Neurite growth could be impaired by ETFDH mutation but restored by mitochondrial cofactors

Muscle Nerve. 2017 Sep;56(3):479-485. doi: 10.1002/mus.25501. Epub 2017 Mar 21.

Abstract

Introduction: c.250G>A (p.Ala84Thr) in ETFDH is the most common mutation that causes later-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD) in the southern Chinese population. No functional study has targeted this mutation.

Methods: Using cells expressing ETFDH-wild-type (WT) or ETFDH-mutant (p.Ala84Thr), reactive oxygen species (ROS) production and neurite length were analyzed, followed by pathomechanism exploration and drug screening.

Results: Increased ROS production and marked neurite shortening were observed in the cells expressing the ETFDH-mutant, compared with WT. Further studies demonstrated that suberic acid, an accumulated intermediate metabolite in MADD, could significantly impair neurite outgrowth of NSC34 cells, but neurite shortening could be restored by supplementation with carnitine, riboflavin, or Coenzyme Q10.

Conclusions: Neurite shortening caused by the c.250G>A mutation in ETFDH suggests that neural defects could be underdiagnosed in human patients with MADD. This impairment might be treatable with mitochondrial cofactor supplementation. Muscle Nerve 56: 479-485, 2017.

Keywords: ETFDH; carnitine; coenzyme Q10; lipid storage myopathy; multiple acyl-coenzyme A dehydrogenase deficiency; neurite shortening; riboflavin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Electron-Transferring Flavoproteins / biosynthesis*
  • Electron-Transferring Flavoproteins / genetics*
  • Humans
  • Iron-Sulfur Proteins / biosynthesis*
  • Iron-Sulfur Proteins / genetics*
  • Mitochondria / genetics*
  • Mitochondria / metabolism*
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / genetics
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / metabolism
  • Mutation / physiology*
  • Neurites / metabolism
  • Neuronal Outgrowth / drug effects
  • Neuronal Outgrowth / physiology*
  • Oxidoreductases Acting on CH-NH Group Donors / biosynthesis*
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Reactive Oxygen Species / metabolism
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / pharmacology

Substances

  • Electron-Transferring Flavoproteins
  • Iron-Sulfur Proteins
  • Reactive Oxygen Species
  • Ubiquinone
  • Oxidoreductases Acting on CH-NH Group Donors
  • electron-transferring-flavoprotein dehydrogenase
  • coenzyme Q10