Kallijarvi 2013 Abstract IOC75

Kallijarvi J (2013) ... Mitochondr Physiol Network 18.03.

Link: IOC75 Open Access

Kallijarvi J (2013)

Event: IOC75

GRACILE syndrome (Fellman disease, MIM 603358), is a neonatal mitochondrial disorder that belongs to the Finnish disease heritage. The GRACILE acronym comes from the most important clinical features of the disorder, namely fetal Growth Restriction, Aminoaciduria, Cholestasis, Iron overload, Lactic acidosis, and Early death during infancy. GRACILE is caused by a homozygous 232A>G missense mutation in the BCS1L gene. The mutation results in deficiency of respiratory chain complex III (CIII, ubiquinol-cytochrome c reductase) and result in death during infancy. Other BCS1L mutations have been associated with a wide spectrum of phenotypes, ranging from mild congenital neurosensory hearing loss and distorted hair to tubulopathy alone, or combined with hepatopathy. BCS1L is a nuclear gene that encodes a mitochondrial AAA-family ATPase. There is strong evidence that it acts as a chaperone that incorporates the Rieske iron-sulfur protein (RISP) into CIII. The GRACILE mutation is situated in the N-terminal import region, and when introduced into yeast bcs1 results in lack of CIII function. We have generated a knock-in mouse model for GRACILE. The main findings in the homozygous mice are growth restriction and progressive liver disorder from the fourth week of life, tubulopathy and death before 6 weeks of age of most of the animals. RISP incorporation into complex III is diminished in symptomatic animals; however, in young animals complex III is correctly assembled. Complex III activity in liver, heart, and kidney of symptomatic mutants is decreased to 20%, 40%, and 40% of controls, respectively. In high-resolution respirometry analysis of liver mitochondria from sick mice, CIII dysfunction results in decreased electron transport capacity through the respiratory chain under maximum substrate input. In line with this, tolerance of mitochondrial respiration to complex III inhibition by myxothiazol decreases with age in GRACILE mouse tissues. However, in patient fibroblasts no alterations in RC activity are detected by respirometry.

Fellman V, Rapola J, Pihko H, Varilo T, Raivio KO (1998). Iron-overload disease in infants involving fetal growth retardation, lactic acidosis, liver haemosiderosis, and aminoaciduria. Lancet 351: 490-493.

Kotarsky H, Karikoski R, Morgelin M, Marjavaara S, Bergman P, Zhang DL et al (2010). Characterization of complex III deficiency and liver dysfunction in GRACILE syndrome caused by a BCS1L mutation. Mitochondrion 10: 497-509.

Leveen P, Kotarsky H, Morgelin M, Karikoski R, Elmer E, Fellman V (2011). The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: a viable mouse model for mitochondrial hepatopathy. Hepatology 53: 437-447.

• Keywords: BCS1L, GRACILE, CIII, Rieske, hepatopathy

Labels:

Stress:Mitochondrial Disease; Degenerative Disease and Defect"Mitochondrial Disease; Degenerative Disease and Defect" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property., Genetic Defect; Knockdown; Overexpression"Genetic Defect; Knockdown; Overexpression" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property.  Organism: Human, Mouse  Tissue;cell: Liver, Kidney  Preparation: Isolated Mitochondria"Isolated Mitochondria" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property.  Enzyme: Complex III  Regulation: Substrate; Glucose; TCA Cycle"Substrate; Glucose; TCA Cycle" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property., Fatty Acid"Fatty Acid" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property., ATP; ADP; AMP; PCr"ATP; ADP; AMP; PCr" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property. 

HRR: Oxygraph-2k 

Affiliations and author contributions

Jukka Kallijärvi, Prof. Vineta Fellman:

Folkhälsan Research Center Biomedicum C314a P.O.Box 63 (Haartmaninkatu 8) FI-00014 University of Helsinki Finland

Vineta Fellman:

Professor of neonatology Department Head Department of Pediatrics Lund University 22185 Lund Sweden

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