Exploration of dietary interventions to treat mitochondrial fatty acid disorders in a mouse model

J Nutr Biochem. 2024 Sep:131:109692. doi: 10.1016/j.jnutbio.2024.109692. Epub 2024 Jun 13.

Abstract

Mitochondrial fatty acids synthesis (mtFAS) is a conserved metabolic pathway essential for mitochondrial respiration. The best characterized mtFAS product is the medium-chain fatty acid octanoate (C8) used as a substrate in the synthesis of lipoic acid (LA), a cofactor required by several mitochondrial enzyme complexes. In humans, mutations in the mtFAS component enoyl reductase MECR cause childhood-onset neurodegenerative disorder MEPAN. A complete deletion of Mecr in mice is embryonically lethal, while selective deletion of Mecr in cerebellar Purkinje cells causes neurodegeneration in these cells. A fundamental question in the research of mtFAS deficiency is if the defect is amenable to treatment by supplementation with known mtFAS products. Here we used the Purkinje-cell specific mtFAS deficiency neurodegeneration model mice to study if feeding the mice with a medium-chain triacylglycerol-rich formula supplemented with LA could slow down or prevent the neurodegeneration in Purkinje cell-specific Mecr KO mice. Feeding started at the age of 4 weeks and continued until the age of 9 months. The neurological status on the mice was assessed at the age of 3, 6, and 9 months with behavioral tests and the state of the Purkinje cell deterioration in the cerebellum was studied histologically. We showed that feeding the mice with medium chain triacylglycerols and LA affected fatty acid profiles in the cerebellum and plasma but did not prevent the development of neurodegeneration in these mice. Our results indicate that dietary supplementation with medium chain fatty acids and LA alone is not an efficient way to treat mtFAS disorders.

Keywords: Lipoic acid; Medium chain fatty acid; Mitochondrial fatty acid synthesis; Mouse model; Neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dietary Supplements
  • Disease Models, Animal*
  • Fatty Acids* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Mitochondria* / metabolism
  • Mitochondrial Diseases / diet therapy
  • Mitochondrial Diseases / metabolism
  • Neurodegenerative Diseases / diet therapy
  • Neurodegenerative Diseases / metabolism
  • Oxidoreductases Acting on CH-CH Group Donors
  • Purkinje Cells* / metabolism
  • Thioctic Acid / pharmacology
  • Triglycerides / metabolism

Substances

  • Fatty Acids
  • Thioctic Acid
  • trans-2-enoyl-CoA reductase (NADPH)
  • Triglycerides
  • Oxidoreductases Acting on CH-CH Group Donors