Multi-omic mitoprotease profiling defines a role for Oct1p in coenzyme Q production

Abstract

SUMMARYMitoproteases 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 CoQrelated 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 posttranslational event for proper CoQ production. Our custom data visualization tool enables efficient exploration of mitoprotease profiles that can serve as the basis for future mechanistic investigations.

PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome

“…The mechanism that links ablation of PARL to the reduced COQ4 and the resulting CoQ deficiency in the brain is, however, not yet clear, as we could not demonstrate that COQ4 is a substrate of PARL. One possibility is that misprocessing of a still undefined PARL substrate affects CoQ biosynthesis upstream of COQ4, similarly to how the yeast intermediate peptidase Oct1p ensures CoQ biosynthesis by cleaving Coq5p (41). An alternative hypothesis is that PARL regulates CoQ biosynthesis indirectly by generating an early stress response that precedes the respiration defects.…”

Coenzyme Q homeostasis in aging: Response to non-genetic interventions

“…Members of the CoQ-synthome need to be processed by proteolysis to be stabilized in the biosynthesis complex. The mitochondrial matrix octapeptidase Oct1p directly processes the N terminus of COQ5 improving its stability [114].…”

More than just a ticket canceller: the mitochondrial processing peptidase tailors complex precursor proteins at internal cleavage sites

“…How is the Arg5,6 precursor processed to give rise to the Arg6 and Arg5 enzymes? A number of proteases in the mitochondrial matrix are described (Quiros et al, 2015;Veling et al, 2017). However, most of them are either implicated in degradation and turnover of proteins (such as the Lon protease Pim1) or known to remove short peptides or single amino acids from the N-termini of mitochondrial precursor proteins (such as Oct1 or Icp55), but not for internal cleavage of proteins into two mature parts (Suzuki et al, 1994;Wagner et al, 1994;Vögtle et al, 2009Vögtle et al, , 2011Poveda-Huertes et al, 2017).…”