title: Muscle choline kinase beta defect causes mitochondrial dysfunction and increased mitophagy.
abstract: Choline kinase is the first step enzyme for phosphatidylcholine (PC) de novo biosynthesis. Loss of choline kinase activity in muscle causes rostrocaudal muscular dystrophy (rmd) in mouse and congenital muscular dystrophy in human, characterized by distinct mitochondrial morphological abnormalities. We performed biochemical and pathological analyses on skeletal muscle mitochondria from rmd mice. No mitochondria were found in the center of muscle fibers, while those located at the periphery of the fibers were significantly enlarged. Muscle mitochondria in rmd mice exhibited significantly decreased PC levels, impaired respiratory chain enzyme activities, decreased mitochondrial ATP synthesis, decreased coenzyme Q and increased superoxide production. Electron microscopy showed the selective autophagic elimination of mitochondria in rmd muscle. Molecular markers of mitophagy, including Parkin, PINK1, LC3, polyubiquitin and p62, were localized to mitochondria of rmd muscle. Quantitative analysis shows that the number of mitochondria in muscle fibers and mitochondrial DNA copy number were decreased. We demonstrated that the genetic defect in choline kinase in muscle results in mitochondrial dysfunction and subsequent mitochondrial loss through enhanced activation of mitophagy. These findings provide a first evidence for a pathomechanistic link between de novo PC biosynthesis and mitochondrial abnormality.
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Mitsuhashi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Minako
authors.initials: M
authors.lastname: Karahashi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Koumura
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.forename: Roger B
authors.initials: RB
authors.lastname: Sher
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002797:Choline Kinase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism; D009136:Muscular Dystrophies / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; D002797:Choline Kinase