title: Increased muscle coenzyme Q10 in riboflavin responsive MADD with ETFDH gene mutations due to secondary mitochondrial proliferation.
abstract: Multiple acyl-coenzyme A dehydrogenation deficiency (MADD) has a wide range of phenotypic variation ranging from a neonatal lethal form to a mild late-onset form. Our previous data showed that in a group of Chinese patients, a mild type of MADD characterized by myopathy with clinically no other systemic involvement was caused by mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene, which encodes electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO). Coenzyme Q10 (CoQ10), a downstream electron receptor of ETF:QO was first reported deficient in muscle of MADD patients with ETFDH gene mutations. Nevertheless, this result was not confirmed in a recently published study. Therefore to elucidate muscle CoQ10 level in a large group of MADD patients may provide further insight into the pathomechanism and therapeutic strategies. In this study, we found that 34 riboflavin responsive patients with ETFDH gene mutations had an elevated CoQ10 pool in muscle by high performance liquid chromatography (HPLC). However, when CoQ10 levels were normalized to citrate synthase, a marker of mitochondrial mass, there was no significant difference between patients and normal controls. Meanwhile, the increased mitochondrial DNA copy number in muscle also supported that the elevated CoQ10 pool was mainly due to mitochondrial mass proliferation. The expression of CoQ10 biosynthesis genes showed no significant changes whereas genes involved in lipid metabolism, such as PPARα, were marked up regulated. Our results suggested that CoQ10 seems not to be a primary factor in riboflavin responsive MADD and the apparent increase in CoQ10 may be secondary to mitochondrial proliferation.
authors.affiliation: Laboratory of Neuromuscular Disorders, Brain Science Research Institute and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wen
authors.forename: Duoling
authors.initials: D
authors.lastname: Li
authors.forename: Jingli
authors.initials: J
authors.lastname: Shan
authors.forename: Shuping
authors.initials: S
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yuying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Pengfei
authors.initials: P
authors.lastname: Lin
authors.forename: Jinfan
authors.initials: J
authors.lastname: Zheng
authors.forename: Danian
authors.initials: D
authors.lastname: Li
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.forename: Chuanzhu
authors.initials: C
authors.lastname: Yan
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics; D044927:Electron-Transferring Flavoproteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000235:genetics / Q000502:physiology*; D063154:Mitochondrial Dynamics; D054069:Multiple Acyl Coenzyme A Dehydrogenase Deficiency / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D012256:Riboflavin / Q000627:therapeutic use; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D044927:Electron-Transferring Flavoproteins; D007506:Iron-Sulfur Proteins; D014451:Ubiquinone; D000587:Oxidoreductases Acting on CH-NH Group Donors; C023120:electron-transferring-flavoprotein dehydrogenase; C024989:coenzyme Q10; D012256:Riboflavin