Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice

Background: Atrial fibrillation (AF) is the most common clinical arrhythmia. Molecular studies suggest that mitochondrial dysfunction is associated with increased risk of AF through reduced production of adenosine triphosphate and increased production of reactive oxidative species. Mitochondrial DNA copy number (mtDNA CN), a marker of mitochondrial function, has been found to be associated with sudden cardiac death and cardiovascular disease (CVD) in ARIC. However, the association between mtDNA CN and incident AF in the general population is unknown. Objective: To examine the prospective association between mtDNA CN and the risk of incident AF. Methods: Cohort study of 10,764 ARIC participants without AF at baseline (1987-89) and followed through December 31, 2014. AF were identified through electrocardiograms, review of hospital discharge codes, and death certificates. DNA samples were isolated from buffy coat. mtDNA CN was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array and standardized using the residual method. Cox proportional hazards models adjusted for demographics and CVD risk factors were used to estimate hazard ratios (HR) for AF comparing the four lowest quintiles of mtDNA CN to the highest quintile. Results: The mean (SD) age was 57.4 (6.0) years. During 21 years of median follow-up, 1,946 participants developed AF. In fully-adjusted models, the HRs (95% CI) for AF comparing quintiles 1 - 4 to quintile 5 of mtDNA CN were 1.17 (1.00, 1.37), 1.17 (0.99, 1.37), 0.92 (0.78, 1.10) and 1.05 (0.89, 1.24), respectively (p-trend 0.044; Figure). The HR for AF comparing 10 th vs 90 th percentile of mtDNA-CN was 1.16 (1.04, 1.30). Conclusions: mtDNA CN was inversely associated with the risk of AF independent of traditional CVD risk factors. Decline in mitochondrial function may be a novel mechanism underlying biological changes that increase the risk of AF in the general population. mtDNA CN may provide potential for novel AF prevention strategies.

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Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

Human Genetics ◽

10.1007/s00439-021-02394-w ◽

2021 ◽

Author(s):

R. J. Longchamps ◽

S. Y. Yang ◽

C. A. Castellani ◽

W. Shi ◽

J. Lane ◽

...

Keyword(s):

Mitochondrial Dna ◽

Platelet Activation ◽

Mitochondrial Function ◽

Copy Number ◽

Nucleotide Metabolism ◽

Dna Copy Number ◽

Mitochondrial Dna Copy Number ◽

Genome Wide ◽

Mitochondrial Dna Depletion ◽

A Genome

AbstractMitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10–15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10–8) and mtDNA replication (p = 1.2 × 10–7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10–4).

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