Purhonen 2014 Abstract MiP2014

Effect of ketogenic diet in mouse model of the mitochondrial hepatopathy GRACILE syndrome.

Link: Mitochondr Physiol Network 19.13 - MiP2014

Purhonen J, Kallijaervi J, Rajendran J, Jauhiainen M, Kotarsky H, Fellman V (2014)

Event: MiP2014

GRACILE syndrome is a mitochondrial hepatopathy caused by mutated BCS1L (homozygous c.232A>G), a gene coding for a respiratory Complex III chaperone [1,2]. BCS1L mutations compromise Rieske iron-sulfur protein incorporation into CIII, which leads to electron transfer system deficiency. In a knock-in mouse model of GRACILE syndrome, the homozygotes are born healthy but display growth failure and progressive liver disorder from the fourth week of life, tubulopathy, loss of adipose tissue and a short life span [3]. Liver pathology is characterized by microvesicular steatosis with progression to fibrosis. Ketogenic diet (KD) is a high-fat and low-carbohydrate diet that has proven beneficial in some forms of epilepsy and in some models of mitochondrial disorders.

We hypothesize that, in homozygotes, KD would increase mitochondrial biogenesis and reduce dependence on glucose and thus alleviate disease progression. To test this hypothesis we fed ketogenic and control diets to groups of homozygous and wild-type mice, starting from one week of age (N=10 per group). The mice were sacrificed at P40-P45 and samples collected for analysis.

The KD had no effect on weight in homozygotes or wild-type mice. All homozygotes had early stage hepatopathy with no differences in standard scoring between diet groups, although subtle differences in liver histology were oberved. Wild-type mice on KD accumulated fat in the liver, whereas KD had no effect on liver fat content in homozygotes. At transcript level several markers of mitochondrial biogenesis (Pgc1a, citrate synthase and subunits of Complexes III and IV) were up-regulated in livers of mutant mice compared to wild-type. mtDNA copy number was not different between groups and there were no signs of increased mitochondrial biogenesis in liver by KD. mRNA levels of genes related to fatty acid and glucose metabolism indicated different responses towards KD in mutant and wild type mice.

The effect of KD on the course of GRACILE hepatopathy and on survival is being investigated in groups with longer follow-up.

Labels: MiParea: mt-Biogenesis;mt-density, Exercise physiology;nutrition;life style 

Organism: Mouse  Tissue;cell: Liver 

Enzyme: Complex III, Complex IV;cytochrome c oxidase  Regulation: Fatty acid 

Event: C3, P-flash  MiP2014 

Affiliation

1-Folkhälsan Research Center; 2-Dep Food Environm Sc, Univ Helsinki; 3-Nat Inst Health Welfare; Helsinki, Finland; 4-Dep Pediatrics, Lund Univ, Sweden; 5-Children’s Hostital, Helsinki Univ Hospital, Univ Helsinki, Finland. − [email protected]

References

1. 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: 490-3.
2. Visapaa I, Fellman V, Vesa J, Dasvarma A, Hutton J, Kumar V, Payne GS, Makarow M, Coster RV, Taylor RW, Turnbull DM, Suomalainen A, Peltonen L (2002) GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 71: 863-76.
3. Levéen P, Kotarsky H, Mörgelin M, Karikoski R, Elmér E, Fellman V (2011) The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: a viable mouse model for mitochondrial hepatopathy. Hepatology 53: 437-47.