The neurogenic basic helix-loop-helix transcription factor NeuroD6 enhances mitochondrial biogenesis and bioenergetics to confer tolerance of neuronal PC12-NeuroD6 cells to the mitochondrial stressor rotenone

Exp Cell Res. 2012 Oct 15;318(17):2200-14. doi: 10.1016/j.yexcr.2012.07.004. Epub 2012 Jul 16.

Abstract

The fundamental question of how and which neuronal specific transcription factors tailor mitochondrial biogenesis and bioenergetics to the need of developing neuronal cells has remained largely unexplored. In this study, we report that the neurogenic basic helix-loop-helix transcription factor NeuroD6 possesses mitochondrial biogenic properties by amplifying the mitochondrial DNA content and TFAM expression levels, a key regulator for mitochondrial biogenesis. NeuroD6-mediated increase in mitochondrial biogenesis in the neuronal progenitor-like PC12-NEUROD6 cells is concomitant with enhanced mitochondrial bioenergetic functions, including increased expression levels of specific subunits of respiratory complexes of the electron transport chain, elevated mitochondrial membrane potential and ATP levels produced by oxidative phosphorylation. Thus, NeuroD6 augments the bioenergetic capacity of PC12-NEUROD6 cells to generate an energetic reserve, which confers tolerance to the mitochondrial stressor, rotenone. We found that NeuroD6 induces an adaptive bioenergetic response throughout rotenone treatment involving maintenance of the mitochondrial membrane potential and ATP levels in conjunction with preservation of the actin network. In conclusion, our results support the concept that NeuroD6 plays an integrative role in regulating and coordinating the onset of neuronal differentiation with acquisition of adequate mitochondrial mass and energetic capacity to ensure energy demanding events, such as cytoskeletal remodeling, plasmalemmal expansion, and growth cone formation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Blotting, Western
  • Cell Differentiation / drug effects
  • Cell Survival / drug effects
  • DNA, Mitochondrial / genetics
  • Drug Tolerance*
  • Energy Metabolism
  • Helix-Loop-Helix Motifs / drug effects
  • Immunoenzyme Techniques
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects*
  • Mitochondria / metabolism*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Organelle Biogenesis*
  • PC12 Cells
  • Rats
  • Reactive Oxygen Species / metabolism
  • Real-Time Polymerase Chain Reaction
  • Rotenone / pharmacology*
  • Uncoupling Agents / pharmacology*

Substances

  • Actins
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA, Mitochondrial
  • Neurod6 protein, rat
  • Reactive Oxygen Species
  • Uncoupling Agents
  • Rotenone
  • Adenosine Triphosphate