title: The proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient livers.
abstract: Methylmalonic acidemia (MMA) is a heterogeneous and severe autosomal recessive inborn error of metabolism most commonly caused by the deficient activity of the vitamin B12 dependent enzyme, methylmalonyl-CoA mutase (MUT). The main treatment for MMA patients is the dietary restriction of propiogenic amino acids and carnitine supplementation. Despite treatment, the prognosis for vitamin B12 non-responsive patients remains poor and is associated with neonatal lethality, persistent morbidity and decreased life expectancy. While multi-organ pathology is a feature of MMA, the liver is severely impacted by mitochondrial dysfunction which likely underlies the metabolic instability experienced by the patients. Liver and/or combined liver/kidney transplantation is therefore sometimes performed in severely affected patients. Using liver specimens from donors and MMA patients undergoing elective liver transplantation collected under a dedicated natural history protocol (clinicaltrials.gov: NCT00078078), we employed proteomics to characterize the liver pathology and impaired hepatic metabolism observed in the patients. Pathway analysis revealed perturbations of enzymes involved in energy metabolism, gluconeogenesis and Krebs cycle anaplerosis. Our findings identify new pathophysiologic and therapeutic targets that could be valuable for designing alternative therapies to alleviate clinical manifestations seen in this disorder.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli, "Federico II", Naples, Italy and CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Caterino
authors.affiliation: Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institute of Health, Bethesda MD 2092, USA. venditti@mail.nih.gov.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Chandler
authors.affiliation: Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institute of Health, Bethesda MD 2092, USA. venditti@mail.nih.gov.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sloan
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dorko
authors.affiliation: Division Genetics and Metabolism, Children's National Medical Center, Washington DC, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Cusmano-Ozog
authors.affiliation: CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ingenito
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Strom
authors.affiliation: CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Esther
authors.initials: E
authors.lastname: Imperlini
authors.affiliation: CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scolamiero
authors.affiliation: Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institute of Health, Bethesda MD 2092, USA. venditti@mail.nih.gov.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Venditti
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli, "Federico II", Naples, Italy and CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Ruoppolo
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism* / Q000601:surgery; D016022:Case-Control Studies; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation; D008297:Male; D053858:Metabolic Networks and Pathways; D020543:Proteome / Q000378:metabolism*; D057825:Two-Dimensional Difference Gel Electrophoresis
chemical_list: D020543:Proteome