Development of Organocatalytic Switches of OGG1 that Protect Mitochondria under Oxidative Stress
Abstract Mitochondrial dysfunction is a major component of neurodegeneration. The mitochondrial genome is prone to oxidative damage, and repair proteins are important to maintain mitochondrial DNA integrity. OGG1 initiates base excision repair of oxidative DNA lesions in both nuclear and mitochondrial genomes. While inhibitors of OGG1 have been extensively explored, pharmacological activation of OGG1 through catalytic reprogramming remains underdeveloped. Herein, we report the discovery of mitochondrial enriched organocatalytic switches of OGG1. Biochemical analysis, mutational profiling, and X-ray crystallography confirmed active-site binding and preferential stimulation of β-elimination over glycosylase turnover, effectively reprogramming OGG1. We demonstrate that ORCAs protect mitochondrial function and morphology under oxidative stress, specifically affecting mitochondrial membrane potential and fragment number while attenuating metabolic stress. Mechanistically, ORCAs improved NAD levels in mouse dissociated cortical neurons and provided neuroprotection in a retina axotomy model. Together, the findings position OGG1-ORCAs as potential novel therapies for the treatment of age-related diseases and neurodegeneration.
Authors
- Paweł Baranczewski (ORCID: https://orcid.org/0000-0001-5772-6791)
- Stefan Knapp (ORCID: https://orcid.org/0000-0001-5995-6494)
- Evert J. Homan (ORCID: https://orcid.org/0000-0002-9057-1848)
- Alicia del Prado (ORCID: https://orcid.org/0000-0002-5480-0367)
- Miguel de Vega (ORCID: https://orcid.org/0000-0003-1285-7549)
- Thomas Helleday (ORCID: https://orcid.org/0000-0002-7384-092X)
- Hannah Stigsdotter
- Pål Stenmark (ORCID: https://orcid.org/0000-0003-4777-3417)
- Rahul Upadhyay (ORCID: https://orcid.org/0000-0002-3843-992X)
- Laurie H. Sanders (ORCID: https://orcid.org/0000-0003-1617-9562)
- Pete A. Williams (ORCID: https://orcid.org/0000-0001-6194-8397)
- Nicholas D. D’Arcy-Evans (ORCID: https://orcid.org/0009-0004-3503-4726)
- Emma Rose Scaletti (ORCID: https://orcid.org/0000-0002-8741-8981)
- Olov A. Wallner (ORCID: https://orcid.org/0000-0002-6481-237X)
- O. Gileadi (ORCID: https://orcid.org/0000-0001-6886-898X)
- Alice Eddershaw (ORCID: https://orcid.org/0000-0002-8381-4135)
- Maurice Michel (ORCID: https://orcid.org/0000-0003-3261-2493)
- Maeve Long (ORCID: https://orcid.org/0000-0001-5146-0750)
- Oliver Mortusewicz (ORCID: https://orcid.org/0000-0002-4290-4994)
- Ingrid Almlöf
- Alexandra Stolz (ORCID: https://orcid.org/0000-0002-3340-439X)
- Elisée Wiita
- Andreas Krämer (ORCID: https://orcid.org/0000-0003-3294-2660)
- Anas Bitar (ORCID: https://orcid.org/0000-0001-7687-5055)
- Alan Nicol
- Richard Svensson
- Oryn Purewal-Sidhu (ORCID: https://orcid.org/0000-0003-1567-9389)
- Natálie Rudolfová (ORCID: https://orcid.org/0009-0000-6725-2198)
- Dinesh Nirmalan (ORCID: https://orcid.org/0009-0009-4869-3882)
- Sara Cano
- James Tribble
- Michael Sundström
Institutions
- Goethe University Frankfurt (DE)
- Uppsala University (SE)
- Karolinska University Hospital (SE)
- Stockholm University (SE)
- Duke University (US)
- King's College London (GB)
- Karolinska Institutet (SE)
- The Royal Victorian Eye & Ear Hospital (AU)
- Institute for Neurodegenerative Disorders (US)
- Duke Medical Center (US)
- Centro de Biología Molecular Severo Ochoa (ES)
- University of Sheffield (GB)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-10-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00526
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00