title: The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism.
abstract: A prerequisite to myelination of peripheral axons by Schwann cells (SCs) is SC differentiation, and recent evidence indicates that reprogramming from a glycolytic to oxidative metabolism occurs during cellular differentiation. Whether this reprogramming is essential for SC differentiation, and the genes that regulate this critical metabolic transition are unknown. Here we show that the tumour suppressor Lkb1 is essential for this metabolic transition and myelination of peripheral axons. Hypomyelination in the Lkb1-mutant nerves and muscle atrophy lead to hindlimb dysfunction and peripheral neuropathy. Lkb1-null SCs failed to optimally activate mitochondrial oxidative metabolism during differentiation. This deficit was caused by Lkb1-regulated diminished production of the mitochondrial Krebs cycle substrate citrate, a precursor to cellular lipids. Consequently, myelin lipids were reduced in Lkb1-mutant mice. Restoring citrate partially rescued Lkb1-mutant SC defects. Thus, Lkb1-mediated metabolic shift during SC differentiation increases mitochondrial metabolism and lipogenesis, necessary for normal myelination.
authors.affiliation: Department of Oncology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Pooya
authors.affiliation: Department of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Oncology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: V B Sameer
authors.initials: VB
authors.lastname: Kumar
authors.affiliation: Department of Oncology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Department of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Fumiyasu
authors.initials: F
authors.lastname: Imai
authors.affiliation: Department of Pathology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Georgianne
authors.initials: G
authors.lastname: Ciraolo
authors.affiliation: Department of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
authors.affiliation: Department of Pathology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Yoshida
authors.initials: Y
authors.lastname: Yutaka
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Jankowski
authors.affiliation: Department of Oncology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Biplab
authors.initials: B
authors.lastname: Dasgupta
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D002454:Cell Differentiation; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases