Engineered flavonoid disrupts mitochondrial AIF/CHCHD4 complex for targeted cancer therapy
Abstract
Cancer metabolism depends on multifaceted mechanisms, including bidirectional interorganelle communication between mitochondria and the nucleus, facilitating cellular adaptation at the transcriptomic, proteomic, and metabolomic levels. The mitochondrial protein complex composed of apoptosis-inducing factor (AIF) and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is essential for this mitochondrio-nuclear communication. The AIF/CHCHD4 complex mediates the mitochondrial import of cysteine-enriched nuclear gene-encoded proteins, thereby adapting the mitochondrial proteome to cellular energy demands. Here, we report the discovery of M30-E05, a compound that binds to the NADH pocket of AIF, preventing its dimerization and disrupting the AIF/ CHCHD4 complex, as demonstrated by molecular docking and gel electrophoresis analysis of mitochondrial AIF/CHCHD4 substrate expression. In cancer cells, M30-E05 reduces the expression of nuclear gene-encoded mitochondrial proteins such as AIF, CHCHD4, cytochrome c oxidase copper chaperone (COX17), and Mitochondrial calcium uptake 1 (MICU1). In addition, M30-E05 fragments the mitochondrial network and impairs mitochondrial respiration, causing profound alterations, particularly in glucose, lipid, and amino acid metabolism, as revealed by kinetic measurements of oxygen consumption and mass spectrometric metabolomics. Importantly, M30-E05 significantly reduces the viability of a human adult and pediatric osteosarcoma cancer cell panel, including those from patient-derived xenografts (PDX) of osteosarcomas, and induces apoptosis. When orally administered for two weeks to immunodeficient NSG mice, M30-E05 inhibited tumor growth in a subcutaneous PDX xenograft model without apparent toxicity. We anticipate that M30-E05, as a first-in-class metabolic inhibitor, could serve as the lead compound for a new class of antineoplastic agents.
Related
- Mitochondrial genome instability disrupts brown adipose tissue through pseudohypoxia-iron-NAD⁺ axis
- Polystyrene microplastic exposure disrupts mitochondrial pathways and nuclear processes in primary intestinal epithelial cells
- Progerin disrupts intestinal epithelial homeostasis by impairing mitochondrial metabolism and absorptive enterocyte maturation
- HAMA microneedles patch loaded with muscle-targeting engineered apoptotic vesicles and attenuating sarcopenia by regulating mitochondrial homeostasis.
- Engineered Natural Membrane Vesicle Exosomes as a Torin2 Delivery Platform for Targeted Therapy of Anaplastic Thyroid Carcinoma.
BibTeX
@article{lai2026engineered,
title = {{Engineered flavonoid disrupts mitochondrial AIF/CHCHD4 complex for targeted cancer therapy}},
author = {Hong Toan Lai and Daniela Dias-Pedroso and Maria Eugénia Marques da Costa and Romain Fernandes and Tran Ngoc Anh Nguyen and Olivia Bawa and Pierre Khneisser and João Gabriel Silva and Yassine Khalij and Michelangelo Campanella and John Griffith Jones and Svetlana Dokudovskaya and Guido Kroemer and Antonin Marchais and Nathalie Gaspar and Birgit Geoerger and Oumar Diane and Liuba Mazzanti and Tâp Ha Duong and Guy Lewin and Laurent Ferrié and Bruno Figadère and Catherine Brenner},
journal = {Acta Pharmaceutica Sinica B},
year = {2026},
month = sep,
doi = {10.1016/j.apsb.2026.06.022},
url = {https://hal.science/hal-05764079v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Engineered flavonoid disrupts mitochondrial AIF/CHCHD4 complex for targeted cancer therapy
AU - Hong Toan Lai
AU - Daniela Dias-Pedroso
AU - Maria Eugénia Marques da Costa
AU - Romain Fernandes
AU - Tran Ngoc Anh Nguyen
AU - Olivia Bawa
AU - Pierre Khneisser
AU - João Gabriel Silva
AU - Yassine Khalij
AU - Michelangelo Campanella
AU - John Griffith Jones
AU - Svetlana Dokudovskaya
AU - Guido Kroemer
AU - Antonin Marchais
AU - Nathalie Gaspar
AU - Birgit Geoerger
AU - Oumar Diane
AU - Liuba Mazzanti
AU - Tâp Ha Duong
AU - Guy Lewin
AU - Laurent Ferrié
AU - Bruno Figadère
AU - Catherine Brenner
PY - 2026
DA - 2026/09/25
JO - Acta Pharmaceutica Sinica B
DO - 10.1016/j.apsb.2026.06.022
UR - https://hal.science/hal-05764079v1
AB - Cancer metabolism depends on multifaceted mechanisms, including bidirectional interorganelle communication between mitochondria and the nucleus, facilitating cellular adaptation at the transcriptomic, proteomic, and metabolomic levels. The mitochondrial protein complex composed of apoptosis-inducing factor (AIF) and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is essential for this mitochondrio-nuclear communication. The AIF/CHCHD4 complex mediates the mitochondrial import of cysteine-enriched nuclear gene-encoded proteins, thereby adapting the mitochondrial proteome to cellular energy demands. Here, we report the discovery of M30-E05, a compound that binds to the NADH pocket of AIF, preventing its dimerization and disrupting the AIF/ CHCHD4 complex, as demonstrated by molecular docking and gel electrophoresis analysis of mitochondrial AIF/CHCHD4 substrate expression. In cancer cells, M30-E05 reduces the expression of nuclear gene-encoded mitochondrial proteins such as AIF, CHCHD4, cytochrome c oxidase copper chaperone (COX17), and Mitochondrial calcium uptake 1 (MICU1). In addition, M30-E05 fragments the mitochondrial network and impairs mitochondrial respiration, causing profound alterations, particularly in glucose, lipid, and amino acid metabolism, as revealed by kinetic measurements of oxygen consumption and mass spectrometric metabolomics. Importantly, M30-E05 significantly reduces the viability of a human adult and pediatric osteosarcoma cancer cell panel, including those from patient-derived xenografts (PDX) of osteosarcomas, and induces apoptosis. When orally administered for two weeks to immunodeficient NSG mice, M30-E05 inhibited tumor growth in a subcutaneous PDX xenograft model without apparent toxicity. We anticipate that M30-E05, as a first-in-class metabolic inhibitor, could serve as the lead compound for a new class of antineoplastic agents.
SN - 2211-3835
ER -