Mitochondria are the powerhouses of human cells, providing energy to support organ function. These power generators orchestrate much more than energy production; they influence biosynthesis, immunity and even cell death. The well-being of mitochondria impacts human health, disease pathology and progression, from the rare primary mitochondrial diseases to the common diseases of aging.
Protons (H+), derived from dietary sugar and fat, are funneled to the respiratory complexes (I-IV) embedded within the inner mitochondrial membrane, providing coupled transfer of electrons to molecular oxygen to power the formation of energy, i.e., ATP, formed by ATP synthase or complex V.
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The engulfment of an α-proteobacterium by a precursor of the eukaryotic cell billions of years ago resulted in the modern-day mitochondrion with the loss of much of its genetic material to the nucleus. Although the mitochondria contain more than 1000 proteins, most are encoded by nuclear DNA. A small fraction of proteins, 37, are encoded by DNA housed within the mitochondria (mtDNA).
Distinguishing this circular, double-stranded 16,568 bp DNA is the nucleotide content of the two strands: the heavy strand is enriched with guanine; the light strand with cytosine. Guanine is susceptible to oxidation due to its redox potential, and 8-oxo-7,8-dihydroguanine (8-oxodG) comprises 70% of oxidized mtDNA lesions.
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mtDNA Damage and Inflammation
Oxidative stress, mitochondrial dysfunction and DNA damage are hallmarks of many diseases of aging. Genetics and especially environmental factors contribute to disease etiology and progression.
Unmanaged oxidation of mtDNA leads to its fragmentation and appearance in the cytosol or extracellular spaces, signaling several pro-inflammatory pathways. Therefore, mtDNA maintenance by the DNA repair mechanisms serves to keep mtDNA intact, preventing the initiation of immune-inflammatory reactions in many age related diseases.
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Mitochondrial DNA Repair/OGG1
Thousands of detrimental DNA modifications occur in each cell every day. Humans have evolved DNA repair mechanisms within the mitochondria and nucleus to correct these potentially mutagenic and disease-promoting lesions.
Base excision repair (BER) is the predominant, conserved pathway that corrects lesions arising from oxidation, deamination and alkylation, and was the first DNA repair pathway found in mitochondria. Recognition and excision of oxidized guanine, 8-oxodG, is performed by the DNA glycosylase, OGG1 (8-Oxoguanine glycosylase), which is the first step in the BER pathway.
Learn more about mtDNA repair and OGG1.
Increasing the Activity of OGG1
Luciole co-founder, William Rumsey together with collaborator Vilhelm Bohr at the National Institutes of Aging demonstrated that small molecules could achieve sufficient activation of OGG1 to result in beneficial effects during oxidative stress in cell-based studies. Importantly, oxidative damage to mtDNA and mitochondrial function was prevented and the BER loss of function due to the Ser326Cys variant was rescued by the OGG1 activators. Subsequent research by S. Lloyd and colleagues at OHSU identified novel small molecule activators of OGG1 that protected human cells from oxidative stress. This technology has been licensed by Luicole.
Luciole is working to discover and develop drugs to slow the progressive cognitive decline in the neurodegenerative diseases.
Learn more about mtDNA and neurodegenerative diseases.
1. Baptiste, Katchur, Fivenson, Croteau, Rumsey and Bohr. Enhanced Mitochondrial DNA Repair of the Common Disease-Associated Variant, Ser326Cys, of hOGG1 Through Small Molecule Intervention. Free Radical Biology and Medicine, 2018.
2. Komakula, Tumova, Kumaraswamy, Burchat, Vartanian, Hong Ye, Dobrzyn, Lloyd and Sampath. The DNA Repair Protein OGG1 Protects Against Obesity by Altering Mitochondrial Energetics in White Adipose Tissue. Nature Scientific Reports, 2018.
3. Sampath and Lloyd. Roles of OGG1 in Transcriptional Regulation and Metabolic Homeostasis. DNA Repair, 2019.
4. Simon, Vartanian, Wong, Nakabeppu, Sharma, Lloyd and Sampath. OGG1 deficiency alters the intestinal microbiome and increases intestinal inflammation in a mouse model. PLOS One, January 14, 2020
5. Komakula, Blaze, Hong Ye, Dobrzyn and Sampath. A Novel Role for the DNA Repair Enzyme 8-Oxoguanine DNA Glycosylase in Adipogenesis. International Journal of Molecular Sciences, 2021.
6. Burchat, Sharma, Ye, Komakula, Dobrzyn, Vartanian, Lloyd and Sampath. Maternal Transmission of Human OGG1 Protects Mice Against Genetically- and Diet-Induced Obesity Through Increased Tissue Mitochondrial Content. Frontiers in Cell and Developmental Biology, 2021.
7. Michael B. Miller, August Yue Huang, Junho Kim, et al. Somatic genomic changes in single Alzheimer’s disease neurons. Nature, 28 April 2022; 604:714