Year: 2026
Type: article
Abstract: Recent advances in mitochondrial network dynamic and signalling highlight mitochondria as key therapeutic targets across diverse diseases. Yet, high drug development failure rates reflect an incomplete understanding of upstream molecular regulators of mitochondrial fate. Here, we address this gap by reverse engineering of the BH3-only protein BNIP3. Structural modelling and sequence-function analyses of its N-terminus identify a critical functional domain and amino acid hotspots that directly activate BCL-2 executioner proteins, triggering mitochondrial cell death. Leveraging these insights, we develop a BNIP3 antagonist peptide (B-017) that disrupts interactions between BNIP3 and BCL-2 executioner proteins, preserving mitochondrial integrity. B-017 demonstrates target specificity, a favourable safety profile, and robust suppression of cell death signalling in human cells. In clinically relevant animal models, it reduces tissue damage in the heart, brain, and liver. Together, these findings position B-017 as a promising therapeutic candidate targeting mitochondrial dysfunction.
Source: Nature Communications
Authors: Ulrike B. Hendgen-Cotta, Anna Roth, Christine Beuck, Daniel Messiha, Stephan Settelmeier, Shah Bahrullah Shah, Sebastian Korste, Kenny Bravo-Rodriguez, Mike Blueggel, Feyza Cansiz, Luiza Martins Nascentes Melo, Jonas Roesler, Sven W. Meckelmann, Oliver J. Schmitz, Farnusch Kaschani, Markus Kaiser, Sonja Esfeld, Omar El Bounkari, Jürgen Bernhagen, Sophie Brameyer, Kirsten Jung, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Matthias Totzeck, Thomas Minor, Michael Ehrmann, Alpaslan Tasdogan, Peter Bayer, Tienush Rassaf
Institutions: West German Heart and Vascular Center Essen, University of Duisburg-Essen, Max Planck Institute of Molecular Physiology, Deutsches Konsortium für Translationale Krebsforschung, LMU Klinikum, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, Munich Cluster for Systems Neurology, German Centre for Cardiovascular Research, Essen University Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funder: Deutsche Forschungsgemeinschaft
Award: G3730525334
OpenAlex ID: W7165024752