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221 Effect of Fasting on Metabolism in Transgenic Mice with Respiratory Chain Complex III Deficiency
  1. N Ljubas1,
  2. E Hansson1,
  3. H Kotarsky1,
  4. V Fellman1,2
  1. 1Department of Pediatrics, University of Lund, Lund, Sweden
  2. 2Department of Pediatrics, University of Helsinki, Helsinki, Finland


Background and aim To generate ATP production, mitochondria host crucial metabolic pathways that interact continuously. Therefore, pathological interruptions in one process might disturb entire cell metabolism. To investigate a neonatal mitochondrial disorder (GRACILE syndrome), we developed a mouse model with c.232A>G mutation in Bcs1l, resulting in a lethal complex III (CIII) deficiency in homozygotes. Our aim was to analyze how CIII deficiency affects metabolic pathways by pressing the mechanisms with fasting.

Methods Homozygous (Bcs1l G/G ) and wild type (Bcs1l A/A ) mice were assessed before and after 4-hour fasting with blood glucose, lactate and ketones, and sacrificed. Liver tissue was obtained for histology (H&E, PAS staining for glycogen and ORO-staining for fat) and ATP measurement.

Results Before fasting, Bcs1l G/G had lower glucose (4.3±1.3 vs. 6.6±1.2, p<0.01) and higher ketone (0.6±0.3 vs. 0.3±0.1, p<0.01) levels, but similar lactate values (4.0±2.2 vs. 3.7±1.4 p=0.8). Glycogen depletion and microvesicular steatosis present in Bcs1l G/G hepatocytes increased after fasting. After fasting, Bcs1l A/A remained euglycemic with increased ketone body production, whereas in Bcs1l G/G mice glucose, ketone and lactate were lower. ATP production of Bcs1l G/G mice was lower than that of Bcs1l A/A (58%±24%).

Conclusion Bcs1l G/G mice switched their metabolism to β-oxidation before fasting and failed to build up compensatory metabolic mechanisms to fasting, resulting in low ATP production. These results elucidate mechanisms explaining the deterioration in Bcs1l G/G mice. The methods used can be implemented as outcome measures in intervention studies aiming at stimulating mitochondrial biogenesis and metabolism in the mouse model.

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