stability. The gene discussed is DNM1L; the disease is atherosclerosis.