Direct Substrate Delivery Into Mitochondrial Fission-Deficient Pancreatic Islets Rescues Insulin Secretion.
In pancreatic β-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission proteinDrp1, we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing ofDrp1increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals thatDrp1does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fueled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient β-cells, demonstrating that defective mitochondrial dynamics solely affect substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights into how mitochondrial dysfunction may cause pancreatic β-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.
Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
Uma D
UD
Kabra
Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
Katrin
K
Pfuhlmann
Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.
Adriana
A
Migliorini
Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.
Susanne
S
Keipert
Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
Daniel
D
Lamp
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Olle
O
Korsgren
Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
Moritz
M
Gegg
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH.
Stephen C
SC
Woods
Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.
Paul T
PT
Pfluger
Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
Heiko
H
Lickert
School of Biomedical and Healthcare Sciences, Plymouth University, Plymouth, U.K.
Charles
C
Affourtit
Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
Matthias H
MH
Tschöp
Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany martin.jastroch@helmholtz-muenchen.de.|German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.
Martin
M
Jastroch
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D034281:Dynamins / Q000037:antagonists & inhibitors; D004734:Energy Metabolism / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D019289:Pyruvic Acid / Q000494:pharmacology
D007328:Insulin; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; C486391:Dnm1l protein, mouse; D034281:Dynamins; D005947:Glucose