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

Lookup NU author(s): Dr Audrey Brown, Meutia Kumaheri, Dr Helen Blair, Dr Alison Heggie, Dr Satomi Miwa, Dr Lynsey Cree, Dr Brendan Payne, Professor Patrick Chinnery, David Gunn, Professor Mark Walker

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 mtDNAdepletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.


Publication metadata

Author(s): Nile DL, Brown AE, Kumaheri MA, Blair HR, Heggie A, Miwa S, Cree LM, Payne B, Chinnery PF, Brown L, Gunn DA, Walker M

Publication type: Article

Publication status: Published

Journal: PLoS One

Year: 2014

Volume: 9

Issue: 12

Online publication date: 22/12/2014

Acceptance date: 24/11/2014

Date deposited: 10/04/2015

ISSN (electronic): 1932-6203

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pone.0115433

DOI: 10.1371/journal.pone.0115433


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