Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment

J Inherit Metab Dis. 2013 Jan;36(1):63-73. doi: 10.1007/s10545-012-9511-0. Epub 2012 Jul 6.

Abstract

Disorders of coenzyme Q(10) (CoQ(10)) biosynthesis represent the most treatable subgroup of mitochondrial diseases. Neurological involvement is frequently observed in CoQ(10) deficiency, typically presenting as cerebellar ataxia and/or seizures. The aetiology of the neurological presentation of CoQ(10) deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ(10) deficiency by treatment of neuronal SH-SY5Y cell line with para-aminobenzoic acid (PABA). PABA is a competitive inhibitor of the CoQ(10) biosynthetic pathway enzyme, COQ2. PABA treatment (1 mM) resulted in a 54 % decrease (46 % residual CoQ(10)) decrease in neuronal CoQ(10) status (p < 0.01). Reduction of neuronal CoQ(10) status was accompanied by a progressive decrease in mitochondrial respiratory chain enzyme activities, with a 67.5 % decrease in cellular ATP production at 46 % residual CoQ(10). Mitochondrial oxidative stress increased four-fold at 77 % and 46 % residual CoQ(10). A 40 % increase in mitochondrial membrane potential was detected at 46 % residual CoQ(10) with depolarisation following oligomycin treatment suggesting a reversal of complex V activity. This neuronal cell model provides insights into the effects of CoQ(10) deficiency on neuronal mitochondrial function and oxidative stress, and will be an important tool to evaluate candidate therapies for neurological conditions associated with CoQ(10) deficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminobenzoic Acid / pharmacology
  • Adenosine Triphosphate / metabolism
  • Ataxia / enzymology
  • Ataxia / metabolism*
  • Cell Line, Tumor
  • Cerebellar Ataxia / metabolism
  • Cerebellar Ataxia / physiopathology
  • DNA, Mitochondrial / genetics
  • Electron Transport
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology
  • Humans
  • Membrane Potential, Mitochondrial / physiology
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Mitochondrial Diseases / enzymology
  • Mitochondrial Diseases / metabolism*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Membranes / physiology
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Muscle Weakness / enzymology
  • Muscle Weakness / metabolism*
  • Oxidative Stress / physiology*
  • Ubiquinone / analogs & derivatives*
  • Ubiquinone / deficiency
  • Ubiquinone / metabolism

Substances

  • DNA, Mitochondrial
  • Ubiquinone
  • Adenosine Triphosphate
  • Mitochondrial Proton-Translocating ATPases
  • coenzyme Q10
  • 4-Aminobenzoic Acid

Supplementary concepts

  • Coenzyme Q10 Deficiency