P. gingivalis induces endothelial dysfunction via mitochondrial fission dependent VDAC1-HK2 disassociation

Mitochondrial dysfunction contributes to Porphyromonas gingivalis (P. gingivalis)-impaired endothelial function. Given the critical role of the mitochondrial permeability transition pore (mPTP) in mitochondrial homeostasis, this study explored how P. gingivalis promotes dynamin-related protein 1 (Drp1)-dependent mPTP overactivation, leading to mitochondrial damage and endothelial dysfunction.

Mitochondrial and endothelial functions were evaluated in P. gingivalis-infected human aortic endothelial cells (HAECs) and C57BL/6 mice. Western blotting, immunofluorescence, and co-immunoprecipitation were used to assess the mitochondrial dynamics and mPTP-related protein interactions. Aortic vasodilation and endothelial integrity were examined following treatment with the Drp1 inhibitor Mdivi-1 or mPTP inhibitor cyclosporin A (CsA).

P. gingivalis infection induced significant mitochondrial fragmentation, excessive mPTP opening, and impaired endothelium-dependent vasorelaxation. These changes were associated with enhanced p-Drp1 and its translocation to mitochondria. Mechanistically, P. gingivalis promoted voltage-dependent anion channel 1 (VDAC1) oligomerization in the out membrane of mitochondrial via p-Drp1 activation, which in turn disrupted the VDAC1-hexokinase 2 (HK2) interaction, facilitating mPTP opening. Inhibition of Drp1 and mPTP opening significantly alleviated mitochondrial dysfunction and restored endothelial function both in vitro and in vivo.

P. gingivalis impairs endothelial function via Drp1-VDAC1-HK2-mediated mPTP overactivation, highlighting a potential therapeutic target against vascular injury in periodontal infection.