MicroRNA-7 Promotes Glycolysis to Protect against 1-Methyl-4-phenylpyridinium-induced Cell Death

J Biol Chem. 2015 May 8;290(19):12425-34. doi: 10.1074/jbc.M114.625962. Epub 2015 Mar 26.

Abstract

Parkinson disease is associated with decreased activity of the mitochondrial electron transport chain. This defect can be recapitulated in vitro by challenging dopaminergic cells with 1-methyl-4-phenylpyridinium (MPP(+)), a neurotoxin that inhibits complex I of electron transport chain. Consequently, oxidative phosphorylation is blocked, and cells become dependent on glycolysis for ATP production. Therefore, increasing the rate of glycolysis might help cells to produce more ATP to meet their energy demands. In the present study, we show that microRNA-7, a non-coding RNA that protects dopaminergic neuronal cells against MPP(+)-induced cell death, promotes glycolysis in dopaminergic SH-SY5Y and differentiated human neural progenitor ReNcell VM cells, as evidenced by increased ATP production, glucose consumption, and lactic acid production. Through a series of experiments, we demonstrate that targeted repression of RelA by microRNA-7, as well as subsequent increase in the neuronal glucose transporter 3 (Glut3), underlies this glycolysis-promoting effect. Consistently, silencing Glut3 expression diminishes the protective effect of microRNA-7 against MPP(+). Further, microRNA-7 fails to prevent MPP(+)-induced cell death when SH-SY5Y cells are cultured in a low glucose medium, as well as when differentiated ReNcell VM cells or primary mouse neurons are treated with the hexokinase inhibitor, 2-deoxy-d-glucose, indicating that a functional glycolytic pathway is required for this protective effect. In conclusion, microRNA-7, by down-regulating RelA, augments Glut3 expression, promotes glycolysis, and subsequently prevents MPP(+)-induced cell death. This protective effect of microRNA-7 could be exploited to correct the defects in oxidative phosphorylation in Parkinson disease.

Keywords: 1-methyl-4-phenylpyridinium; NF-kappa B (NF-KB); Parkinson disease; RelA; glycolysis; microRNA (miRNA); microRNA-7; neurodegenerative disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 1-Methyl-4-phenylpyridinium / chemistry*
  • Adenosine Triphosphate / chemistry
  • Animals
  • Cell Death*
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Survival
  • Deoxyglucose / chemistry
  • Glucose / chemistry
  • Glucose Transporter Type 3 / metabolism
  • Glycolysis
  • HEK293 Cells
  • Humans
  • Lactic Acid / chemistry
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • Mitochondria / metabolism
  • Neurons / metabolism
  • Oxidative Phosphorylation
  • Oxygen / chemistry
  • Parkinson Disease / metabolism
  • Phosphorylation
  • Transcription Factor RelA / metabolism*

Substances

  • Glucose Transporter Type 3
  • MIRN7 microRNA, human
  • MIRN7 microRNA, mouse
  • MicroRNAs
  • RELA protein, human
  • SLC2A3 protein, human
  • Transcription Factor RelA
  • Lactic Acid
  • Adenosine Triphosphate
  • Deoxyglucose
  • Glucose
  • 1-Methyl-4-phenylpyridinium
  • Oxygen