Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism
ABSTRACT Various genes have been identified for monogenic disorders resembling Parkinson's disease. The products of some of these genes are associated with mitochondria and have been implicated in cellular protection against oxidative damage. In the present study we analysed fibroblasts from a patient carrying the homozygous mutation p.W437X in the PTEN-induced kinase 1 (PINK1), which manifested a very early onset parkinsonism.
Patient's fibroblasts did not show variation in the mtDNA copy number or in the expression of the oxidative phosphorylation complexes. Sequence analysis of the patient's mtDNA presented two new missense mutations in the ND5 (m.12397A>G, p.T21A) and ND6 (m. 14319T>C, p.N119D) genes coding for two subunits of complex I. The two mutations were homoplasmic in both the patient and the patient's mother. Patient's fibroblasts resulted in enhanced constitutive production of the superoxide anion radical that was abrogated by inhibitor of the complex I. Moreover enzyme kinetic analysis of the NADH:ubiquinone oxidoreductase showed changes in the substrates affinity.
To our knowledge, this is the first report showing co-segregation of a Parkinson's disease related nuclear gene mutation with mtDNA mutation(s). Our observation might shed light on the clinical heterogeneity of the hereditary cases of Parkinson's disease, highlighting the hitherto unappreciated impact of coexisting mtDNA mutations in determining the development and the clinical course of the disease.
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ABSTRACT: Mitochondria are essential for mammalian and human cell function as they generate ATP via aerobic respiration. The proteins required in the electron transport chain are mainly encoded by the circular mitochondrial genome but other essential mitochondrial proteins such as DNA repair genes, are coded in the nuclear genome and require transport into the mitochondria. In this review we summarize current knowledge on the association of point mutations and deletions in the mitochondrial genome that are detrimental to mitochondrial function and are associated with accelerated ageing and neurological disorders including Alzheimer's, Parkinson's, Huntington's and Amyotrophic lateral sclerosis (ALS). Mutations in the nuclear encoded genes that disrupt mitochondrial functions are also discussed. It is evident that a greater understanding of the causes of mutations that adversely affect mitochondrial metabolism is required to develop preventive measures against accelerated ageing and neurological disorders caused by mitochondrial dysfunction.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 09/2013; DOI:10.1016/j.mrrev.2013.09.001 · 4.44 Impact Factor
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ABSTRACT: Mutations in PTEN-induced putative kinase 1 (PINK1) cause recessive forms of Parkinson's disease (PD). PINK1 acts upstream of parkin, regulating mitochondrial elimination (mitophagy) in cultured cells treated with mitochondrial uncouplers that cause mitochondrial depolarization. PINK1 loss-of-function decreases mitochondrial membrane potential, resulting in mitochondrial dysfunction, although the exact function of PINK1 in mitochondria has not been fully elucidated. We have previously found that PINK1 deficiency causes a decrease in mitochondrial membrane potential, which is not due to a proton leak, but to respiratory chain defects. Here, we examine mitochondrial respiratory chain defects in PINK1-deficient cells, and find both complex I and complex III are defective. These results suggest that mitochondrial respiratory chain defects may be associated with PD pathogenesis caused by mutations in the PINK1 gene.Neuroscience Letters 08/2014; 580. DOI:10.1016/j.neulet.2014.07.045 · 2.06 Impact Factor
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ABSTRACT: Complex I is the point of entry in the mitochondrial electron transport chain for NADH reducing equivalents, and it behaves as a regulatable pacemaker of respiratory ATP production in human cells. Defects in complex I are associated with several human neurological disorders, including primary mitochondrial diseases, Parkinson disease (PD), and Down syndrome, and understanding the activity and regulation of complex I may reveal aspects of the underlying pathogenic mechanisms. Complex I is regulated by cyclic AMP (cAMP) and the protein kinase A (PKA) signal transduction pathway, and elucidating the role of the cAMP/PKA system in regulating complex I and oxygen free radical production provides new perspectives for devising therapeutic strategies for neurological diseases.Trends in Molecular Medicine 12/2012; 19(1). DOI:10.1016/j.molmed.2012.11.005 · 10.11 Impact Factor