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. Thousands of detrimental DNA modifications occur in every cell each day. Humans have evolved repair mechanisms to correct these potentially mutagenic and disease-promoting lesions. 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). The Ogg1 gene is expressed as eight forms; the predominant ones are 1a and 2a. The 2a protein is linked to the inner mitochondrial membrane, closely situated to the mtDNA, although 1a has also been detected within mitochondria.

 

The most common human loss-of-function variant of Ogg1 is the Ser326Cys SNP. This amino acid change in the protein results 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.

The risk of disease increases when found in combination with variants of other DNA repair proteins. Deficiency of Ogg1 in murine models of stroke, for example, show increased vulnerability to neuronal cell death which highlights the requirement for sufficient BER activity.