OGG1 'organocatalytic switches' reprogram DNA repair to protect mitochondria
- Most OGG1 work has aimed at inhibitors; these mitochondria-enriched ORCAs instead reprogram the enzyme's catalysis.
- Biochemistry, mutagenesis and X-ray crystallography showed active-site binding that favors beta-elimination over glycosylase turnover.
- ORCAs protected mitochondrial function under oxidative stress, raised NAD levels in cortical neurons and were neuroprotective in a retina axotomy model.
💡 Points
Activating rather than inhibiting an enzyme is rare and hard to do, so a crystal structure showing the mechanism is what makes this credible. The open question is long-term safety: pushing a repair enzyme to a different catalytic outcome could create unusual DNA lesions, and the neuroprotection data are still early.
Development of Organocatalytic Switches of OGG1 that Protect Mitochondria under Oxidative Stress ↗