scholarly journals Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

2021 ◽  
Author(s):  
Stephanie Y. Yang ◽  
Christina A. Castellani ◽  
Ryan J. Longchamps ◽  
Vamsee K. Pillalamarri ◽  
Brian O'Rourke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mitochondrial Dna ◽  
Neurodegenerative Disease ◽  
Copy Number ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number

scholarly journals Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

2020 ◽  
Author(s):  
Stephanie Y. Yang ◽  
Christina A. Castellani ◽  
Ryan J. Longchamps ◽  
Vamsee K. Pillalamarri ◽  
Brian O’Rourke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mitochondrial Dna ◽  
Neurodegenerative Disease ◽  
Whole Blood ◽  
Copy Number ◽  
Rna Binding ◽  
Inverse Association ◽  
Dna Copy Number ◽  
Related Disease ◽  
Mitochondrial Dna Copy Number

ABSTRACTBackgroundMitochondrial DNA copy number (mtDNA-CN) can be used as a proxy for mitochondrial function and is associated with a number of aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect risk for diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated the relationships between mtDNA-CN measured in whole blood and gene expression from whole blood as well as 47 additional tissues.ResultsWe evaluated associations between blood-derived mtDNA-CN and gene expression in whole blood for 418 individuals, correcting for known confounders and surrogate variables derived from RNA-sequencing. Using a permutation-derived cutoff (p<2.70e-6), mtDNA-CN was significantly associated with expression for 721 genes in whole blood, including nuclear genes that are required for mitochondrial DNA replication. Significantly enriched pathways included splicing (p=1.03e-8) and ubiquitin-mediated proteolysis (p=2.4e-10). Genes with target sequences for the mitochondrial transcription factor NRF1 were also enriched (p=1.76e-35).In non-blood tissues, there were more significantly associated genes than expected in 30 out of 47 tested tissues, suggesting that global gene expression in those tissues is correlated with mtDNA-CN. Pathways that were associated in multiple tissues included RNA-binding, catalysis, and neurodegenerative disease. We evaluated the association between mtDNA-CN and incident neurodegenerative disease in an independent dataset, the UK Biobank, using a Cox proportional-hazards model. Higher mtDNA-CN was significantly associated with lower risk for incident neurodegenerative disease (HR=0.73, 95% CI= 0.66;0.90).ConclusionsThe observation that mtDNA-CN measured in whole blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Key pathways in maintaining cellular homeostasis, including splicing, RNA binding, and catalytic genes were significantly associated with mtDNA-CN, reinforcing the importance of mitochondria in aging-related disease. As a specific example, genes involved in neurodegenerative disease were significantly enriched in multiple tissues. This finding, validated in a large independent cohort study showing an inverse association between mtDNA-CN and neurodegenerative disease, solidifies the link between blood-derived mtDNA-CN, altered gene expression in both blood and non-blood tissues, and aging-related disease.

scholarly journals Luteal phase-derived oocyte-cumulus complexes: gene expression and mitochondrial DNA copy number

2019 ◽  
Vol 112 (3) ◽  
pp. e257-e258
Author(s):  
Bella Martazanova ◽  
Nona Mishieva ◽  
Anna Korolkova ◽  
Khava Bogatyreva ◽  
Maria Veykova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Luteal Phase ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number

scholarly journals Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Christina A. Castellani ◽  
Ryan J. Longchamps ◽  
Jason A. Sumpter ◽  
Charles E. Newcomb ◽  
John A. Lane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Nuclear Dna ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
Genome Wide Significance ◽  
Experimental Modification

Abstract Background Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. Methods To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. Results Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10− 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10− 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the “neuroactive ligand receptor interaction” KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10− 12), as well as the TFAM knockout methylation (P = 4.41 × 10− 4) and expression (P = 4.30 × 10− 4) studies. Conclusions These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

scholarly journals Mitochondrial DNA Copy Number (mtDNA-CN) Can Influence Mortality and Cardiovascular Disease via Methylation of Nuclear DNA CpGs

2019 ◽  
Author(s):  
Christina A. Castellani ◽  
Ryan J. Longchamps ◽  
Jason A. Sumpter ◽  
Charles E. Newcomb ◽  
John A. Lane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Nuclear Dna ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
Genome Wide Significance ◽  
Experimental Modification

ABSTRACTBackgroundMitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.MethodsTo investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2,507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings we assayed an additional 2,528 participants from the Cardiovascular Health Study (CHS) (N=533) and Framingham Heart Study (FHS) (N=1,995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.ResultsThirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P<5×10-8). Meta-analysis across all cohorts identified six mtDNA-CN associated CpGs at genome-wide significance (P<5×10-8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN directly drives changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the ‘neuroactive ligand receptor interaction’ KEGG pathway was found to be highly overrepresented in the ARIC cohort (P= 5.24×10-12), as well as the TFAM knockout methylation (P=4.41×10-4) and expression (P=4.30×10-4) studies.ConclusionsThese results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

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