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

## TL;DR

The bacteria P. gingivalis harms blood vessel function by causing mitochondrial damage through a specific protein interaction pathway.

## Contribution

The study reveals a novel mechanism involving Drp1, VDAC1, and HK2 in P. gingivalis-induced mitochondrial and endothelial dysfunction.

## Key findings

- P. gingivalis causes mitochondrial fragmentation and mPTP overactivation in endothelial cells.
- VDAC1 oligomerization disrupts its interaction with HK2, promoting mPTP opening.
- Inhibiting Drp1 or mPTP restores endothelial and mitochondrial function in infected cells and mice.

## Abstract

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.

This study found that P. gingivalis induces endothelial dysfunction through Drp1-VDAC1-HK2 mediated mPTP overactivation.