Long-Term Air Pollution Exposure and Mitochondrial DNA Copy Number: An Analysis of UK Biobank Data

Hong, Yun Soo; Battle, Stephanie L.; Puiu, Daniela; Shi, Wenmei; Pankratz, Nathan; Zhao, Di; Arking, Dan E.; Güallar, Eliseo

doi:10.1289/ehp11946

Cited by 5 publications

(5 citation statements)

References 11 publications

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“…While we identified mitochondrial genomic impairments in V 2 O 5 -exposed D2 animals, we did not find any changes in nDNA lesions on the basis of strain, exposure, or time point (Figure 4). This is a conflicting finding to those in the current literature [30,[32][33][34]. However, our results and the literature may be incongruent due to cell type, in vitro versus in vivo, or species-specific responses (e.g., nDNA damage and breaks occurring in human cells versus hamster cells).…”

Section: Discussioncontrasting

confidence: 94%

“…In addition to their increased mtDNA lesions, D2 V 2 O 5 -exposed animals also had reduced mtDNA copies at 112 days post-exposure, which is supported by other findings [29]. For example, Hong et al [30] conducted a large-scale study involving 45,665 whole blood samples from participants derived from the U.K. Biobank and found a linear inverse relationship between carbon and nitric oxide (NO 2 ) concentrations and mtDNA copy number. Similarly, using whole blood from 60 truck drivers and 60 office workers in Beijing before the 2008 Summer Olympic Games, Hou et al [31] showed an inverse relationship between mtDNA copy number and exposure to personal particulate matter and elemental carbon, with more significant exposures corresponding to decreases in mtDNA copy number.…”

Section: Discussionmentioning

confidence: 57%

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Vanadium Pentoxide Exposure Causes Strain-Dependent Changes in Mitochondrial DNA Heteroplasmy, Copy Number, and Lesions, but Not Nuclear DNA Lesions

Dobson,

Kleeberger,

Burkholder

et al. 2023

IJMS

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Interstitial lung diseases (ILDs) are lethal lung diseases characterized by pulmonary inflammation and progressive lung interstitial scarring. We previously developed a mouse model of ILD using vanadium pentoxide (V2O5) and identified several gene candidates on chromosome 4 associated with pulmonary fibrosis. While these data indicated a significant genetic contribution to ILD susceptibility, they did not include any potential associations and interactions with the mitochondrial genome that might influence disease risk. To conduct this pilot work, we selected the two divergent strains we previously categorized as V2O5-resistant C57BL6J (B6) and -responsive DBA/2J (D2) and compared their mitochondrial genome characteristics, including DNA variants, heteroplasmy, lesions, and copy numbers at 14- and 112-days post-exposure. While we did not find changes in the mitochondrial genome at 14 days post-exposure, at 112 days, we found that the responsive D2 strain exhibited significantly fewer mtDNA copies and more lesions than control animals. Alongside these findings, mtDNA heteroplasmy frequency decreased. These data suggest that mice previously shown to exhibit increased susceptibility to pulmonary fibrosis and inflammation sustain damage to the mitochondrial genome that is evident at 112 days post-V2O5 exposure.

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Section: Discussioncontrasting

confidence: 94%

Section: Discussionmentioning

confidence: 57%

Vanadium Pentoxide Exposure Causes Strain-Dependent Changes in Mitochondrial DNA Heteroplasmy, Copy Number, and Lesions, but Not Nuclear DNA Lesions

Dobson,

Kleeberger,

Burkholder

et al. 2023

IJMS

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“…Our results demonstrate a reduction in mtDNA-CN and widespread changes to nDNA methylation and gene expression following TFAM knockout. These dynamics have also been found to be influenced by environmental stimuli [76]. It has been proposed that these environmental stimuli affect the bidirectional cross-talk between the mitochondrial and nuclear genome through several key mitochondrial metabolites [77].…”

Section: Mtdna-cn Remodels the Nuclear Epigenome And Transcriptomementioning

confidence: 99%

Mitochondrial DNA copy number reduction viain vitro TFAMknockout remodels the nuclear epigenome and transcriptome

