Reverse engineering of BNIP3 identifies a mitochondrial protective peptide

Nat Commun. 2026 Jun 17;17(1):5359. doi: 10.1038/s41467-026-73993-2.

Ulrike B Hendgen-Cotta ^# ¹, Anna Roth ², Christine Beuck ³, Daniel Messiha ², Stephan Settelmeier ², Shah Bahrullah Shah ², Sebastian Korste ², Kenny Bravo-Rodriguez ⁴, Mike Blueggel ³, Feyza Cansiz ⁵, Luiza Martins Nascentes Melo ⁵, Jonas Roesler ⁵, Sven W Meckelmann ⁶, Oliver J Schmitz ⁶, Farnusch Kaschani ⁷, Markus Kaiser ⁸, Sonja Esfeld ², Omar El Bounkari ⁹, Jürgen Bernhagen ⁹ ¹⁰ ¹¹, Sophie Brameyer ¹², Kirsten Jung ¹², Linda-Isabell Schmitt ¹³, Markus Leo ¹³, Tim Hagenacker ¹³, Matthias Totzeck ², Thomas Minor ¹⁴, Michael Ehrmann ¹⁵, Alpaslan Tasdogan ⁵, Peter Bayer ³, Tienush Rassaf ^# ¹⁶

Affiliations

1 Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. [email protected].
2 Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
3 Center of Medical Biotechnology, Research Group Structural and Medicinal Biochemistry, Faculty of Biology, University of Duisburg-Essen, Essen, Germany.
4 Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
5 Department of Dermatology, Medical Faculty, University of Duisburg-Essen & German Cancer Consortium (DKTK), Essen, Germany.
6 Applied Analytical Chemistry, University of Duisburg-Essen, Essen, Germany.
7 Center of Medical Biotechnology, Analytics Core Facility Essen, Faculty of Biology, University of Duisburg-Essen, Essen, Germany.
8 Center of Medical Biotechnology, Chemical Biology, Faculty of Biology, University of Duisburg-Essen, Essen, Germany.
9 Division of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilians-University (LMU) Munich, Munich, Munich, Germany.
10 German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
11 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
12 Faculty of Biology, Microbiology, Ludwig-Maximilians-University (LMU) Munich, Martinsried, Germany.
13 Department auf Neurology and Center for Translational Neuro and Behavioral Science, Medical Faculty, University Hospital Essen, Essen, Germany.
14 Surgical Research Department, Medical Faculty, University Hospital Essen, Essen, Germany.
15 Center of Medical Biotechnology, Department of Microbiology, Faculty of Biology, University of Duisburg-Essen, Essen, Germany.
16 Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. [email protected].
# Contributed equally.

PMID: 42309990 DOI: 10.1038/s41467-026-73993-2

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.

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HY-P7537

BCL2 Protein, Human (His)

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