Reactive Aldehyde DNA Damage in Mitochondrial Mutagenesis and Disease Pathophysio

Mercer University Macon, Macon GA

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Abstract

DESCRIPTION (provided by applicant): Human health is dependent upon the stability of the nuclear and mitochondrial genomes of each cell. Mitochondria generate energy through oxidative phosphorylation (OXPHOS), but this process also produces reactive oxygen species (ROS) that damage the intracellular environment [1,22,23]. ROS production increases if OXPHOS is impaired, which is the case in mitochondrial genetic diseases, chronic diseases states, and inflammation [20-24]. ROS interact with lipids and nucleic acids to release a host of reactive aldehydes, including malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and nucleic acid base propenals [1,12, 25]. These agents damage guanine bases in DNA to form M1dG, which induces mutations and interferes with DNA replication and transcription [1,10,11,13]. M1dG is two-fold greater in mitochondrial DNA (mtDNA) than nuclear DNA, and M1dG and reactive aldehydes are measurable in human tissues, blood and urine [2-9,15-17,31]. Nucleotide excision repair (NER), the mechanism implicated in M1dG processing in the nucleus, is absent in mitochondria, therefore, little is known about repair of mtDNA or M1dG effects on mitochondrial genome integrity [18,19]. Indeed, the limited DNA repair capacity of mitochondria leaves genes in mtDNA susceptible to mutagenesis during replication and transcription, and M1dG disruption of gene expression may be a causative factor of the diminished cellular energy production and tissue pathology in many disease states and in normal human aging. The NIGMS supports the investigation of molecular mechanisms underlying onset and treatment of human disease. M1dG and its metabolites are under investigation for use as a clinical biomarker for disease [2,4,9,16,17]. The goal of the proposed work is to gain understanding about the mitochondrial processing of M1dG, which will be critical for correlating clinical measurements and tissue pathology. The Specific Aims of this project are: I) to assess the effects of M1dG on mitochondrial transcription, II) to determine M1dG effects on mitochondrial replication, III) to identify mitochondrial M1dG recognition proteins that may facilitate repair or initiate mitochondrial destruction. PUBLIC HEALTH RELEVANCE: Reactive aldehydes are produced in cells under oxidative stress and are associated with diseases in a variety of human tissues. These biological chemicals cause a form of DNA damage, called M1dG. Mitochondria, which are the energy factories of cells, contain DNA that is particularly susceptible to reactive aldehydes and M1dG formation. M1dG may interfere with correct "reading" or "copying" of the mitochondrial DNA, processes that are necessary for energy generation. Mitochondria may remove the M1dG to repair its DNA or they may destroy the damaged genetic material. M1dG and its metabolites are found in human body fluids and are being studied as clinical biomarkers for disease and disease progression. An investigation of how M1dG affects the ability of mitochondria to "read" and "copy" their DNA will help establish relationships between clinical measurements of M1dG and diseases of human tissues.