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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