title: Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc transferase.
abstract: Cells allocate substantial resources toward monitoring levels of nutrients that can be used for ATP generation by mitochondria. Among the many specialized cell types, neurons are particularly dependent on mitochondria due to their complex morphology and regional energy needs. Here, we report a molecular mechanism by which nutrient availability in the form of extracellular glucose and the enzyme O-GlcNAc Transferase (OGT), whose activity depends on glucose availability, regulates mitochondrial motility in neurons. Activation of OGT diminishes mitochondrial motility. We establish the mitochondrial motor-adaptor protein Milton as a required substrate for OGT to arrest mitochondrial motility by mapping and mutating the key O-GlcNAcylated serine residues. We find that the GlcNAcylation state of Milton is altered by extracellular glucose and that OGT alters mitochondrial motility in vivo. Our findings suggest that, by dynamically regulating Milton GlcNAcylation, OGT tailors mitochondrial dynamics in neurons based on nutrient availability.
authors.affiliation: The F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gulcin
authors.initials: G
authors.lastname: Pekkurnaz
authors.affiliation: Department of Chemistry, Biological Mass Spectrometry Facility, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trinidad
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94304, USA.
authors.forename: Xinnan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Kong
authors.affiliation: The F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: thomas.schwarz@childrens.harvard.edu.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Schwarz
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism; D002352:Carrier Proteins; D004331:Drosophila melanogaster; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016415:Sequence Alignment
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; C531552:TRAK1 protein, human; C509169:Trak1 protein, mouse; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D005947:Glucose