Mitochondrial DNA copy number and heteroplasmy load correlate with skeletal muscle oxidative capacity by P31 MR spectroscopy

Tian, Qu; Moore, Ann Zenobia; Oppong, Richard; Ding, Jun; Zampino, Marta; Fishbein, Kenneth W.; Spencer, Richard G.; Ferrucci, Luigi

doi:10.1111/acel.13487

Cited by 9 publications

(3 citation statements)

References 20 publications

(22 reference statements)

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“…Depletion of CN impedes mtDNA replication 47 , while the persistence of abasic sites blocks replication 48 . Heteroplasmy and low levels of absolute CN may influence the onset of human age-related diseases 49 , whereas high levels of wild type mtDNA can offset deleterious pathogenic mtDNA mutations 50 and support organ function 51 . Thus, the protection against PQ-induced mtDNA damage and the accelerated recovery of CN post-H 2 O 2 exposure by our OGG1 activators may provide a therapeutic means to slow disease pathology.…”

Section: Discussionmentioning

confidence: 99%

Small molecule-mediated allosteric activation of the base excision repair enzyme 8-oxoguanine DNA glycosylase and its impact on mitochondrial function

Tian

Katchur

Jiang

et al. 2022

Sci Rep

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Abstract8-Oxoguanine DNA glycosylase (OGG1) initiates base excision repair of the oxidative DNA damage product 8-oxoguanine. OGG1 is bifunctional; catalyzing glycosyl bond cleavage, followed by phosphodiester backbone incision via a β-elimination apurinic lyase reaction. The product from the glycosylase reaction, 8-oxoguanine, and its analogues, 8-bromoguanine and 8-aminoguanine, trigger the rate-limiting AP lyase reaction. The precise activation mechanism remains unclear. The product-assisted catalysis hypothesis suggests that 8-oxoguanine and analogues bind at the product recognition (PR) pocket to enhance strand cleavage as catalytic bases. Alternatively, they may allosterically activate OGG1 by binding outside of the PR pocket to induce an active-site conformational change to accelerate apurinic lyase. Herein, steady-state kinetic analyses demonstrated random binding of substrate and activator. 9-Deazaguanine, which can’t function as a substrate-competent base, activated OGG1, albeit with a lower Emax value than 8-bromoguanine and 8-aminoguanine. Random compound screening identified small molecules with Emax values similar to 8-bromoguanine. Paraquat-induced mitochondrial dysfunction was attenuated by several small molecule OGG1 activators; benefits included enhanced mitochondrial membrane and DNA integrity, less cytochrome c translocation, ATP preservation, and mitochondrial membrane dynamics. Our results support an allosteric mechanism of OGG1 and not product-assisted catalysis. OGG1 small molecule activators may improve mitochondrial function in oxidative stress-related diseases.

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Section: Discussionmentioning

confidence: 99%

Small molecule-mediated allosteric activation of the base excision repair enzyme 8-oxoguanine DNA glycosylase and its impact on mitochondrial function

Tian

Katchur

Jiang

et al. 2022

Sci Rep

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show abstract

“…The proportion of mutated mtDNA relative to wild type and absolute CN may in uence the onset of human age-related diseases [49], whereas high levels of wild type mtDNA offset the deleterious consequences of pathogenic mtDNA mutations [50]. Even for simple daily tasks, elderly humans with increased CN have improved skeletal muscle post-exercise phosphocreatine recovery times despite high heteroplasmy [51]. Thus, the preservation of mtDNA integrity by the OGG1 activators may provide a therapeutic means to maintain wild type mtDNA and potentially slow disease pathology.…”

Section: Discussionmentioning

confidence: 99%

Small Molecule-Mediated Allosteric Activation of the Base Excision Repair Enzyme 8-Oxoguanine DNA Glycosylase: Impact on Mitochondrial Function

