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

Area of Science:

• Neuroscience
• Vascular Biology
• Pharmacology

Background:

• Cerebral cavernous malformations (CCM) are common CNS vascular diseases causing hemorrhage and seizures.
• Metformin, an antidiabetic drug, has anti-inflammatory and anti-proliferative properties relevant to CCM pathogenesis.
• The therapeutic potential of metformin for CCM is not yet understood.

Purpose of the Study:

• To investigate the efficacy of metformin in mitigating CCM lesion development in a mouse model.
• To explore the underlying mechanisms of metformin's action on CCM pathology and mitochondrial function.

Main Methods:

• Utilized Slco1c1 CreERT2; Pdcd10fl/fl (Pdcd10BECKO) mice to model CCM.
• Employed super-resolution confocal and transmission electron microscopy (TEM) to assess mitochondrial structure.
• Analyzed CCM lesion burden, iron and collagen deposition, endothelial cell proliferation, and tight junction integrity.

Main Results:

• Metformin treatment significantly reduced CCM lesion burden, iron, and collagen accumulation in Pdcd10BECKO mice.
• Metformin normalized endothelial cell tight junction defects and excessive proliferation caused by PDCD10 deficiency.
• Improved mitochondrial structure and function, including mitochondrial membrane potential and reduced mitoROS, by downregulating KLF4.

Conclusions:

• Metformin effectively suppresses CCM development in a relevant mouse model.
• The drug ameliorates CCM-associated vascular defects and mitochondrial dysfunction.
• Targeting KLF4-mediated mitochondrial damage with metformin shows potential as a novel therapeutic strategy for CCM.