High-dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy

Brain Pathol. 2020 Sep;30(5):945-963. doi: 10.1111/bpa.12869. Epub 2020 Jul 7.

Abstract

Biotin is an essential cofactor for carboxylases that regulates the energy metabolism. Recently, high-dose pharmaceutical-grade biotin (MD1003) was shown to improve clinical parameters in a subset of patients with chronic progressive multiple sclerosis. To gain insight into the mechanisms of action, we investigated the efficacy of high-dose biotin in a genetic model of chronic axonopathy caused by oxidative damage and bioenergetic failure, the Abcd1- mouse model of adrenomyeloneuropathy. High-dose biotin restored redox homeostasis driven by NRF-2, mitochondria biogenesis and ATP levels, and reversed axonal demise and locomotor impairment. Moreover, we uncovered a concerted dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord likely driven by aberrant SREBP-1c/mTORC1signaling. This resulted in increased triglyceride levels and lipid droplets in motor neurons. High-dose biotin normalized the hyperactivation of mTORC1, thus restoring lipid homeostasis. These results shed light into the mechanism of action of high-dose biotin of relevance for neurodegenerative and metabolic disorders.

Keywords: NRF2; SREBP-1c; axonal degeneration; biotin; mTORC1; multiple sclerosis; redox homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily D, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily D, Member 1 / metabolism
  • Adrenoleukodystrophy / genetics
  • Adrenoleukodystrophy / metabolism
  • Adrenoleukodystrophy / therapy*
  • Animals
  • Axons / metabolism
  • Biotin / metabolism
  • Biotin / pharmacology*
  • Cell Line
  • Disease Models, Animal
  • Energy Metabolism
  • Homeostasis
  • Humans
  • Lipids
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / physiology
  • Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • Abcd1 protein, mouse
  • Lipids
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Biotin
  • Mechanistic Target of Rapamycin Complex 1