Phosphorylation of MCAD selectively rescues PINK1 deficiencies in behavior and metabolism

Mol Biol Cell. 2018 May 15;29(10):1219-1227. doi: 10.1091/mbc.E18-03-0155. Epub 2018 Mar 22.

Abstract

PTEN-induced putative kinase 1 (PINK1) is a mitochondria-targeted kinase whose mutations are a cause of Parkinson's disease. We set out to better understand PINK1's effects on mitochondrial proteins in vivo. Using an unbiased phosphoproteomic screen in Drosophila, we found that PINK1 mediates the phosphorylation of MCAD, a mitochondrial matrix protein critical to fatty acid metabolism. By mimicking phosphorylation of this protein in a PINK1 null background, we restored PINK1 null's climbing, flight, thorax, and wing deficiencies. Owing to MCAD's role in fatty acid metabolism, we examined the metabolic profile of PINK1 null flies, where we uncovered significant disruptions in both acylcarnitines and amino acids. Some of these disruptions were rescued by phosphorylation of MCAD, consistent with MCAD's rescue of PINK1 null's organismal phenotypes. Our work validates and extends the current knowledge of PINK1, identifies a novel function of MCAD, and illuminates the need for and effectiveness of metabolic profiling in models of neurodegenerative disease.

Publication types

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

MeSH terms

  • Acyl-CoA Dehydrogenase / genetics
  • Acyl-CoA Dehydrogenase / metabolism*
  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Amino Acids / deficiency
  • Amino Acids / metabolism
  • Animals
  • Animals, Genetically Modified
  • Carnitine / analogs & derivatives
  • Carnitine / metabolism
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / metabolism*
  • Oxidation-Reduction
  • Phenotype
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / metabolism

Substances

  • Amino Acids
  • Drosophila Proteins
  • acylcarnitine
  • Phosphoserine
  • Adenosine Triphosphate
  • Acyl-CoA Dehydrogenase
  • MCAD protein, Drosophila
  • PINK1 protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • Carnitine