Research Article: Circulating mitochondrial DNA: New indices of type 2 diabetes-related cognitive impairment in Mexican Americans

Date Published: March 12, 2019

Publisher: Public Library of Science

Author(s): Talisa Silzer, Robert Barber, Jie Sun, Gita Pathak, Leigh Johnson, Sid O’Bryant, Nicole Phillips, Ornit Chiba-Falek.


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 (mtDNACN) 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 mtDNACN 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. MtDNACN 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 mtDNACN. 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 mtDNACN) is intimately linked to both T2D and CI phenotypes as well as aging.

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The difference in effect observed for these mitochondrial indices when comparing T2D and CI may be due to their dissimilar risks, as T2D is often regarded as a disease of lifestyle and AD has a larger presumed genetic component. Fig 10 provides a hypothetical schematic which summarizes the findings from this study. The data provided here indicate that CFmtDNA and mtDNACN are likely indicative of two different mitochondrially-sourced pathogeneses, both ultimately resulting in cognitive impairment. CFmtDNA appears to be a T2D-centric phenotype, which is exacerbated with advancing age, as seen in individuals with both T2D and CI. We posit that systemic, metabolic challenges in the confluence of diabetes and age result in T2D-related cognitive decline, and the release of mtDNA into the extracellular space may be indicative of this progression. On the other hand, mtDNACN effects are more pronounced in individuals who are aged and have CI in the absence of T2D. This perhaps indicates that unknown genetic and/or lifestyle-based risk factors for advancing age or altered mitochondrial dynamics (i.e., variants in LRRK2/MUC19?) may contribute to decreased cognitive function, as indicated by depressed mtDNACN. However, it should be noted that diabetes medications such as Metformin are known to target mitochondrial function; these effects were not accounted for here and may be a confounding factor in interpretation of this study. Follow-up studies to evaluate the impact of altered mitochondrial indices (i.e., CFmtDNA and mtDNACN) on biological function will help to paint a more complete picture of the role mitochondria and mitochondrial function are playing in the pathophysiology of these two age-related diseases.




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