PPARγ activation rescues mitochondrial function from inhibition of complex I and loss of PINK1

Exp Neurol. 2014 Mar;253:16-27. doi: 10.1016/j.expneurol.2013.12.012. Epub 2013 Dec 26.

Abstract

Parkinson's disease has long been associated with impaired mitochondrial complex I activity, while several gene defects associated with familial Parkinson's involve defects in mitochondrial function or 'quality control' pathways, causing an imbalance between mitochondrial biogenesis and removal of dysfunctional mitochondria by autophagy. Amongst these are mutations of the gene for PTEN-induced kinase 1 (PINK1) in which mitochondrial function is abnormal. Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor and ligand-dependent transcription factor, regulates pathways of inflammation, lipid and carbohydrate metabolism, antioxidant defences and mitochondrial biogenesis. We have found that inhibition of complex I in human differentiated SHSY-5Y cells by the complex I inhibitor rotenone irreversibly decrease mitochondrial mass, membrane potential and oxygen consumption, while increasing free radical generation and autophagy. Similar changes are seen in PINK1 knockdown cells, in which potential, oxygen consumption and mitochondrial mass are all decreased. In both models, all these changes were reversed by pre-treatment of the cells with the PPARγ agonist, rosiglitazone, which increased mitochondrial biogenesis, increased oxygen consumption and suppressed free radical generation and autophagy. Thus, rosiglitazone is neuroprotective in two different models of mitochondrial dysfunction associated with Parkinson's disease through a direct impact on mitochondrial function.

Keywords: Autophagy; Cell death; Mitochondrial biogenesis; Oxidative stress; PINK1; Rotenone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Autophagy / drug effects
  • Cell Line, Tumor
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Enzyme Inhibitors / pharmacology
  • High Mobility Group Proteins / metabolism
  • Humans
  • Insecticides / pharmacology
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / physiology
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / metabolism
  • Nerve Tissue Proteins / metabolism*
  • Oxygen Consumption
  • PPAR gamma / agonists
  • PPAR gamma / metabolism*
  • PTEN Phosphohydrolase
  • Positive Transcriptional Elongation Factor B / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Reactive Oxygen Species / metabolism
  • Rotenone / pharmacology
  • Transfection

Substances

  • Adaptor Proteins, Vesicular Transport
  • Enzyme Inhibitors
  • High Mobility Group Proteins
  • Insecticides
  • MAP1LC3B protein, human
  • Microtubule-Associated Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nerve Tissue Proteins
  • PPAR gamma
  • Reactive Oxygen Species
  • complexin I
  • Rotenone
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Protein Kinases
  • Positive Transcriptional Elongation Factor B
  • PTEN-induced putative kinase
  • PTEN Phosphohydrolase
  • PTEN protein, human