Regulation of Ca2+ Signalling and Ca2+-mediated Cell Death by the Transcriptional Coactivator PGC-1alpha

Cell Death Differ. 2006 Apr;13(4):586-96. doi: 10.1038/sj.cdd.4401784.

Abstract

Mitochondrial Ca2+ uptake controls cellular functions as diverse as aerobic metabolism, cytosolic Ca2+signalling and mitochondrial participation in apoptosis. Modulatory inputs converging on the organelle can regulate this process, determining the final outcome of Ca2+-mediated cell stimulation. We investigated in HeLa cells and primary skeletal myotubes the effect on Ca2+ signalling of the transcriptional peroxisome-proliferator-activated-receptor-gamma-coactivator-1alpha (PGC-1alpha), which triggers organelle biogenesis and modifies the mitochondrial proteome. PGC-1alpha selectively reduced mitochondrial Ca2+ responses to cell stimulation by reducing the efficacy of mitochondrial Ca2+ uptake sites and increasing organelle volume. In turn, this affected ER Ca2+ release and cytosolic responses in HeLa cells. Most importantly, the modulation of mitochondrial Ca2+ uptake significantly reduced cellular sensitivity to the Ca2+-mediated proapoptotic effect of C2 ceramide. These results reveal a primary role of PGC-1alpha in shaping mitochondrial participation in calcium signalling, that underlies its protective role against stress and proapoptotic stimuli in pathophysiological conditions.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Albuterol / pharmacology
  • Animals
  • Apoptosis*
  • Calcium / metabolism*
  • Calcium Channels / metabolism
  • Calcium Signaling*
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Histamine / pharmacology
  • Homeostasis
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ion Channels
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Mitochondria, Muscle / drug effects
  • Mitochondria, Muscle / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Mitochondrial Swelling
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle Fibers, Skeletal / pathology
  • Nuclear Respiratory Factor 1 / genetics
  • Nuclear Respiratory Factor 1 / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Rats
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Uncoupling Protein 2

Substances

  • Adrenergic beta-Agonists
  • Calcium Channels
  • Enzyme Inhibitors
  • Heat-Shock Proteins
  • ITPR1 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ion Channels
  • Membrane Transport Proteins
  • Mitochondrial Proteins
  • N-acetylsphingosine
  • Nuclear Respiratory Factor 1
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Uncoupling Protein 2
  • Histamine
  • Sphingosine
  • Albuterol
  • Calcium