Reverse engineering of BNIP3 identifies a mitochondrial protective peptide
Abstract
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.
Article Details
Authors (30)
Ulrike B. Hendgen-Cotta
Anna Roth
Christine Beuck
Faculty of Biology
Daniel Messiha
Stephan Settelmeier
Shah Bahrullah Shah
Sebastian Korste
Kenny Bravo-Rodriguez
Mike Blueggel
Faculty of Biology
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
Institute of Evolutionary Ecology and Conservation Genomics, Department of Biology, Ulm University
Linda-Isabell Schmitt
Markus Leo
Tim Hagenacker
Matthias Totzeck
Thomas Minor
Michael Ehrmann
Alpaslan Tasdogan
Peter Bayer
Faculty of Biology
Tienush Rassaf