Nguyen,

Win,

Nagano

et al. 2024

Preprint

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Mitochondrial DNA copy number (mtDNA-CN) is associated with several age-related chronic diseases and is a predictor of all-cause mortality. Here, we examine site-specific differential nuclear DNA (nDNA) methylation and differential gene expression resulting fromin vitroreduction of mtDNA-CN to uncover shared genes and biological pathways mediating the effect of mtDNA-CN on disease. Epigenome and transcriptome profiles were generated for three independent human embryonic kidney (HEK293T) cell lines harbouring a mitochondrial transcription factor A (TFAM) heterozygous knockout generated via CRISPR-Cas9, and matched control lines. We identified 4,242 differentially methylated sites, 228 differentially methylated regions, and 179 differentially expressed genes associated with mtDNA-CN. Integrated analysis uncovered 381 Gene-CpG pairs. GABAA receptor genes and related pathways, the neuroactive ligand receptor interaction pathway, ABCD1/2 gene activity, and cell signalling processes were overrepresented, providing insight into the underlying biological mechanisms facilitating these associations. We also report evidence implicating chromatin state regulatory mechanisms as modulators of mtDNA-CN effect on gene expression. We demonstrate that mitochondrial DNA variation signals to the nuclear DNA epigenome and transcriptome and may lead to nuclear remodelling relevant to development, aging, and complex disease.

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“…1 MtDNA exists in cells in a different copy number (mtDNAcn) depending on the tissue type, health status of cells or environmental exposures. [2][3][4][5][6][7][8][9][10][11][12][13] Also, increasing evidence demonstrated the presence of mtDNA in body fluids as circulating cell-free mtDNA (ccf-mtDNA). 14 Ccf-mtDNA can circulate in body fluids as naked or contained in lipid-based vesicles.…”

Section: Introductionmentioning

confidence: 99%

“…It consists of 16 569 base pairs, and it contains 37 genes: 13 encoding for oxidative phosphorylation mRNAs, 22 for tRNAs, and 2 for rRNAs 1 . MtDNA exists in cells in a different copy number (mtDNAcn) depending on the tissue type, health status of cells or environmental exposures 2‐13 . Also, increasing evidence demonstrated the presence of mtDNA in body fluids as circulating cell‐free mtDNA (ccf‐mtDNA) 14 .…”

Section: Introductionmentioning

confidence: 99%

Exploring mitochondrial DNA copy number in circulating cell‐free DNA and extracellular vesicles across cardiovascular health status: A prospective case–control pilot study

Rucci,

de Simone,

Salathia

et al. 2024

The FASEB Journal

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Cardiovascular disease (CVD) is a leading global cause of mortality, difficult to predict in advance. Evidence indicates that the copy number of mitochondrial DNA (mtDNAcn) in blood is altered in individuals with CVD. MtDNA released into circulation may act as a mediator of inflammation, a recognized factor in the development of CVD, in the long distance. This pilot study aims to test if levels of mtDNAcn in buffy coat DNA (BC‐mtDNA), in circulating cellfree DNA (cf‐mtDNA), or in DNA extracted from plasma extracellular vesicles (EV‐mtDNA) are altered in CVD patients and if they can predict heart attack in advance. A group of 144 people with different CVD statuses (50 that had CVD, 94 healthy) was selected from the LifeLines Biobank according to the incidence of new cardiovascular event monitored in 6 years (50 among controls had heart attack after the basal assessment). MtDNAcn was quantified in total cf‐DNA and EV‐DNA from plasma as well as in buffy coat. EVs have been characterized by their size, polydispersity index, count rate, and zeta potential, by Dynamic Light Scattering. BC‐mtDNAcn and cf‐mtDNAcn were not different between CVD patients and healthy subjects. EVs carried higher mtDNAcn in subject with a previous history of CVD than controls, also adjusting the analysis for the EVs derived count rate. Despite mtDNAcn was not able to predict CVD in advance, the detection of increased EV‐mtDNAcn in CVD patients in this pilot study suggests the need for further investigations to determine its pathophysiological role in inflammation.

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Long-Term Air Pollution Exposure and Mitochondrial DNA Copy Number: An Analysis of UK Biobank Data

Cited by 5 publications

References 11 publications

Vanadium Pentoxide Exposure Causes Strain-Dependent Changes in Mitochondrial DNA Heteroplasmy, Copy Number, and Lesions, but Not Nuclear DNA Lesions

Vanadium Pentoxide Exposure Causes Strain-Dependent Changes in Mitochondrial DNA Heteroplasmy, Copy Number, and Lesions, but Not Nuclear DNA Lesions

Mitochondrial DNA copy number reduction viain vitro TFAMknockout remodels the nuclear epigenome and transcriptome

Exploring mitochondrial DNA copy number in circulating cell‐free DNA and extracellular vesicles across cardiovascular health status: A prospective case–control pilot study

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