Ketogenic diet attenuates hepatopathy in mouse model of respiratory chain complex III deficiency caused by a Bcs1l mutation

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.

Alternative oxidase‐mediated respiration prevents lethal mitochondrial cardiomyopathy

“…These changes were fully or partially prevented in GROX mice, further implying that the underlying metabolic stress was relieved. The surprising partial rescue of cIII assembly and activity by AOX in cardiac mitochondria was similar to what we observed in liver mitochondria upon attenuation of hepatopathy by ketogenic diet (Purhonen et al , ) and could be secondary to the general improvement in mitochondrial structure and function.…”

“…Previous studies have shown disrupted hepatic mitochondrial ultrastructure in younger Bcs1l mutant mice (Levéen et al , ; Purhonen et al , ). In the P150 GRAC mice, electron microscopy showed abnormal mitochondrial ultrastructure in hepatocytes as well as in kidney tubular cells, and, importantly, in cardiomyocytes already at onset of the cardiomyopathy (Fig B).…”

“…However, Western blot analysis using the abundance of RC complex subunits as a proxy showed no significant changes in mitochondrial mass between the groups (Fig EV3I) in any tissue. We previously identified an upregulated set of genes, which we designated cIII stress signature, in P45 Bcs1l mutant livers (Purhonen et al , ). This gene set was also highly upregulated in all three GRAC tissues.…”

“…Bcs1l c.A232G homozygotes survive to over P150 in the C57BL/6JCrl background (Purhonen et al , ). The two mouse strains were crossed to generate double heterozygous mice, which were backcrossed to the C57BL/6JCrl background for several generations.…”

“…In the slightly different C57BL/6JCrl substrain, the homozygotes develop the same early manifestations but do not succumb to the early metabolic crisis. This extends their survival to over 150 days (Purhonen et al , ) and brings additional later‐onset phenotypes, such as cerebral astrogliosis (Tegelberg et al , ).…”