Chlamydial membrane vesicles deliver the chlamydial porin OmpA to mitochondria to inhibit apoptosis

Mesesan, A.; Oehler, H.; Kontchou, C. W.; Haimovici, A.; Helmstädter, M.; Kretz, O.; Schilling, O.; Nazarenko, I.; Matti, U.; Ries, J.; Gentle, I.; Häcker, G.

doi:10.1101/2025.06.02.657351

bioRxiv · 10.1101/2025.06.02.657351

Chlamydial membrane vesicles deliver the chlamydial porin OmpA to mitochondria to inhibit apoptosis

Mesesan, A.·Oehler, H.·Kontchou, C. W.·Haimovici, A.·Helmstädter, M.·Kretz, O.·Schilling, O.·Nazarenko, I.·Matti, U.·Ries, J.·Gentle, I.·Häcker, G.

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Abstract

Chlamydiae are obligate intracellular bacteria that inhibit mitochondrial apoptosis to maintain integrity of the host cell. We have previously reported that a chlamydial outer membrane {beta}-barrel protein, the porin OmpA, can during ectopic expression inhibit mitochondrial apoptosis through direct interaction with the BCL-2-family effectors BAX and BAK. We here show that OmpA from Chlamydia trachomatis (Ctr) uses membrane vesicles for its delivery to the outer mitochondrial membrane during Ctr infection. Using a number of imaging and fractionation techniques, we show that OmpA during infection reaches mitochondria and is inserted into mitochondrial membranes. Purified membrane vesicles (MV) from Ctr-infected cells contained OmpA. When added to uninfected cells, MV fused with mitochondrial membranes, causing the interaction of OmpA with BAK and the cytosolic retro-translocation of BAX. MV addition to uninfected cells protected the cells against apoptosis. We propose a structural model of this BAK inhibition by OmpA that reenacts the inhibition of BAK by the mitochondrial porin VDAC2. The results provide evidence that the porin from Chlamydia, as well as the structurally similar porin from the related Simkania, specifically exploits its relationship to mitochondrial porins to protect the infected cell against apoptosis and to enable intracellular growth of the bacteria in human cells.

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Mesesan, A., Oehler, H., Kontchou, C. W., Haimovici, A., Helmstädter, M., Kretz, O., Schilling, O., Nazarenko, I., Matti, U., Ries, J., Gentle, I., Häcker, G.. 2025-06-03. Chlamydial membrane vesicles deliver the chlamydial porin OmpA to mitochondria to inhibit apoptosis. https://doi.org/10.1101/2025.06.02.657351

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