title: Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy.
abstract: Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells [SCs]) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response (ISR) through the actions of heme-regulated inhibitor (HRI) kinase, and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines (ACs), an intermediate of fatty acid β-oxidation. Importantly, we show that ACs are released from SCs and induce axonal degeneration. A maladaptive ISR as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies.
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Andreu
authors.initials: A
authors.lastname: Viader
authors.forename: Yo
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Sungsu
authors.initials: S
authors.lastname: Kim
authors.forename: Amy
authors.initials: A
authors.lastname: Strickland
authors.forename: Cayce S
authors.initials: CS
authors.lastname: Workman
authors.forename: Kui
authors.initials: K
authors.lastname: Yang
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
mesh_terms: D000814:Aniline Compounds; D000818:Animals; D001369:Axons / Q000473:pathology*; D015153:Blotting, Western; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D005456:Fluorescent Dyes; D005727:Ganglia, Spinal / Q000166:cytology; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046228:Microarray Analysis; D017237:Mitochondrial Encephalomyopathies / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D010523:Peripheral Nervous System Diseases / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D012583:Schwann Cells / Q000378:metabolism*; D014966:Xanthenes
chemical_list: D000814:Aniline Compounds; D005227:Fatty Acids; C409648:Fluo 4; D005456:Fluorescent Dyes; D014966:Xanthenes; C116917:acylcarnitine; D017346:Protein Serine-Threonine Kinases; C531557:eIF2alpha kinase, mouse; D002331:Carnitine