Abstract
Mutations in PINK1 cause early-onset Parkinson's disease (PD). Studies in Drosophilamelanogaster have highlighted mitochondrial dysfunction on loss of Pink1 as a central mechanism of PD pathogenesis. Here we show that global analysis of transcriptional changes in Drosophila pink1 mutants reveals an upregulation of genes involved in nucleotide metabolism, critical for neuronal mitochondrial DNA synthesis. These key transcriptional changes were also detected in brains of PD patients harbouring PINK1 mutations. We demonstrate that genetic enhancement of the nucleotide salvage pathway in neurons of pink1 mutant flies rescues mitochondrial impairment. In addition, pharmacological approaches enhancing nucleotide pools reduce mitochondrial dysfunction caused by Pink1 deficiency. We conclude that loss of Pink1 evokes the activation of a previously unidentified metabolic reprogramming pathway to increase nucleotide pools and promote mitochondrial biogenesis. We propose that targeting strategies enhancing nucleotide synthesis pathways may reverse mitochondrial dysfunction and rescue neurodegeneration in PD and, potentially, other diseases linked to mitochondrial impairment.
Highlights
The role of mitochondrial impairment in Parkinson’s disease (PD) has long been debated
We show that both the genetic enhancement of the nucleotide salvage pathway by overexpression of deoxyribonucleoside kinases (dNKs) and the pharmacological manipulation of nucleotide metabolism enhance mitochondrial biogenesis, suppressing mitochondrial dysfunction associated with the PD phenotypes due to Pink[1] deficiency
Maintaining parkin mutants on a dNs- or FAsupplemented diet rescued the loss of ΔΨm (Supplementary Fig. 7c) and dopaminergic neurons (Supplementary Fig. 7d), and the indirect flight muscle defects (Supplementary Fig. 7e,f). These results suggest that both dNs- and folic acid (FA)-mediated enhancement of nucleotide pools and mitochondrial biogenesis compensate for the mitochondrial dysfunction observed on disruption of the Pink1–Parkin pathway
Summary
The role of mitochondrial impairment in PD has long been debated. Recently, the identification of causative mutations in PINK1, a gene encoding a mitochondrial kinase in PD patients has renewed interest in the role of mitochondrial damage in PD (ref. 1). The identification of causative mutations in PINK1, a gene encoding a mitochondrial kinase in PD patients has renewed interest in the role of mitochondrial damage in PD Molecular quality control represents the first level of the mitochondrial defence mechanism This involves the upregulation of nuclear genes that encode for mitochondrial chaperones and proteases that remove misfolded and non-assembled polypeptides in mitochondria, a form of mitochondrial retrograde signalling that is commonly referred to as the mitochondrial unfolded protein response[3] (UPRmt). Invertebrates such as Drosophila have recently emerged as powerful model systems to study the mechanisms of PD-associated neurodegeneration. We show that both the genetic enhancement of the nucleotide salvage pathway by overexpression of dNK and the pharmacological manipulation of nucleotide metabolism enhance mitochondrial biogenesis, suppressing mitochondrial dysfunction associated with the PD phenotypes due to Pink[1] deficiency
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