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Kabra, U.D. ; Pfuhlmann, K. ; Migliorini, A. ; Keipert, S. ; Lamp, D. ; Korsgren, O.* ; Gegg, M. ; Woods, S.C.* ; Pfluger, P.T. ; Lickert, H. ; Affourtit, C.* ; Tschöp, M.H. ; Jastroch, M.

Direct substrate delivery into mitochondrial-fission deficient pancreatic islets rescues insulin secretion.

Diabetes 66, 1247-1257 (2017)
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In pancreatic beta cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion (GSIS). Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1, we here demonstrate that mitochondrial fission is necessary for GSIS in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fuelled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient beta cells, demonstrating that defective mitochondrial dynamics solely impact substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights in how mitochondrial dysfunction may cause pancreatic beta cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Dynamin-related Protein-1; Beta-cell Apoptosis; Drp1; Division; Gtpase; Dysfunction; Protects; Disease; Stress; Fusion
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Journal Diabetes
Quellenangaben Volume: 66, Issue: 5, Pages: 1247-1257 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, VA.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Institute of Diabetes and Regeneration Research (IDR)