Mitochondrial DNA copy number and diabetes: the Atherosclerosis Risk in Communities (ARIC) study

Abstract

IntroductionMitochondrial DNA copy number (mtDNA-CN) is a measure of mitochondrial dysfunction and is associated with diabetes in experimental models. To explore the temporality of mitochondrial dysfunction and diabetes, we estimated the prevalent and incident association of mtDNA-CN and diabetes.Research design and methodsWe assessed the associations of mtDNA-CN measured from buffy coat with prevalent and incident diabetes, stratified by race, in 8954 white and 2444 black participants in the Atherosclerosis Risk in Communities (ARIC) study, an observational cohort study. Follow-up for incident analyses was complete through visit 6, 2016.ResultsMean age at mtDNA-CN measurement was 57 years and 59% were female. Prevalence of diabetes at time of mtDNA-CN measurement was higher in blacks (563/2444, 23%) than whites (855/8954, 10%). The fully adjusted odds of prevalent diabetes for the 10th vs 90th percentile of mtDNA-CN was 1.05 (95% CI 0.74 to 1.49) among black and 1.49 (95% CI 1.20 to 1.85) among white participants. Over a median follow-up time of 19 years (Q1, Q3: 11, 24 years), we observed 617 incident diabetes cases among 1744 black and 2121 cases among 7713 white participants free of diabetes at baseline. The fully adjusted hazard of incident diabetes for the 10th vs 90th percentile of mtDNA-CN was 1.07 (95% CI 0.84 to 1.38) among black and 0.97 (95% CI 0.86 to 1.10) among white participants.ConclusionsLower mtDNA-CN in buffy coat was associated with prevalent diabetes in white but not black ARIC participants. Lower mtDNA-CN was not associated with incident diabetes over 20 years of follow-up in whites or blacks.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

“…This finding is consistent with a large body of work showing that mtDNA-CN measured in blood is associated with numerous aging-related phenotypes for which the primary tissue of interest is not blood (e.g. chronic kidney disease (Tin et al 2016 ), heart failure (Hong et al 2020 ), and diabetes (DeBarmore et al 2020 )). Also consistent with this finding is recent work demonstrating that mtDNA-CN measured in blood is associated with mtRNA expression across numerous non-blood tissues, suggesting a link between mitochondrial activity measured in blood and other tissues (Yang et al 2021 ).…”

Genetic analysis of mitochondrial DNA copy number and associated traits identifies loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation, and reveals a causal association of mitochondrial function with mortality

“…Cluster 4 is most strongly enriched for SNPs in which the mtDNA-CN increasing allele is associated with increased PLT, plateletcrit (PLTCRIT, a measure of total platelet mass), serum calcium (Figure 4E), serum phosphate, as well as decreased mean corpuscular volume (MCV) and mean spherical cellular volume (Figure 4F) (Supplemental Table 12). The cluster 4 phenotypes, and supported by the genes identified for this cluster, implicate megakaryocyte proliferation and proplatelet formation ( MYB, AK3, JAK2 ) 63 , and apoptosis and autophagy ( BAK1, BCL2, TYMP ) 64 . Cluster 5 did not yield any specific trait enrichment (all significant results reflected the strong enrichment observed in clusters 1-4); however, gene set enrichment for this cluster identified multiple mtDNA-related gene ontology terms, including mitochondrial genome maintenance, regulation of phospholipid efflux, and amyloid-beta clearance (Supplemental Table 13).…”

“…Cluster 4 is most strongly enriched for SNPs in which the mtDNA-CN increasing allele is associated with increased PLT/PLTCRIT and serum calcium/phosphate. Examining the genes assigned to the cluster, we implicate megakaryocyte proliferation and proplatelet formation ( MYB, AK3, JAK2 ) 63 , and apoptosis and autophagy ( BAK1, BCL2, TYMP ) 64 . Megakaryocytes are used to form proplatelets, and the process includes an important role for both intra- and extracellular calcium levels 91 .…”

Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise studies

“…Associations between mtDNA-CN and metabolic syndrome have been previously reported, supporting this finding [ 19 ]. As individuals with prevalent diabetes are known to have lower mtDNA-CN [ 20 ] and type 2 diabetes is a disease primarily characterized by decreased insulin sensitivity [ 21 ], we re-examined this association after adjusting insulin sensitivity for diabetes status. The association between mtDNA-CN and insulin sensitivity remained, even after accounting for diabetes status (P = 0.007).…”