title: Mitochondrial dysfunction in mut methylmalonic acidemia.
abstract: Methylmalonic acidemia is an autosomal recessive inborn error of metabolism caused by defective activity of methylmalonyl-CoA mutase (MUT) that exhibits multiorgan system pathology. To examine whether mitochondrial dysfunction is a feature of this organic acidemia, a background-modified Mut-knockout mouse model was constructed and used to examine mitochondrial ultrastructure and respiratory chain function in the tissues that manifest pathology in humans. In parallel, the liver from a patient with mut methylmalonic acidemia was studied in a similar fashion. Megamitochondria formed early in life in the hepatocytes of the Mut(-/-) animals and progressively enlarged. Liver extracts prepared from the mutants at multiple time points displayed respiratory chain dysfunction, with diminished cytochrome c oxidase activity and reduced intracellular glutathione compared to control littermates. Over time, the exocrine pancreas and proximal tubules of the kidney also exhibited megamitochondria, and older mutant mice eventually developed tubulointerstitial renal disease. The patient liver displayed similar morphological and enzymatic findings as observed in the murine tissues. These murine and human studies establish that megamitochondria formation with respiratory chain dysfunction occur in a tissue-specific fashion in methylmalonic acidemia and suggest treatment approaches based on improving mitochondrial function and ameliorating the effects of oxidative stress.
authors.affiliation: Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Chandler
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Zerfas
authors.forename: Sara
authors.initials: S
authors.lastname: Shanske
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sloan
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoffmann
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.forename: Charles P
authors.initials: CP
authors.lastname: Venditti
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002675:Child, Preschool; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D008765:Methylmalonyl-CoA Mutase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D018384:Oxidative Stress
chemical_list: D003576:Electron Transport Complex IV; D008765:Methylmalonyl-CoA Mutase; D005978:Glutathione