# Mitochondrial DNA, Nuclear DNA Methylation, and Cardiometabolic Disease Traits

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $583,029

## Abstract

PROJECT SUMMARY
Energy metabolism plays a critical role in human disease. Mitochondria, the energy powerhouses of the cell,
have their own genome (mtDNA) which is present up to thousands of copies per cell. mtDNA encodes genes for
proteins of energy metabolism. We (led by Liu, PI of this application) recently discovered that lower mtDNA copy
number in whole blood is an independent predictor for higher levels of cardiovascular disease (CMD) risk factors
in ~60,000 participants from multiple ancestries. For example, one standard deviation of decrease in mtDNA
copy number was associated with increased odds of obesity (OR=1.15, p=8e-31) and metabolic syndrome
(OR=1.14, p=1e-32), as well as with increased levels of several quantitative traits defining these diseases.
Despite these findings, the molecular basis underlying the association of mtDNA with CMD is unclear because
the nuclear genome (nDNA) also encodes many of the proteins engaged in mitochondrial energy production and
biosynthesis, and thus, maintenance of mitochondrial function requires extensive coordination of mtDNA and
nDNA. A mouse hybrid nDNA-mtDNA system was developed. Using this model, the researchers found
differential nDNA methylation, gene expression, and cellular adaptive response in hybrid mice of identical nDNA,
but with different mtDNA background. Additionally, we (led by Arking, Co-I of this application) identified several
significant DNA methylation sites associated with mtDNA copy number. In addition, experimental modification of
mtDNA copy number through knockout via CRISPR-Cas9 of TFAM, a regulator of mtDNA replication,
demonstrated that modulation of mtDNA copy number directly drives changes in nDNA methylation of specific
CpGs and gene expression of nearby transcripts. Based on these previous studies in mouse model and our own
research, we hypothesize that methylation and gene expression of nDNA mediate the effects of mtDNA on
cardiometabolic disease traits. In this proposed proposal, we will leverage existing resources, including whole
genome sequencing and multi-omics in six large cohorts of multiple ancestries; we will rigorously test our
hypothesis by pursuing four specific aims. In Aim 1 and Aim 2, we will perform association analyses to identify
mtDNA-associated nDNA methylation sites and gene expression levels, respectively. mtDNA features include
mtDNA homoplasmic and heteroplasmic mutations, and mtDNA copy number. In Aim 3, we will investigate
whether nDNA methylation and/or gene expression mediates the effects of mtDNA copy number and
heteroplasmy on continuous cardiometabolic disease traits. In Aim 4, we will perform integrative analyses to
identify gene regulation networks underlying mtDNA and cardiometabolic disease traits. We will also functionally
test the impact of mtDNA on these gene networks via edited cell lines (e.g., via CRISPR-Cas9 system). The
body of knowledge generated by this research project will deepen our understanding of molecular mechanism...

## Key facts

- **NIH application ID:** 10475148
- **Project number:** 5R01HL155569-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Chunyu Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $583,029
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475148

## Citation

> US National Institutes of Health, RePORTER application 10475148, Mitochondrial DNA, Nuclear DNA Methylation, and Cardiometabolic Disease Traits (5R01HL155569-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10475148. Licensed CC0.

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