title: DJ-1 knock-down impairs astrocyte mitochondrial function.
abstract: Mitochondrial dysfunction has long been implicated in the pathogenesis of Parkinson's disease (PD). PD brain tissues show evidence for mitochondrial respiratory chain Complex I deficiency. Pharmacological inhibitors of Complex I, such as rotenone, cause experimental parkinsonism. The cytoprotective protein DJ-1, whose deletion is sufficient to cause genetic PD, is also known to have mitochondria-stabilizing properties. We have previously shown that DJ-1 is over-expressed in PD astrocytes, and that DJ-1 deficiency impairs the capacity of astrocytes to protect co-cultured neurons against rotenone. Since DJ-1 modulated, astrocyte-mediated neuroprotection against rotenone may depend upon proper astrocytic mitochondrial functioning, we hypothesized that DJ-1 deficiency would impair astrocyte mitochondrial motility, fission/fusion dynamics, membrane potential maintenance, and respiration, both at baseline and as an enhancement of rotenone-induced mitochondrial dysfunction. In astrocyte-enriched cultures, we observed that DJ-1 knock-down reduced mitochondrial motility primarily in the cellular processes of both untreated and rotenone treated cells. In these same cultures, DJ-1 knock-down did not appreciably affect mitochondrial fission, fusion, or respiration, but did enhance rotenone-induced reductions in the mitochondrial membrane potential. In neuron-astrocyte co-cultures, astrocytic DJ-1 knock-down reduced astrocyte process mitochondrial motility in untreated cells, but this effect was not maintained in the presence of rotenone. In the same co-cultures, astrocytic DJ-1 knock-down significantly reduced mitochondrial fusion in the astrocyte cell bodies, but not the processes, under the same conditions of rotenone treatment in which DJ-1 deficiency is known to impair astrocyte-mediated neuroprotection. Our studies therefore demonstrated the following new findings: (i) DJ-1 deficiency can impair astrocyte mitochondrial physiology at multiple levels, (ii) astrocyte mitochondrial dynamics vary with sub-cellular region, and (iii) the physical presence of neurons can affect astrocyte mitochondrial behavior.
authors: Department of Neurology, Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: N J
authors: NJ
authors: Larsen
authors: G
authors: G
authors: Ambrosi
authors: S J
authors: SJ
authors: Mullett
authors: S B
authors: SB
authors: Berman
authors: D A
authors: DA
authors: Hinkle
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D002468:Cell Physiological Phenomena / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques / Q000379:methods; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology*; D057054:Molecular Imaging / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015513:Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D012402:Rotenone / Q000494:pharmacology
chemical_list: D015513:Oncogene Proteins; D012402:Rotenone; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1