A neo-substrate that amplifies catalytic activity of parkinson's-disease-related kinase PINK1

Cell. 2013 Aug 15;154(4):737-47. doi: 10.1016/j.cell.2013.07.030.

Abstract

Mitochondria have long been implicated in the pathogenesis of Parkinson's disease (PD). Mutations in the mitochondrial kinase PINK1 that reduce kinase activity are associated with mitochondrial defects and result in an autosomal-recessive form of early-onset PD. Therapeutic approaches for enhancing the activity of PINK1 have not been considered because no allosteric regulatory sites for PINK1 are known. Here, we show that an alternative strategy, a neo-substrate approach involving the ATP analog kinetin triphosphate (KTP), can be used to increase the activity of both PD-related mutant PINK1(G309D) and PINK1(WT). Moreover, we show that application of the KTP precursor kinetin to cells results in biologically significant increases in PINK1 activity, manifest as higher levels of Parkin recruitment to depolarized mitochondria, reduced mitochondrial motility in axons, and lower levels of apoptosis. Discovery of neo-substrates for kinases could provide a heretofore-unappreciated modality for regulating kinase activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives
  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Axons / metabolism
  • Cell Line
  • Cells, Cultured
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Kinetin / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Molecular Sequence Data
  • Neurons / cytology
  • Neurons / metabolism
  • Parkinson Disease / enzymology
  • Parkinson Disease / genetics
  • Parkinson Disease / pathology*
  • Phosphorylation
  • Protein Kinases / chemistry
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism*
  • Rats
  • Sequence Alignment
  • Ubiquitin-Protein Ligases / metabolism
  • bcl-X Protein / metabolism

Substances

  • BCL2L1 protein, human
  • bcl-X Protein
  • Adenosine Triphosphate
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • Kinetin