Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson's disease

http://www.nature.com/ncb/journal/v16/n2/full/ncb2901.html

Loss of the mitochondrially-localised kinase PINK1 can cause early-onset Parkinson's disease, and a possible cause of this is through mitochondrial dysfunction following mutation of the Pink1 gene. The authors used a combination of transcriptional and metabolic profiling to discover that Pink1 mutant Drosophila have changes in nucleotide metabolism, in addition to the upregulation of the mitochondrial unfolded protein response which has been observed previously.

Following loss of pink1 a number of metabolic pathways were significantly upregulated, including glycine and serine metabolism, as well as nucleotide salvage, purine biosynthesis, and folate metabolism. The authors interpret this as a metabolic stress response induced by the cell to compensate for mitochondrial impairment due to loss of pink1.

The increase in folate metabolism was due to an upregulation of the kinase dNK, which was found to be the rate-limiting enzyme in the nucleotide salvage pathway. Pink1 mutants have upregulated dNK expression, which is shown to lead to organellar biogenesis. The authors find that inducing overexpression of dNK rescues mitochondrial dysfunction in pink1 mutant flies through enhancement of the nucleotide salvage pathway, and that dietary supplementation with deoxynucleosides also improved the suppression of mitochondrial dysfunction.