Abstract
Mitochondrial disorders are among the most prevalent inborn errors of metabolism but largely lack treatments and have poor outcomes. High-fat, low-carbohydrate ketogenic diets (KDs) have shown beneficial effects in mouse models of mitochondrial myopathies, with induction of mitochondrial biogenesis as the suggested main mechanism. We fed KD to mice with respiratory chain complex III (CIII) deficiency and progressive hepatopathy due to mutated BCS1L, a CIII assembly factor. The mutant mice became persistently ketotic and tolerated the KD for up to 11 weeks. Liver disease progression was attenuated by KD as shown by delayed fibrosis, reduced cell death, inhibition of hepatic progenitor cell response and stellate cell activation, and normalization of liver enzyme activities. Despite no clear signs of increased mitochondrial biogenesis in the liver, CIII assembly and activity were improved and mitochondrial morphology in hepatocytes normalized. Induction of hepatic glutathione transferase genes and elevated total glutathione level were normalized by KD. Histological findings and transcriptome changes indicated modulation of liver macrophage populations by the mutation and the diet. These results reveal a striking beneficial hepatic response to KD in mice with mitochondrial hepatopathy and warrant further investigations of dietary modification in the management of these conditions in patients.
Highlights
Mitochondrial disorders can manifest as hepatopathy, mainly in infants, with or without other organ manifestations[1]
Studies in animal models have suggested that modulation of mitochondria-related functions, including reduced reactive oxygen species production, promotion of mitochondrial biogenesis and stimulation of glutathione biosynthesis contribute to their beneficial effects in the brain[8,9,10]
We demonstrate that ketogenic diets (KDs) ameliorated hepatopathy in complex III (CIII) deficient Bcs1l mutant mice at the level of liver histology and liver enzymes, mitochondrial structure and function, and gene expression
Summary
Mitochondrial disorders can manifest as hepatopathy, mainly in infants, with or without other organ manifestations[1]. Supportive treatments, such as adjustment of nutrition and vitamin supplementation to alleviate the metabolic imbalance, are available for these patients[1, 2]. Carbohydrate-restricted high-fat ketogenic diets stimulate mitochondrial β-oxidation and ketone body production in the liver[8, 9]. With the hypothesis that KD may induce mitochondrial biogenesis to compensate reduced RC function, improve energy metabolism and ameliorate disease progression, we performed a dietary intervention to assess the effect of KD on liver disease in the Bcs1l mutant model of CIII dysfunction
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