TY - JOUR
T1 - Circulating mitochondrial DNA
T2 - New indices of type 2 diabetes-related cognitive impairment in Mexican Americans
AU - Silzer, Talisa
AU - Barber, Robert
AU - Sun, Jie
AU - Pathak, Gita
AU - Johnson, Leigh
AU - O’Bryant, Sid
AU - Phillips, Nicole
N1 - Funding Information:
This study was supported by Institute for Aging and Alzheimer’s Disease Research Seed Grant 2015-RI6137, to RB and NP; and the National Institute on Aging of the National Institutes of Health under award number R01AG054073, to SO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Research reported here was supported by the Institute for Aging and Alzheimer’s Disease Research Seed Grant 2015-RI6137 and National Institute on Aging of the National Institutes of Health under Award Number R01AG054073. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The research team also thanks the local Fort Worth community, participants of the Health & Aging Brain Study and Dr. Frank Wendt for his assistance in sample genotyping.
Publisher Copyright:
© 2019 Silzer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019/3
Y1 - 2019/3
N2 - Mitochondrial function has been implicated and studied in numerous complex age-related diseases. Understanding the potential role of mitochondria in disease pathophysiology is of importance due to the rise in prevalence of complex age-related diseases, such as type 2 diabetes (T2D) and Alzheimer’s disease (AD). These two diseases specifically share common pathophysiological characteristics which potentially point to a common root cause or factors for disease exacerbation. Studying the shared phenomena in Mexican Americans is of particular importance due to the disproportionate prevalence of both T2D and AD in this population. Here, we assessed the potential role of mitochondria in T2D and cognitive impairment (CI) in a Mexican American cohort by analyzing blood-based indices of mitochondrial DNA copy number (mtDNA CN ) and cell-free mitochondrial DNA (CFmtDNA). These mitochondrial metrics were also analyzed for correlation with relevant neuropsychological variables and physiological data collected as indicators of disease and/or disease progression. We found mtDNA CN to be significantly decreased in individuals with CI, while CFmtDNA was significantly elevated in T2D; further, CFmtDNA elevation was significantly exacerbated in individuals with both diseases. MtDNA CN was found to negatively correlate with age and fatty acid binding protein concentration, while positively correlating with CFmtDNA as well as CERAD total recall score. Candidate gene SNP-set analysis was performed on genes previously implicated in maintenance and control of mitochondrial dynamics to determine if nuclear variants may account for variability in mtDNA CN . The results point to a single significant locus, in the LRRK2/MUC19 region, encoding leucine rich repeat kinase 2 and mucin 19. This locus has been previously implicated in Parkinson’s disease, among others; rs7302859 was the driver SNP. These combined findings further indicate that mitochondrial dysfunction (as assessed by proxy via mtDNA CN ) is intimately linked to both T2D and CI phenotypes as well as aging.
AB - Mitochondrial function has been implicated and studied in numerous complex age-related diseases. Understanding the potential role of mitochondria in disease pathophysiology is of importance due to the rise in prevalence of complex age-related diseases, such as type 2 diabetes (T2D) and Alzheimer’s disease (AD). These two diseases specifically share common pathophysiological characteristics which potentially point to a common root cause or factors for disease exacerbation. Studying the shared phenomena in Mexican Americans is of particular importance due to the disproportionate prevalence of both T2D and AD in this population. Here, we assessed the potential role of mitochondria in T2D and cognitive impairment (CI) in a Mexican American cohort by analyzing blood-based indices of mitochondrial DNA copy number (mtDNA CN ) and cell-free mitochondrial DNA (CFmtDNA). These mitochondrial metrics were also analyzed for correlation with relevant neuropsychological variables and physiological data collected as indicators of disease and/or disease progression. We found mtDNA CN to be significantly decreased in individuals with CI, while CFmtDNA was significantly elevated in T2D; further, CFmtDNA elevation was significantly exacerbated in individuals with both diseases. MtDNA CN was found to negatively correlate with age and fatty acid binding protein concentration, while positively correlating with CFmtDNA as well as CERAD total recall score. Candidate gene SNP-set analysis was performed on genes previously implicated in maintenance and control of mitochondrial dynamics to determine if nuclear variants may account for variability in mtDNA CN . The results point to a single significant locus, in the LRRK2/MUC19 region, encoding leucine rich repeat kinase 2 and mucin 19. This locus has been previously implicated in Parkinson’s disease, among others; rs7302859 was the driver SNP. These combined findings further indicate that mitochondrial dysfunction (as assessed by proxy via mtDNA CN ) is intimately linked to both T2D and CI phenotypes as well as aging.
UR - http://www.scopus.com/inward/record.url?scp=85062845230&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0213527
DO - 10.1371/journal.pone.0213527
M3 - Article
C2 - 30861027
AN - SCOPUS:85062845230
SN - 1932-6203
VL - 14
JO - PLoS ONE
JF - PLoS ONE
IS - 3
M1 - e0213527
ER -