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.

Schwann Cell O-GlcNAc Glycosylation Is Required for Myelin Maintenance and Axon Integrity

“…1D), reflecting the successful and specific excision of OGT in SCs. Although OGT is reported to be critical for cell viability and proliferation in many tissues and cell types (Shafi et al, 2000;O'Donnell et al, 2004), we observed no death or altered proliferation in SCs lacking OGT (data not shown).…”

“…All animal experiments were performed in compliance with institutional animal protocols. OGT-SCKO mice (P 0 -Cre Ϫ/ϩ , OGT loxP/loxP ) and control (Ctrl) littermates (P 0 -Cre Ϫ/Ϫ , OGT loxP/loxP ) were generated by crossing OGT loxP/loxP mice (O'Donnell et al, 2004) to P 0 -Cre mice (Feltri et al, 1999). In all experiments, mice of either sex were used.…”

“…Despite the identification of many genetic and environmental causes of PN, the mechanisms by which SCs promote axon integrity remain elusive. Recently, we and others showed that perturbations of SC metabolism in mice, such as those caused by mitochondrial dysfunction or loss of crucial energy sensors, lead to axonal loss and peripheral neuropathy (Nave, 2010;Viader et al, 2011Viader et al, , 2013Fü nfschilling et al, 2012;Beirowski et al, 2014;Norrmén et al, 2014;Pooya et al, 2014;Shen et al, 2014). These observations indicate that SC metabolism plays a crucial role in the ability of these glial cells to promote axon health and implicate them in the development of neuropathies of metabolic etiology, such as diabetic peripheral neuropathy.…”

“…Metabolic interactions between axons and SCs are thought to involve Cajal bands, the SC cytoplasm-filled channels present along myelinated fibers (Nave, 2010). Periaxin (PRX), an abundantly expressed SC protein, mediates the formation of Cajal bands via promoting the abaxonal apposition of compact myelin and SC plasma membrane.…”

Odanacatib Inhibits Resistin-induced Hypertrophic H9c2 Cardiomyoblast Cells Through LKB1/AMPK Pathway

“…LKB1 is a serine/threonine protein kinase that is expressed in almost all human tissues. LKB1 is a tumor suppressor gene closely related to the occurrence of many kinds of tumors 23 . The activation of LKB1 requires the binding of MO25 and STRAD to the complex 24 .…”