Multi-omic Mitoprotease Profiling Defines a Role for Oct1p in Coenzyme Q Production

Mike T. Veling, Andrew G. Reidenbach, Elyse C. Freiberger, Nicholas W. Kwiecien, Paul D. Hutchins, Michael J. Drahnak, Adam Jochem, Arne Ulbrich, Matthew J.P. Rush, Jason D. Russell, Joshua J. Coon, David J. Pagliarini

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Mitoproteases are becoming recognized as key regulators of diverse mitochondrial functions, although their direct substrates are often difficult to discern. Through multi-omic profiling of diverse Saccharomyces cerevisiae mitoprotease deletion strains, we predicted numerous associations between mitoproteases and distinct mitochondrial processes. These include a strong association between the mitochondrial matrix octapeptidase Oct1p and coenzyme Q (CoQ) biosynthesis—a pathway essential for mitochondrial respiration. Through Edman sequencing and in vitro and in vivo biochemistry, we demonstrated that Oct1p directly processes the N terminus of the CoQ-related methyltransferase, Coq5p, which markedly improves its stability. A single mutation to the Oct1p recognition motif in Coq5p disrupted its processing in vivo, leading to CoQ deficiency and respiratory incompetence. This work defines the Oct1p processing of Coq5p as an essential post-translational event for proper CoQ production. Additionally, our data visualization tool enables efficient exploration of mitoprotease profiles that can serve as the basis for future mechanistic investigations. By generating proteomic, lipidomic, and metabolomic profiles of select yeast deletion strains, Veling et al. reveal numerous connections between mitoproteases and their biological functions. In particular, the authors discover that Oct1p processes the methyltransferase Coq5p, a key post-translational event required for proper mitochondrial coenzyme Q production.

Original languageEnglish
Pages (from-to)970-977.e11
JournalMolecular cell
Volume68
Issue number5
DOIs
StatePublished - Dec 7 2017

Keywords

  • Coq5p
  • MIPEP
  • Oct1p
  • coenzyme Q
  • mitochondria
  • mitoproteases
  • multi-omic
  • oligopeptidase
  • protease
  • transomic
  • ubiquinone

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