Mysterin, also known as RNF213, is a unique ubiquitin ligase with a huge molecular size (591 kDa), dynein-like motor ATPase activity, and lipid-directed ubiquitylation activity. It plays a central role in cell-autonomous immunity by tagging various intracellular pathogens, including Salmonella, for clearance via xenophagy and inflammatory pathways (Otten et al., Nature, 2021). We originally identified and cloned mysterin as the causative gene for moyamoya disease (MMD), a rare cerebrovascular disorder (#Liu, #Morito et al., PLOS ONE, 2011). Despite this genetic link, the mechanistic connection between mysterin’s physiological function in host defense and its role in MMD pathogenesis has remained unknown. We recently found that MMD-associated mysterin mutant mistakes mitochondria for cell-invading pathogens, inducing their mitophagic removal and inflammatory response. In the presentation, I will detail these findings and discuss how they may explain the long-standing enigma of MMD pathogenesis.