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

Abstract

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.

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

“…In this context, circulating mtDNA is increasingly acknowledged as a pivotal mediator linking mitochondrial dysfunction to inflammation [30,34,35]. Of all mitochondrial components, mtDNA is the most susceptible to be sensed as a "non-self" molecule due to the presence within its structure of aberrant/devoid CpG methylation motifs that can trigger inflammation [34][35][36][37][38][39][40]. Fragmented mtDNA as well as circular double-stranded or linear single-stranded mtDNA molecules and nucleoids have been found in the human plasma in various disease conditions [37,38,[41][42][43].…”

“…Via these structures, mtDNA nucleoids (i.e., mtDNA complexed with the mitochondrial transcription factor A) can be displaced into the cytosol [ 37 , 38 , 65 ]. Altered mitochondrial dynamics have also been associated with mtDNA-driven inflammation [ 34 , 35 , 36 , 39 , 40 ]. In particular, preclinical models of optic atrophy 1 ablation and dynamin related protein 1 (Drp1) overexpression show hyper-fragmented mitochondria and giant mtDNA nucleoids outside of mitochondria that are able to trigger an immune response [ 66 ].…”

A case for measuring both cellular and cell‐free mitochondrial DNA as a disease biomarker in human blood

“…This result supports the importance of measuring both cellular and cell-free mtDNA-if only cellular content had been measured the alteration in the cf levels would have been missed. Several studies have quantified circulating mtDNA in diabetic patients to evaluate its potential as a biomarker, particularly in the development of various complications associated with diabetes 13,26,55,56 and higher levels of mtDNA have been previously reported in plasma of patients with diabetes compared to healthy controls. 13,56 Similarly to our findings, Silzer et al 55 reported differing trends in cellular and cf mtDNA in their study of type 2 diabetes and cognitive dysfunction; plasma mtDNA content increased only in T2D patients with cognitive impairment, while the buffy coat mtDNA content was altered with cognitive impairment regardless of diabetes status.…”

Mitochondrial Functions, Cognition, and the Evolution of Intelligence: Reply to Commentaries and Moving Forward

“…There are several preliminary studies that suggest this might be a useful approach ( Mengel-From et al 2014 ; Silzer et al 2019 ), with the caution that the relation between mtDNA copy number measured in peripheral cells (e.g., white blood cells) in many of these studies and mtDNA copy number in brain cells is not well understood. In the larger of these studies ( N = 1067), Mengel-From et al found steady mtDNA copy numbers through age 48 years in healthy individuals and age-related declines thereafter.…”

“…For older individuals, higher mtDNA copy numbers were associated with better physical health and higher cognitive performance; “higher mtDNA copy number was consistently associated with higher cognitive composite score and MMSE [Mini Mental State Examination]” ( Mengel-From et al 2014, p. 1152 ). In a sample of older women, J. W. Lee et al ( 2010 ) found that higher mtDNA copy number was associated with higher MMSE scores ( r = 0.33), controlling age and years of education, and Silzer et al ( 2019 ) found that higher copy number was associated with better list learning and memory scores in older adults ( r = 0.46).…”