Mitochondrial DNA Repair/OGG1
Luciole Pharmaceuticals aims to preserve mtDNA health to slow the progression of disease by harnessing the power of the cell’s intrinsic capability to repair DNA. Humans have evolved repair mechanisms to correct the thousands of potentially mutagenic and disease-promoting DNA lesions that occur every day.
Base excision repair (BER) is the predominant pathway to remove and repair lesions arising from oxidation, deamination and alkylation. The first step in the BER pathway, recognition and excision of oxidized guanine, is performed by the DNA glycosylase, OGG1 (8-Oxoguanine glycosylase). Ogg1 is linked to the inner mitochondrial membrane, closely situated to the mtDNA.
The most common human loss-of-function variant of Ogg1 is the Ser326Cys single nucleotide polymorphism (SNP). This SNP changes a serine to a cysteine in the protein, resulting in up to a 70% loss of function and activity. Consequently, the ability to repair the mitochondria and preserve the cell is decreased. The variant occurs at high levels in both Caucasian populations (up to 40% have one variant gene) and more so in Asians (up to 60%). Not surprisingly, this variant has been associated with multiple diseases including cancers, neurodegenerative diseases like Alzheimer’s disease and Huntington’s disease, obesity and Type II diabetes, coronary heart disease, as well as all-cause mortality.
Deficiency of Ogg1 in animal models of stroke, for example, show increased vulnerability to neuronal cell death which highlights the requirement for sufficient BER activity.