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bioRxiv · 10.1101/2025.08.25.672219

Transcriptional activation by MNRR1 is effected by recruiting p300 and can be induced by minimal peptides

Purandare, N.·Pasupathi, V.·Padhan, D.·Rai, S.·Grossman, L. I.·Aras, S.
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Abstract

Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22, AAG10), which functions in both the mitochondria and the nucleus, modulates mitochondrial function as well as cellular stress response. We have previously shown that stress response is predominantly mediated by its nuclear function as a transcriptional regulator; it operates at a conserved 8-bp DNA element that responds to moderate hypoxia, that we have termed the oxygen responsive element (ORE). This 8-bp element is the consensus DNA binding site for the transcription factor Recombination Signal Binding Protein For Immunoglobulin Kappa J Region (RBPJ{kappa}). We previously addressed the mechanism of nuclear MNRR1 by showing that it displaces the inhibitory transcriptional regulator CXXC-type zinc finger protein 5 (CXXC5), facilitating activation of genes harboring the ORE, and that it most effectively does so after deacetylation by SIRT1 at Lys119. A deacetyl mimetic mutant (K-R) rescues the phenotype in both genetic and environmental inflammatory models of defective mitochondrial function. Here we have refined the mechanism by which MNRR1 regulates transcription at the ORE. We show that MNRR1 interacts with RBPJ{kappa} and recruits the transcriptional co-activator p300 to facilitate transcription. We also show that a minimal domain of MNRR1 is sufficient to activate its nuclear function. Peptides based on this minimal domain can activate transcription by MNRR1 by enhancing p300 and RBPJ{kappa} interaction. MNRR1 peptides activate downstream pathways such as mitochondrial biogenesis and the unfolded protein response (UPRmt) in an in vitro model for MELAS.

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Purandare, N., Pasupathi, V., Padhan, D., Rai, S., Grossman, L. I., Aras, S.. 2025-08-29. Transcriptional activation by MNRR1 is effected by recruiting p300 and can be induced by minimal peptides. https://doi.org/10.1101/2025.08.25.672219

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