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Mol Cell. 2017 Dec 7;68(5):970-977.e11. doi: 10.1016/j.molcel.2017.11.023.

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

Author information

1
Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
2
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
3
Genome Center of Wisconsin, Madison, WI 53706, USA.
4
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
5
Morgridge Institute for Research, Madison, WI 53715, USA.
6
Morgridge Institute for Research, Madison, WI 53715, USA; Genome Center of Wisconsin, Madison, WI 53706, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
7
Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: dpagliarini@morgridge.org.

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.

KEYWORDS:

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

PMID:
29220658
PMCID:
PMC5730362
DOI:
10.1016/j.molcel.2017.11.023
[Indexed for MEDLINE]
Free PMC Article

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