Tian¹,

Katchur²,

Jiang³

et al. 2022

Preprint

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8-Oxoguanine DNA glycosylase (OGG1) initiates base excision repair of the oxidative DNA damage product 8-oxoguanine. OGG1 is bifunctional; catalyzing glycosyl bond cleavage, followed by phosphodiester backbone incision via a β-elimination apurinic lyase reaction. The product from the glycosylase reaction, 8-oxoguanine, and its analogues, 8-bromoguanine and 8-aminoguanine, trigger the rate-limiting AP lyase reaction. The precise activation mechanism remains unclear. The product-assisted catalysis hypothesis suggests that 8-oxoguanine and analogues bind at the product recognition (PR) pocket to enhance strand cleavage as catalytic bases. Alternatively, they may allosterically activate OGG1 by binding outside of the PR pocket to induce an active-site conformational change to accelerate apurinic lyase. Herein, steady-state kinetic analyses demonstrated random binding of substrate and activator. 9-Deazaguanine, which can’t function as a substrate-competent base, activated OGG1, albeit with a lower Emax value than 8-bromoguanine and 8-aminoguanine. Random compound screening identified small molecules with Emax values similar to 8-bromoGua. Paraquat-induced mitochondrial dysfunction was attenuated by several small molecule OGG1 activators; benefits included enhanced mitochondrial membrane and DNA integrity, less cytochrome c translocation, ATP preservation, and mitochondrial membrane dynamics. Our results support an allosteric mechanism of OGG1 and not product-assisted catalysis. OGG1 small molecule activators may improve mitochondrial function in oxidative stress-related diseases.

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“…Variation in mtDNA-CN or heteroplasmy affects mitochondrial function. Generally, decreasing mtDNA-CN and/or increasing heteroplasmy negatively affects mitochondrial function; conversely, increasing mtDNA-CN and/or decreasing heteroplasmy enhances mitochondrial function ( 26 ).…”

Section: Mitochondrial Dna Variation and Mitochondrial Functionmentioning

confidence: 99%

Mitochondrial genomic integrity and the nuclear epigenome in health and disease

et al. 2022

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Bidirectional crosstalk between the nuclear and mitochondrial genomes is essential for proper cell functioning. Mitochondrial DNA copy number (mtDNA-CN) and heteroplasmy influence mitochondrial function, which can influence the nuclear genome and contribute to health and disease.Evidence shows that mtDNA-CN and heteroplasmic variation are associated with aging, complex disease, and all-cause mortality. Further, the nuclear epigenome may mediate the effects of mtDNA variation on disease. In this way, mitochondria act as an environmental biosensor translating vital information about the state of the cell to the nuclear genome.Cellular communication between mtDNA variation and the nuclear epigenome can be achieved by modification of metabolites and intermediates of the citric acid cycle and oxidative phosphorylation. These essential molecules (e.g. ATP, acetyl-CoA, ɑ-ketoglutarate and S-adenosylmethionine) act as substrates and cofactors for enzymes involved in epigenetic modifications.The role of mitochondria as an environmental biosensor is emerging as a critical modifier of disease states. Uncovering the mechanisms of these dynamics in disease processes is expected to lead to earlier and improved treatment for a variety of diseases. However, the influence of mtDNA-CN and heteroplasmy variation on mitochondrially-derived epigenome-modifying metabolites and intermediates is poorly understood. This perspective will focus on the relationship between mtDNA-CN, heteroplasmy, and epigenome modifying cofactors and substrates, and the influence of their dynamics on the nuclear epigenome in health and disease.

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Mitochondrial DNA copy number and heteroplasmy load correlate with skeletal muscle oxidative capacity by P31 MR spectroscopy

Cited by 9 publications

References 20 publications

Small molecule-mediated allosteric activation of the base excision repair enzyme 8-oxoguanine DNA glycosylase and its impact on mitochondrial function

Small molecule-mediated allosteric activation of the base excision repair enzyme 8-oxoguanine DNA glycosylase and its impact on mitochondrial function

Small Molecule-Mediated Allosteric Activation of the Base Excision Repair Enzyme 8-Oxoguanine DNA Glycosylase: Impact on Mitochondrial Function

Mitochondrial genomic integrity and the nuclear epigenome in health and disease

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