Milton1 coordinates mitochondrial motility, form, and function with nutrient status in β cells
Dane M. Wolf,1,3 Kyle M. Trudeau,1 Mayuko Segawa,3 Amanda Hanson,1 Ilan Y. Benador,1,3 Shili Xu,3 Gilad Twig,1 Gulcin Pekkurnaz,2,4 Thomas L. Schwarz,2 Marc Liesa,3 and Orian S. Shirihai1,3*
1Department of Medicine, Obesity and Nutrition Section, Evans Biomedical Research Center, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118, USA; 2The F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; 3Department of Medicine, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, CA 90095, USA; 4Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
*Corresponding author: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Room 33-131, Los Angeles, California 90095, USA. Tel: +1-617-230-8570; Fax: +1-617-638-7124; e-mail: OShirihai@mednet.ucla.edu.
Mitochondrial fission and fragmentation are required for β-cell response to nutrient stimuli and proper insulin secretion. The component of mitochondrial dynamics that senses nutrient exposure has not been identified. The interrelatedness of mitochondrial dynamics and motility suggested the possibility that the mitochondrial motor complex may serve as a relay mechanism between nutrient exposure and changes to mitochondrial architecture. We found that, simultaneous to the induction of fragmentation in response to physiological glucose stimulation, β-cell mitochondria decrease motility. O-GlcNAcylation of Milton1, a mitochondrial motor-complex adaptor protein, reversed a mitochondrial clustering phenotype induced by overexpression of Milton1. Remarkably, glucose-induced mitochondrial fragmentation via dephosphorylation of fission protein, Drp1, was also dependent on Milton1 O-GlcNAcylation. Finally, we show that Milton1 O-GlcNAcylation is required for glucose-stimulated respiration and insulin secretion. Overall, our results indicate that mitochondrial motility regulates the β-cell response to physiological nutrient stimulation and that Milton1 O-GlcNAcylation serves as a relay between nutrient exposure and changes in mitochondrial architecture.
Funding: NIH and NIDDK