Oxidized TRX1 and DPP8/9 stabilize the MIA40-AIFM1 complex during intrinsic apoptosis

Tsamouri, L. P.; Geeson, M. B.; Teplova, M.; Li, B.; Lai, Z.; Tellez, A. V.; Ball, D. P.; Chakravarti, A.; Sen, S.; de la Cruz, M. J.; Bachovchin, D. A.

doi:10.64898/2026.10.26.761918

bioRxiv · 10.64898/2026.10.26.761918

Oxidized TRX1 and DPP8/9 stabilize the MIA40-AIFM1 complex during intrinsic apoptosis

Tsamouri, L. P.·Geeson, M. B.·Teplova, M.·Li, B.·Lai, Z.·Tellez, A. V.·Ball, D. P.·Chakravarti, A.·Sen, S.·de la Cruz, M. J.·Bachovchin, D. A.

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Abstract

Mammalian cells execute diverse death programs with distinct immunological consequences. Mitochondrial outer membrane permeabilization (MOMP) drives typically immunologically silent intrinsic apoptosis by releasing cytochrome c and other proapoptotic proteins into the cytosol. Here, we show that MOMP also engages two established repressors of the pyroptosis-inducing NLRP1 inflammasome, oxidized thioredoxin-1 (oxTRX1) and catalytically active DPP8/9, in a coordinated redox and proteostasis program. Immediately after MOMP, oxTRX1 forms a disulfide with MIA40 Cys4 at the MIA40-AIFM1 interface. Subsequently, DPP8/9 cleave AK2, targeting this competing AIFM1 ligand for degradation. Biochemical reconstitution and cryo-EM reveal that oxTRX1 promotes AIFM1 dimerization and preferentially stabilizes MIA40-AIFM1 over AK2-AIFM1. Thus, redox-dependent complex assembly and selective proteolysis converge to favor MIA40-bound AIFM1 after MOMP. These findings suggest how post-MOMP remodeling could reinforce NLRP1 restraint during apoptosis and how disruption of this program could trigger pyroptosis.

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Tsamouri, L. P., Geeson, M. B., Teplova, M., Li, B., Lai, Z., Tellez, A. V., Ball, D. P., Chakravarti, A., Sen, S., de la Cruz, M. J., Bachovchin, D. A.. 2026-10-28. Oxidized TRX1 and DPP8/9 stabilize the MIA40-AIFM1 complex during intrinsic apoptosis. https://doi.org/10.64898/2026.10.26.761918

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