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Mutations in complex mitochondrial DNA sequences may impact age-related conditions and genetic diseases

Mutations in complex structures within the genomes of mitochondria, the powerhouses of cells, could be culprits in genetic diseases, cancer and aging, according to a new NIA Intramural Research Program (IRP)-led study published in Human Molecular Genetics.

DNA Polymerase, B NDA, and G-quadruplex (non-B DNA) showing DNA process in image.
Spontaneously formed complex G-quadruplex (G4) DNA structures are obstacles for DNA replicating enzymes. When the polymerase encounters the G4 structure, it may stall, leading to incomplete or inaccurate DNA synthesis and causing mutations in the mitochondrial genome.

Mitochondria provide energy for vital biochemical processes and proper cell function. They contain their own genomes, consisting of circular DNA molecules that encode proteins important for cellular respiration and energy production. Mitochondrial DNA mutations can cause breakdowns in normal cell function, leading to mitochondrial diseases that can affect the brain, nerves, muscles, heart and other body systems.

Scientists from the NIA IRP’s Laboratory of Molecular Gerontology and Translational Gerontology Branch and their colleagues investigated whether mitochondrial mutations are due to mistakes made during synthesis of certain DNA sequences. The researchers zeroed in on mitochondrial DNA sequences that spontaneously form G-quadruplexes (G4), a complex structure with four interacting DNA strands, instead of the normal DNA double helix shape. They found that when enzymes crucial for DNA replication encountered a G4 structure, they often failed to work properly, leading to errors in the newly formed DNA resulting in damaged mitochondrial genomes.

Working with mitochondrial DNA sequences obtained from blood cells from 2,700 individuals participating in two NIA-supported Italian longitudinal studies of aging SardiNIA and InCHIANTI, they found that these stable G4 DNA structures contained most of the mitochondrial DNA mutations. The researchers also noted how mitochondrial G4 DNA sequences were difficult to copy even in optimal lab environments, making them particularly difficult to study.

Future study of mutations that harm mitochondrial function may help researchers and clinicians to develop potential treatment strategies for mitochondrial diseases and identify additional genetic risk factors.

This work was supported in part by NIA Inter-Lab grant 1Z1AAG000699-01.

References: Butler TJ, et al. Mitochondrial genetic variation is enriched in G-quadruplex regions that stall DNA synthesis in vitro. Human Molecular Genetics, in press.

Estep KN, et al. G4-interacting DNA helicases and polymerases: Potential therapeutic targets. Current Medicinal Chemistry. 2019;26(16):2881-2897. doi: 10.2174/0929867324666171116123345.