Mechanisms Controlling Mitochondrial Biogenesis and Respiration Through the Thermogenic Coactivator PGC-1

Cell. 1999 Jul 9;98(1):115-24. doi: 10.1016/S0092-8674(00)80611-X.

Abstract

Mitochondrial number and function are altered in response to external stimuli in eukaryotes. While several transcription/replication factors directly regulate mitochondrial genes, the coordination of these factors into a program responsive to the environment is not understood. We show here that PGC-1, a cold-inducible coactivator of nuclear receptors, stimulates mitochondrial biogenesis and respiration in muscle cells through an induction of uncoupling protein 2 (UCP-2) and through regulation of the nuclear respiratory factors (NRFs). PGC-1 stimulates a powerful induction of NRF-1 and NRF-2 gene expression; in addition, PGC-1 binds to and coactivates the transcriptional function of NRF-1 on the promoter for mitochondrial transcription factor A (mtTFA), a direct regulator of mitochondrial DNA replication/transcription. These data elucidate a pathway that directly links external physiological stimuli to the regulation of mitochondrial biogenesis and function.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • GA-Binding Protein Transcription Factor
  • Gene Expression Regulation*
  • Heat-Shock Proteins / metabolism
  • Ion Channels
  • Membrane Transport Proteins*
  • Mice
  • Mitochondria, Muscle / physiology*
  • Mitochondria, Muscle / ultrastructure
  • Mitochondrial Proteins*
  • Models, Biological
  • NF-E2-Related Factor 1
  • Nuclear Respiratory Factor 1
  • Nuclear Respiratory Factors
  • Oxygen Consumption*
  • Protein Biosynthesis
  • Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Uncoupling Protein 2

Substances

  • DNA-Binding Proteins
  • GA-Binding Protein Transcription Factor
  • Heat-Shock Proteins
  • Ion Channels
  • Membrane Transport Proteins
  • Mitochondrial Proteins
  • NF-E2-Related Factor 1
  • Nrf1 protein, mouse
  • Nuclear Respiratory Factor 1
  • Nuclear Respiratory Factors
  • Proteins
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • Ucp2 protein, mouse
  • Uncoupling Protein 2
  • peroxisome-proliferator-activated receptor-gamma coactivator-1