Age-Related Mitochondrial DNA Depletion and the Impact on Pancreatic Beta Cell Function

Abstract

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.

Reduced peripheral blood mtDNA content is associated with impaired glucose‐stimulated islet β cell function in a Chinese population with different degrees of glucose tolerance

“…In addition, β cell mitochondria with decreased mtDNA content synthesize less ATP upon glucose stimulation. This results in K-ATP channel closing and decreased postprandial insulin release, which leads to hyperglycaemia [10,21]. In the present study, we demonstrated a positive relationship between mtDNA content and glucose-stimulated insulin secretion.…”

“…Accumulating evidence suggests that mtDNA content is associated with T2DM [4,5,9,10]. Previous studies focused on the relationship between peripheral blood mtDNA content and FPG [5,16].…”

When two obese parents are worse than one! Impacts on embryo and fetal development

“…Similar to what we found in a genetic mouse model of female obesity (88), we found that mtDNA copy number was reduced in fetal livers of female and male offspring from maternal HFD exposure, with levels not being further reduced by the addition of paternal obesity. In a number of tissues mtDNA copy is tightly associated with different types of cancer (49,57,58), cellular telomere length (82), and tissue-specific processes (15); therefore, disruption of mtDNA copy number is linked with a number of diseases and mortality (2,65). As offspring from female rodents fed high-calorie diets (before conception through to lactation) are smaller and have metabolic syndrome, similar to phenotypes reported in offspring generated in our study and others (35,52), reductions in mtDNA content in fetal tissues perhaps could be one of the mechanisms for a later predisposition to chronic disease.…”

Circulating cell-free mitochondrial DNA as the probable inducer of early endothelial dysfunction in the prediabetic patient

“…For example, the increase in mtDNA levels has been associated with the proinflammatory state (Pinti et al, 2014;Olivieri et al, 2013), and with changes in the endothelial permeability and liberation of mtDNA (Sun et al, 2013). Besides, the age-related mtDNA depletion could be a marker of aging, but is also a risk factor for the development of type 2 diabetes (Nile et al, 2014). On the other hand, the increase in mtDNA levels has been considered a biomarker of the inflammatory state (Wang et al, 2015) but, in contrast, also as a protection factor in patients or in models of acute myocardial infarction (Muravyeva et al, 2014).…”