Environmental determinants of mitochondrial DNA copy number

This dissertation was designed to examine environmental determinants of mitochondrial DNA copy number (mtDNA-CN), a biomarker for mitochondrial dysfunction, and the association of mtDNA-CN with a health outcome. Low levels of mitochondrial DNA copy number (mtDNA-CN) are a biomarker of mitochondrial dysfunction often induced by oxidative stress. We sought to examine whether environmental factors are associated with mtDNA-CN using the UK Biobank Study. We also evaluated the association of mtDNA-CN with incident heart failure (HF) using the Atherosclerosis Risk in Communities (ARIC) Study. First, we evaluated the association between long-term exposure to air pollutants (PM ≤ 10 µm diameter [PM10], nitrogen dioxide [NO2]) and mtDNA-CN in the UK Biobank. An increase of 10 µg/m3 in annual average PM10 and NO2 exposure was associated with an adjusted difference in mtDNA-CN of -0.089 (95% confidence interval [CI]; -0.090, -0.087) and -0.018 (-0.018, -0.017), respectively. The associations persisted for lags of up to 3 years. Second, we evaluated the seasonal trends of mtDNA-CN and the association between short-term exposure to ambient temperature and mtDNA-CN. mtDNA-CN, on average, was lower in the warmer months and higher in the colder months. The average difference in mtDNA-CN by 10°C increase in daily maximum temperature (Tmax) was -0.07 (95% CI -0.08, -0.06) and the results were similar across different temperature metrics. The inverse association between ambient temperature and mtDNA-CN persisted over 7 days with the strongest association at lag 0. This association was most explained by metabolites involved in glucose and lipid metabolism, including pyruvate, lactate, and ketone bodies. Third, we examined the association between mtDNA-CN and the risk of incident HF from the ARIC study. We found that the hazard ratios (95% CI) for HF comparing the 2nd through 5th quintiles of mtDNA-CN to the 1st quintile were 0.91 (0.80–1.04), 0.82 (0.72–0.93), 0.81 (0.71–0.92), and 0.74 (0.65–0.85), respectively (P for trend < 0.001). These findings suggest that mitochondria and mitochondrial DNA are common targets of environmental stressors, as reflected by low mtDNA-CN, and mitochondrial dysfunction may explain the potential mechanism of various adverse health effects associated with environmental exposures