Interplay between Mitochondrial DNA Haplogroups, Mitochondrial Function, Oxidative Stress, and Hypertension

National Institute On Aging

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Abstract

Thus far, there are few studies that examine the contribution of mtDNA haplogroup to differences in risk factors for age-related health disparities such as in hypertension. The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study examines the interaction of race and socioeconomic status on the development of age-associated health disparities among middle-aged AAs and whites residing in Baltimore City. It is possible that population differences in haplogroups could contribute to disparities in mitochondrial function and oxidative stress, and thus contribute to hypertension health disparities. Our interest in cellular mtDNA which can be released outside of the cell as circulating cell-free mtDNA (ccf-mtDNA) and act as a damage associated molecular pattern (DAMP) molecule leading to activation of the innate immune response following cellular damage or stress has led us to examine and its potential role in age-related health disparities. Ccf-mtDNA has been reported to be present in extracellular vesicles (EVs). EVs are small (30–400 nm), lipid-bound vesicles, which are secreted by cells into many bodily fluids EVs contain proteins, lipids, and nucleic acids that can be delivered to target cells, as part of intercellular communication systems. Although we found no significant differences in EV mtDNA levels with mortality status, we did find that EV mtDNA levels were significantly higher in frail individuals. This led us to examine whether plasma ccf-mtDNA and EV mtDNA levels differed by race, sex and hypertension, an age-associated disease with health disparities. EV concentration was significantly higher in White participants compared with African American participants but there were no significant differences in EV concentration with hypertension. We next examined mtDNA from whole plasma and in EVs. Both plasma and EV mtDNA levels were significantly higher in African American participants compared with White participants. Due to the association of race, a social construct, with levels of plasma and EV mtDNA, we examined how ancestry affected this relationship. Sequentially accumulated single nucleotide polymorphisms (SNPs) define mtDNA haplogroups as a set of shared SNPs in a population. mtDNA haplogroups have been associated with differences in mitochondrial function, differing levels of mtDNA damage, oxidative phosphorylation efficiency, and ROS production and selected diseases. We also examined the association between haplogroup and hypertension. Therefore, we haplotyped cohort participants and categorized the resulting haplogroups by ancestry into African, European, and Other. There was concordance between self-identified race and mtDNA haplogroup for most participants; 72% of the African American participants, 79% of White participants, or 75% of all participants. We found that there was no association between mtDNA haplogroup and hypertension status in the cohort. However, this result may be inconclusive because of the limited cohort size. There was a significant interaction between race and mtDNA haplogroup for EV mtDNA levels. EV mtDNA levels were significantly higher in participants who self-identified as African American with the African haplogroup compared with participants who self-identified as White with the African haplogroup, as well as participants who self-identified as African American with the European haplogroup. These results indicate that race and ancestry are associated with EV mtDNA levels. However, for plasma mtDNA levels, there were no significant interactions between race and mtDNA haplogroup, suggesting that the different pools of ccf-mtDNA may represent different mechanisms of sorting. We then assessed the relationship between EV mtDNA, race, hypertension status, and mtDNA haplogroup and several circulating inflammatory proteins: interferon gamma (IFN-), IL-6, tumor necrosis factor alpha (TNF-) trimer, E-selectin, MCP-1, sRAGE, SAA, P-selectin, and fibrinogen. These proteins were chosen based on their previous association with the social determinants of health (SDOH), age, or mortality. Two inflammatory proteins, MCP-1 and P-selectin, were significantly associated with race. Overall, MCP-1 and P-selectin serum levels were higher in White participants than African American participants. However, we found that TNF- trimer, SAA, sRAGE, and E-selectin levels were associated with mtDNA haplogroup, race, and EV mtDNA. We report higher EV mtDNA levels in African Americans with African ancestry compared with European ancestry. It may seem surprising that individuals who identify as African American can have either the African or European haplogroup. However, race is a social construct, whereas mtDNA haplogroup reflects genetic ancestry. Maternally inherited mtDNA haplogroups are influenced by population migration. Over time this results in a haplogroup of one ethnicity dispersed among another ethnic group that may yield discordance between race and ancestry. In fact, several other studies examining mtDNA haplogroups and race have also reported discordance of race and ancestry. Our study was an initial step into important investigations of the role of ccf-mtDNA as DAMPs that may contribute to the weathering associated with health disparities among populations at risk. This work begins to examine the role of ancestry, not just the social construct of race, as risk factors for the development of age-related chronic disease. Our findings highlight that race and ancestry may be crucial factors when examining health and biomarker differences between groups. These findings contribute to the extant literature on the interplay between race, mtDNA haplogroup, and circulating factors, including EVs and their cargo and inflammatory markers. In further work this year in a longitudinal study, we examined plasma EVs from African American and White obese adults who developed CKD compared with a matched control group. This study is unique as it yielded both cross‐sectional and longitudinal results. In our cross‐sectional analysis at visit 1, we found that EV mtDNA levels were associated with future CKD status through separate interactions with race, poverty and sex. Thus, EV mtDNA levels are influenced differentially by future CKD status across sex, poverty and race in this cohort of obese adults. We also observed cross‐sectional differences in EV mtDNA levels with future CKD status and mtDNA haplogroup. In our longitudinal analysis, EV mtDNA levels were lower in participants who developed CKD only for those in the African haplogroup. Furthermore, EV mtDNA levels were associated with age and sex in the African and European mtDNA haplogroups, respectively. Future advances in understanding the drivers of health disparities may need to consider these and other complex factors to understand the biological mechanisms through which the SDOH lead to disparate health outcomes.