Genetic variants in nuclear DNA along with environmental factors modify mitochondrial DNA copy number: a population-based exome-wide association study

AbstractMitochondrial dysfunction is an important factor of the aging process and may play a key role in various diseases. Mitochondrial DNA copy number (mtDNA-CN) is an indirect measure of mitochondrial dysfunction and is associated with type 2 diabetes mellitus (T2DM); however, whether mtDNA-CN can predict the risk of developing T2DM is not well-known. We quantified absolute mtDNA-CN in both prevalent and incident T2DM by well-optimized droplet digital PCR (ddPCR) method in a population-based follow-up study of middle aged (50–59 years) Swedish women (n = 2387). The median follow-up period was 17 years. Compared to those who were free of T2DM, mtDNA-CN was significantly lower in both prevalent T2DM and in women who developed T2DM during the follow-up period. Mitochondrial DNA-copy number was also associated with glucose intolerance, systolic blood pressure, smoking status and education. In multivariable Cox regression analysis, lower baseline mtDNA-CN was prospectively associated with a higher risk of T2DM, independent of age, BMI, education, smoking status and physical activity. Moreover, interaction term analysis showed that smoking increased the effect of low mtDNA-CN at baseline on the risk of incident T2DM. Mitochondrial DNA-copy number may be a risk factor of T2DM in women. The clinical usefulness of mtDNA-CN to predict the future risk of T2DM warrants further investigation.

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PCR‐Based Analysis of Mitochondrial DNA Copy Number, Mitochondrial DNA Damage, and Nuclear DNA Damage

Current Protocols in Toxicology ◽

10.1002/0471140856.tx2011s67 ◽

2016 ◽

Vol 67 (1) ◽

Cited By ~ 30

Author(s):

Claudia P. Gonzalez‐Hunt ◽

John P. Rooney ◽

Ian T. Ryde ◽

Charumathi Anbalagan ◽

Rashmi Joglekar ◽

...

Keyword(s):

Dna Damage ◽

Mitochondrial Dna ◽

Copy Number ◽

Nuclear Dna ◽

Dna Copy Number ◽

Mitochondrial Dna Damage ◽

Mitochondrial Dna Copy Number

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Association Between HIV Infection and Mitochondrial DNA Copy Number in Peripheral Blood: A Population-Based, Prospective Cohort Study

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy658 ◽

2018 ◽

Vol 219 (8) ◽

pp. 1285-1293 ◽

Cited By ~ 6

Author(s):

Jing Sun ◽

Ryan J Longchamps ◽

Damani A Piggott ◽

Christina A Castellani ◽

Jason A Sumpter ◽

...

Keyword(s):

Mitochondrial Dna ◽

Cohort Study ◽

Hiv Infection ◽

Prospective Cohort Study ◽

Peripheral Blood ◽

Prospective Cohort ◽

Copy Number ◽

Population Based ◽

Dna Copy Number ◽

Mitochondrial Dna Copy Number

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

Genome Medicine ◽

10.1186/s13073-020-00778-7 ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 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.

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Sperm Mitochondrial DNA Copy Number and Integrity in Infertile Men: A Comparison With Nuclear DNA Integrity

Fertility and Sterility ◽

10.1016/j.fertnstert.2005.07.011 ◽

2005 ◽

Vol 84 ◽

pp. S5 ◽

Cited By ~ 1

Author(s):

G. Song ◽

M.C. Graham ◽

V. Lewis

Keyword(s):

Mitochondrial Dna ◽

Copy Number ◽

Nuclear Dna ◽

Dna Integrity ◽

Dna Copy Number ◽

Infertile Men ◽

Mitochondrial Dna Copy Number

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

10.1101/673293 ◽

2019 ◽

Cited By ~ 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

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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