KRIT1 and Reactive Oxigen Species: a novel molecular pathway involved in Cerebral Cavernous Malformations.

KRIT1 is a gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Comprehensive analysis of the KRIT1 gene in CCM patients has suggested that KRIT1 functions need to be severely impaired for pathogenesis. However, the molecular and cellular functions of KRIT1 as well as CCM pathogenesis mechanisms are still research challenges. We found that KRIT1 is involved in the maintenance of the intracellular Reactive Oxygen Species (ROS) homeostasis to prevent oxidative cellular damage. Specifically, KRIT1 loss/down-regulation is associated with a significant increase in intracellular ROS levels. Moreover, the modulation of intracellular ROS levels by KRIT1 is strictly correlated with the modulation of the expression of proteins involved in oxidative stress responses, including SOD2, FoxO1, COX2 and c-Jun. Furthermore, the KRIT1-dependent maintenance of low ROS levels facilitates the downregulation of cyclin D1 expression required for cell transition from proliferative growth to quiescence. Conversely, cell treatment with ROS scavenging agents overcomes the upregulation of cyclin D1 and the reduced cell capacity to exit from the proliferative cycle caused by KRIT1 loss. Finally, the enhanced ROS levels in KRIT1-/- cells are associated with an increased cell susceptibility to oxidative DNA damage. Taken together, our results point to a mechanistic model whereby KRIT1 limits the accumulation of intracellular oxidants and prevent oxidative stress-mediated cellular dysfunction and DNA damage, suggesting a novel mechanism for CCM pathogenesis.