Phosphorylation of Mitochondrial Matrix Proteins Regulates Their Selective Mitophagic Degradation

Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20517-20527. doi: 10.1073/pnas.1901759116. Epub 2019 Sep 23.

Abstract

Mitophagy is an important quality-control mechanism in eukaryotic cells, and defects in mitophagy correlate with aging phenomena and neurodegenerative disorders. It is known that different mitochondrial matrix proteins undergo mitophagy with very different rates but, to date, the mechanism underlying this selectivity at the individual protein level has remained obscure. We now present evidence indicating that protein phosphorylation within the mitochondrial matrix plays a mechanistic role in regulating selective mitophagic degradation in yeast via involvement of the Aup1 mitochondrial protein phosphatase, as well as 2 known matrix-localized protein kinases, Pkp1 and Pkp2. By focusing on a specific matrix phosphoprotein reporter, we also demonstrate that phospho-mimetic and nonphosphorylatable point mutations at known phosphosites in the reporter increased or decreased its tendency to undergo mitophagy. Finally, we show that phosphorylation of the reporter protein is dynamically regulated during mitophagy in an Aup1-dependent manner. Our results indicate that structural determinants on a mitochondrial matrix protein can govern its mitophagic fate, and that protein phosphorylation regulates these determinants.

Keywords: Saccharomyces cerevisiae; autophagy; mitophagy; phosphatase; protein phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mitophagy*
  • Mutation
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • Mitochondrial Proteins
  • Saccharomyces cerevisiae Proteins
  • Protein Kinases
  • PTC6 protein, S cerevisiae
  • Phosphoprotein Phosphatases