Functional plasticity of AIF revealed by dimerization and CHCHD4 interaction states
- 1University of Zaragoza
Abstract
Apoptosis-inducing factor is a mitochondrial flavoprotein that links redox metabolism to mitochondrial homeostasis through its interaction with the disulfide relay protein CHCHD4. Although NADH-dependent AIF dimerization has been proposed as the activated state mediating CHCHD4 engagement, whether it is strictly required for productive AIF-CHCHD4 function remains unclear. Here, combining cellular, biochemical and biophysical approaches, we show that disruption of the AIF dimer interface compromises oxidative phosphorylation, respiratory-chain organization and CHCHD4-dependent mitochondrial homeostasis, yet preserves partial AIF function. Our data reveal that the AIF-CHCHD4 system operates as a conformational dynamic redox module in which distinct AIF oligomeric and redox states sustain CHCHD4 activity with different efficiencies. Mechanistically, dimerization is coupled to NADH-dependent conformational changes that regulate coenzyme binding, charge-transfer complex stabilization and catalytic efficiency. In turn, CHCHD4 binding remodels AIF conformational and redox properties, partially compensating for defects in dimer stabilization or redox coupling. Consistently, a peptide derived from the CHCHD4 N-terminus partially restores redox function in a pathogenic AIF variant defective in dimer stabilization, supporting partner-assisted allosteric regulation as a potential therapeutic strategy.
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BibTeX
@misc{soriano2026functional,
title = {{Functional plasticity of AIF revealed by dimerization and CHCHD4 interaction states}},
author = {O. Soriano and S. Hernandez-Hatibi and R. Gracia-Domingo and S. Romero-Tamayo and M. Ferrer and A. Velazquez-Campoy and J. Marco-Brualla and P. Fernandez-Silva and S. A. Susin and M. Medina and R. Moreno-Loshuertos and P. Ferreira Neila},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.748248},
url = {https://www.biorxiv.org/content/10.64898/2026.08.31.748248v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Functional plasticity of AIF revealed by dimerization and CHCHD4 interaction states
AU - O. Soriano
AU - S. Hernandez-Hatibi
AU - R. Gracia-Domingo
AU - S. Romero-Tamayo
AU - M. Ferrer
AU - A. Velazquez-Campoy
AU - J. Marco-Brualla
AU - P. Fernandez-Silva
AU - S. A. Susin
AU - M. Medina
AU - R. Moreno-Loshuertos
AU - P. Ferreira Neila
PY - 2026
DA - 2026/08/31
PB - bioRxiv
DO - 10.64898/2026.08.31.748248
UR - https://www.biorxiv.org/content/10.64898/2026.08.31.748248v1
AB - Apoptosis-inducing factor is a mitochondrial flavoprotein that links redox metabolism to mitochondrial homeostasis through its interaction with the disulfide relay protein CHCHD4. Although NADH-dependent AIF dimerization has been proposed as the activated state mediating CHCHD4 engagement, whether it is strictly required for productive AIF-CHCHD4 function remains unclear. Here, combining cellular, biochemical and biophysical approaches, we show that disruption of the AIF dimer interface compromises oxidative phosphorylation, respiratory-chain organization and CHCHD4-dependent mitochondrial homeostasis, yet preserves partial AIF function. Our data reveal that the AIF-CHCHD4 system operates as a conformational dynamic redox module in which distinct AIF oligomeric and redox states sustain CHCHD4 activity with different efficiencies. Mechanistically, dimerization is coupled to NADH-dependent conformational changes that regulate coenzyme binding, charge-transfer complex stabilization and catalytic efficiency. In turn, CHCHD4 binding remodels AIF conformational and redox properties, partially compensating for defects in dimer stabilization or redox coupling. Consistently, a peptide derived from the CHCHD4 N-terminus partially restores redox function in a pathogenic AIF variant defective in dimer stabilization, supporting partner-assisted allosteric regulation as a potential therapeutic strategy.
ER -