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Lookup NU author(s): Dr Audrey Brown, Meutia Kumaheri, Dr Helen Porteous, Dr Alison Heggie, Dr Satomi Miwa, Dr Lynsey Cree, Dr Brendan PayneORCiD, Professor Patrick Chinnery, David Gunn, Professor Mark Walker
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
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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