Mitochondrial Dysfunction and Oxidative Damage in parkin-deficient Mice*

By J. Palacino, D. Šagi, M. Goldberg, S. Krauss, C. Motz, Maik A. Wacker, J. Klose, Jie Shen. Journal of Biological Chemistry, 2004

965 citations recorded by the source corpus.

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.

Subfields: Food Science, Oceanography

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Citations in the corpus

Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, positive): “Although no gross behavioural changes were found in mice where Parkin was deleted (Goldberg et al., 2003; Itier et al., 2003; Perez and Palmiter, 2005; Von Coelln et al., 2004), the activity of striatal neuron mitochondria was impaired (Palacino et al., 2004).”
Mitochondrial Dysfunction in Parkinson's Disease (2011, background): “Recent work in Parkin null mice has shown a reduction in subunits of Complex I and IV and reduced function in the mitochondrial respiratory chain along with increased oxidative stress in brain tissue [88].”
Molecular pathophysiology of Parkinson's disease. (2005, background): “Proteomic analysis has instead revealed reduced levels of several proteins involved in mitochondrial oxidative phosphorylation and protection from oxidative stress in the ventral midbrain of parkin knockout mice (Palacino et al. 2004).”
Role of Oxidative Stress in Parkinson's Disease (2013, background): “Mice deficient in parkin gene have shown reduced striatal respiratory chain activity along with oxidative damage [29].”
Molecular pathways to neurodegeneration (2004, background): “Parkin knockout mice manifest decreased oxidative phosphorylation and increased oxidative stres”
Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL (2010, methodology): “…cases of Parkinson’s disease, PINK1 (Valente et al., 2004) and Parkin (Kitada et al., 1998), have been found to work in the same pathway (Clark et al., 2006; Park et al., 2006; Yang et al., 2006) linked to mitochondrial maintenance (Greene et al., 2003; Palacino et al., 2004; Gautier et al., 2008).”