biostudies-literatureSheridan MNIDCR NIH HHSNIDDK NIH HHSNCI NIH HHSNational Institutes of Health109860https://www.ebi.ac.uk/biostudies/studies/S-EPMC11108982biostudies-literatureUnknown27(6)Mechanisms by which <i>Porphyromonas gingivalis</i> (<i>P. gingivalis</i>) infection enhances oral tumor growth or resistance to cell death remain elusive. Here, we determined that <i>P. gingivalis</i> infection mediates therapeutic resistance via inhibiting lethal mitophagy in cancer cells and tumors. Mechanistically, <i>P. gingivalis</i> targets the LC3B-ceramide complex by associating with LC3B via bacterial major fimbriae (FimA) protein, preventing ceramide-dependent mitophagy in response to various therapeutic agents. Moreover, ceramide-mediated mitophagy is induced by Annexin A2 (ANXA2)-ceramide association involving the E142 residue of ANXA2. Inhibition of ANXA2-ceramide-LC3B complex formation by wild-type <i>P. gingivalis</i> prevented ceramide-dependent mitophagy. Moreover, a FimAiScienceOpportunistic pathogen <i>Porphyromonas gingivalis</i> targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors.PMC11108982P30 CA138313R01 DE030313P30 DK123704Engevik MOgretmen BWellslager BSheridan MOleinik NPandruvada SYilmaz OKassir MFLee HGPeterson YSzulc ZMChowdhury NfalseOpportunistic pathogen <i>Porphyromonas gingivalis</i> targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors.Mechanisms by which <i>Porphyromonas gingivalis</i> (<i>P. gingivalis</i>) infection enhances oral tumor growth or resistance to cell death remain elusive. Here, we determined that <i>P. gingivalis</i> infection mediates therapeutic resistance via inhibiting lethal mitophagy in cancer cells and tumors. Mechanistically, <i>P. gingivalis</i> targets the LC3B-ceramide complex by associating with LC3B via bacterial major fimbriae (FimA) protein, preventing ceramide-dependent mitophagy in response to various therapeutic agents. Moreover, ceramide-mediated mitophagy is induced by Annexin A2 (ANXA2)-ceramide association involving the E142 residue of ANXA2. Inhibition of ANXA2-ceramide-LC3B complex formation by wild-type <i>P. gingivalis</i> prevented ceramide-dependent mitophagy. Moreover, a FimA2024-01-01T00:00:00Z2024 Jun2026-06-01T11:51:36.077Z2026-04-08T11:59:35.555ZS-EPMC111089823877948210.1016/j.isci.2024.109860