title: Multiple OXPHOS deficiency in the liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria.
abstract: We investigated respiratory chain (RC), tricarboxylic acid cycle (TCA) enzyme activities, and oxidative stress in the tissues of six patients with organic aciduria (OA) presenting various severe complications to further document the role of mitochondrial OXPHOS dysfunction in the development of complications. Two children with propionic acidemia (PA), presenting a severe cardiomyopathy, and four with methylmalonic aciduria (MMA), who developed a neurologic disease (3/4) and renal failure (2/4), were followed. We measured RC and TCA cycle enzyme activity in patient tissues and assessed oxidative metabolism in fibroblasts in vitro. Various RC deficiencies were found in tissues of patients with PA and MMA. TCA cycle enzyme activities were normal when investigated and reactive oxygen species were decreased as well as detoxifying systems activities in the two patients tested. In conclusion, mitochondrial dysfunction was found in all investigated tissues of six patients with organic acidemia presenting with severe complications. Reactive oxygen species production and detoxification were decreased in fibroblast primary cultures. Our results bring further support for a role of secondary respiratory deficiency in the development of late multiorgan complications of these diseases.
authors.affiliation: Metabolic Unit and Paediatric Department, Hôpital Necker-Enfants Malades, INSERM-U781, University Paris Descartes, Paris, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: de Keyzer
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Benoist
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.forename: Florence
authors.initials: F
authors.lastname: Lacaille
authors.forename: Laurence
authors.initials: L
authors.lastname: Hubert
authors.forename: Dominique
authors.initials: D
authors.lastname: Chrétien
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chadefeaux-Vekemans
authors.forename: Patrick
authors.initials: P
authors.lastname: Niaudet
authors.forename: Guy
authors.initials: G
authors.lastname: Touati
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay