Targeting OXCT1 with the methyl donor S-adenosylmethionine as a therapeutic strategy for cerebral cavernous malformations

Cerebral cavernous malformations (CCMs) are low-flow, thin-walled vascular conglomerates that arise within the central nervous system and constitute a significant cause of stroke. Experimental evidence indicates that mitochondrial dysfunction contributes to the pathogenesis of CCM, a disease that can be caused by PDCD10 deficiency. However, the specific mechanisms underlying mitochondrial homeostatic imbalance remain unclear. 3-oxoacid CoA-transferase 1 (OXCT1), localized in the mitochondrial matrix, serves as the rate-limiting enzyme of ketone body metabolism. Additionally, it also modulates diverse mitochondrial functions. Although the function of OXCT1 has been implicated in various diseases, its role in the progression of CCM awaits elucidation. Utilizing RNA-seq data from the CRISPR/Cas9-generated PDCD10-knockout endothelial cell line, primary endothelial cells from Pdcd10^BECKO mice, and CCM patient-derived endothelial cells, this study identified OXCT1 as a hub gene involved in mitochondrial pathways during CCM progression. Loss-of-function mutations of OXCT1 in malformed vascular endothelium accelerated disease progression and mediated mitochondrial impairment. High-throughput virtual screening identified S-adenosylmethionine (SAMe) as a small-molecule drug targeting the active site of OXCT1. Furthermore, SAMe is an orally available drug with high bioavailability and a favorable safety profile, which effectively suppressed disease progression in our murine model of CCM. In conclusion, this study provides initial evidence that OXCT1 is a novel therapeutic target in CCM and that SAMe holds promise as a potential treatment.

Cerebral cavernous malformation; Mitochondrial dysfunction; OXCT1; PDCD10; S-adenosylmethionine.