Mitochondrial dysfunction and oxidative damage in parkin-deficient mice.
Loss-of-function mutations in parkin are the predominant cause of familial Parkinson's disease. We previously reported that parkin-/- mice exhibit nigrostriatal deficits in the absence of nigral degeneration. Parkin has been shown to function as an E3 ubiquitin ligase. Loss of parkin function, therefore, has been hypothesized to cause nigral degeneration via an aberrant accumulation of its substrates. Here we employed a proteomic approach to determine whether loss of parkin function results in alterations in abundance and/or modification of proteins in the ventral midbrain of parkin-/- mice. Two-dimensional gel electrophoresis followed by mass spectrometry revealed decreased abundance of a number of proteins involved in mitochondrial function or oxidative stress. Consistent with reductions in several subunits of complexes I and IV, functional assays showed reductions in respiratory capacity of striatal mitochondria isolated from parkin-/- mice. Electron microscopic analysis revealed no gross morphological abnormalities in striatal mitochondria of parkin-/- mice. In addition, parkin-/- mice showed a delayed rate of weight gain, suggesting broader metabolic abnormalities. Accompanying these deficits in mitochondrial function, parkin-/- mice also exhibited decreased levels of proteins involved in protection from oxidative stress. Consistent with these findings, parkin-/- mice showed decreased serum antioxidant capacity and increased protein and lipid peroxidation. The combination of proteomic, genetic, and physiological analyses reveal an essential role for parkin in the regulation of mitochondrial function and provide the first direct evidence of mitochondrial dysfunction and oxidative damage in the absence of nigral degeneration in a genetic mouse model of Parkinson's disease.
Palacino
James J
JJ
Center for Neurologic Diseases, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sagi
Dijana
D
Goldberg
Matthew S
MS
Krauss
Stefan
S
Motz
Claudia
C
Wacker
Maik
M
Klose
Joachim
J
Shen
Jie
J
D000818:Animals; D000975:Antioxidants; D001479:Basal Ganglia / Q000648:ultrastructure; D019069:Cell Respiration; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000032:analysis; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000209:etiology; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D015430:Weight Gain
D000975:Antioxidants; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein