PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity

Aging (Albany NY). 2015 Sep;7(9):629-47. doi: 10.18632/aging.100790.

Abstract

Due to its role in regulation of mitochondrial function, PGC1α is emerging as an important player in ageing and neurodegenerative disorders. PGC1α exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1α in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1αin vitro and in vivo in the regulatory context of MB and MD in response to lead (II) acetate as a relevant model of neurotoxicity. We show that there is an adaptive response (AR) to lead, orchestrated by the BAP31-calcium signalling system operating between the ER and mitochondria. We find that this hormetic response is controlled by a cell-tolerated increase of PGC1α expression, which in turn induces a balanced expression of fusion/fission genes by binding to their promoters and implying its direct role in regulation of MD. However, dysregulation of PGC1α expression through either stable downregulation or overexpression, renders cells more susceptible to lead insult leading to mitochondrial fragmentation and cell death. Our data provide novel evidence that PGC1α expression is a key regulator of MD and the maintenance of tolerated PGC1α expression may offer a promising strategy for neuroprotective therapies.

Keywords: BAP3; Drp1; Lead; PGC-1α; calcium; mitochondrial biogenesis and dynamics; neurotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Animals
  • Apoptosis / drug effects
  • Cell Death / drug effects
  • Cell Line
  • Dopaminergic Neurons / drug effects
  • Endoplasmic Reticulum / drug effects
  • Lead Poisoning, Nervous System / genetics*
  • Lead Poisoning, Nervous System / physiopathology
  • Membrane Proteins / genetics
  • Mitochondrial Dynamics / genetics
  • Neuroprotective Agents / pharmacology
  • Organelle Biogenesis
  • Organometallic Compounds / toxicity
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Rats
  • Signal Transduction / drug effects
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics*

Substances

  • Bcap31 protein, rat
  • Membrane Proteins
  • Neuroprotective Agents
  • Organometallic Compounds
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Transcription Factors
  • lead acetate