Metformin limits cerebral cavernous malformation development by targeting KLF4-mediated mitochondrial damage

Abstract

Cerebral cavernous malformations (CCM) present prevalent vascular diseases of the central nervous system, which can result in hemorrhage and seizures. Metformin, a first-line antidiabetic with established safety profiles, demonstrates pleiotropic effects, including the inhibition of cellular proliferation, inflammation, and angiogenesis, all of which are implicated in the pathogenesis of CCM. However, the therapeutic benefits of metformin in the realm of CCM remain unclear. This study aims to investigate the effect of metformin on the growth of CCM lesions in Slco1c1 CreERT2; Pdcd10 ^fl/fl (Pdcd10^BECKO) mice. Super-resolution confocal microscopy and transmission electron microscopy (TEM) were employed to evaluate mitochondrial structure. The results showed that metformin administration significantly attenuated CCM lesion burden, reduced iron deposition, and decreased collagen accumulation in Pdcd10^BECKO mice. Metformin also normalized the defects from PDCD10 deficiency, including disruption of tight junctions and excessive proliferation of endothelial cells. Moreover, metformin significantly improved mitochondrial structural anomalies and dysfunction associated with PDCD10 deficiency, characterized by the presence of mitochondrial puncta and the loss of cristae, followed by impaired mitochondrial membrane potential and increased mitoROS in endothelial cells with the mutation. Metformin provided these beneficial effects by downregulating KLF4. In conclusion, these findings indicate that metformin suppresses the development of CCM in Pdcd10^BECKO mice by targeting KLF4-mediated mitochondrial damage, thereby providing promising prospects as a novel therapeutic approach for CCM.