| First Author | Gautier CA | Year | 2008 |
| Journal | Proc Natl Acad Sci U S A | Volume | 105 |
| Issue | 32 | Pages | 11364-9 |
| PubMed ID | 18687901 | Mgi Jnum | J:140335 |
| Mgi Id | MGI:3813389 | Doi | 10.1073/pnas.0802076105 |
| Citation | Gautier CA, et al. (2008) Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A 105(32):11364-9 |
| abstractText | Parkinson's disease (PD) is a common neurodegenerative disorder thought to be associated with mitochondrial dysfunction. Loss of function mutations in the putative mitochondrial protein PINK1 (PTEN-induced kinase 1) have been linked to familial forms of PD, but the relation of PINK1 to mammalian mitochondrial function remains unclear. Here, we report that germline deletion of the PINK1 gene in mice significantly impairs mitochondrial functions. Quantitative electron microscopic studies of the striatum in PINK1(-/-) mice at 3-4 and 24 months revealed no gross changes in the ultrastructure or the total number of mitochondria, although the number of larger mitochondria is selectively increased. Functional assays showed impaired mitochondrial respiration in the striatum but not in the cerebral cortex at 3-4 months of age, suggesting specificity of this defect for dopaminergic circuitry. Aconitase activity associated with the Krebs cycle is also reduced in the striatum of PINK1(-/-) mice. Interestingly, mitochondrial respiration activities in the cerebral cortex are decreased in PINK1(-/-) mice at 2 years compared with control mice, indicating that aging can exacerbate mitochondrial dysfunction in these mice. Furthermore, mitochondrial respiration defects can be induced in the cerebral cortex of PINK1(-/-) mice by cellular stress, such as exposure to H(2)O(2) or mild heat shock. Together, our findings demonstrate that mammalian PINK1 is important for mitochondrial function and provides critical protection against both intrinsic and environmental stress, suggesting a pathogenic mechanism by which loss of PINK1 may lead to nigrostriatal degeneration in PD. |
