title: The impact of mitochondrial tRNA mutations on the amount of ATP synthase differs in the brain compared to other tissues.
abstract: The impact of point mutations in mitochondrial tRNA genes on the amount and stability of respiratory chain complexes and ATP synthase (OXPHOS) has been broadly characterized in cultured skin fibroblasts, skeletal muscle samples, and mitochondrial cybrids. However, less is known about how these mutations affect other tissues, especially the brain. We have compared OXPHOS protein deficiency patterns in skeletal muscle mitochondria of patients with Leigh (8363G>A), MERRF (8344A>G), and MELAS (3243A>G) syndromes. Both mutations that affect mt-tRNA(Lys) (8363G>A, 8344A>G) resulted in severe combined deficiency of complexes I and IV, compared to an isolated severe defect of complex I in the 3243A>G sample (mt-tRNA(LeuUUR). Furthermore, we compared obtained patterns with those found in the heart, frontal cortex, and liver of 8363G>A and 3243A>G patients. In the frontal cortex mitochondria of both patients, the patterns of OXPHOS deficiencies differed substantially from those observed in other tissues, and this difference was particularly striking for ATP synthase. Surprisingly, in the frontal cortex of the 3243A>G patient, whose ATP synthase level was below the detection limit, the assembly of complex IV, as inferred from 2D-PAGE immunoblotting, appeared to be hindered by some factor other than the availability of mtDNA-encoded subunits.
authors.affiliation: Department of Pediatrics and Center of Applied Genomics, First Faculty of Medicine, Charles University in Prague, Ke Karlovu 2, Prague 2, 128 08, Czech Republic.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fornuskova
authors.forename: Olga
authors.initials: O
authors.lastname: Brantova
authors.forename: Marketa
authors.initials: M
authors.lastname: Tesarova
authors.forename: Lukas
authors.initials: L
authors.lastname: Stiburek
authors.forename: Tomas
authors.initials: T
authors.lastname: Honzik
authors.forename: Laszlo
authors.initials: L
authors.lastname: Wenchich
authors.forename: Evzenie
authors.initials: E
authors.lastname: Tietzeova
authors.forename: Hana
authors.initials: H
authors.lastname: Hansikova
authors.forename: Jiri
authors.initials: J
authors.lastname: Zeman
mesh_terms: D000293:Adolescent; D001921:Brain / Q000201:enzymology*; D002648:Child; D004579:Electron Transport / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007231:Infant, Newborn; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D021122:Protein Subunits / Q000378:metabolism; D012357:RNA, Transfer, Lys / Q000235:genetics*
chemical_list: D021122:Protein Subunits; D012357:RNA, Transfer, Lys; D025261:Mitochondrial Proton-Translocating ATPases