Redox Regulation of the Mitochondrial Quality Control Protease Oma1

Iryna Bohovych, Jonathan V. Dietz, Samantha Swenson, Nataliya Zahayko, Oleh Khalimonchuk

Research output: Contribution to journalReview article

4 Scopus citations

Abstract

Aims: Normal mitochondrial function and integrity are crucial for cellular physiology. Given the paramount role of mitochondrial quality control proteases in these processes, our study focused on investigating mechanisms by which the activity of a key quality control protease Oma1 is regulated under normal conditions and in response to homeostatic insults. Results: Oma1 was found to be a redox-dependent protein that exists in a semi-oxidized state in yeast and mammalian mitochondria. Biochemical and genetic analyses provide evidence that activity and stability of the Oma1 oligomeric complex can be dynamically tuned in a reduction/oxidation-sensitive manner. Mechanistically, these features appear to be mediated by two intermembrane space (IMS)-exposed highly conserved cysteine residues, Cys272 and Cys332. These residues form a disulfide bond, which likely plays a structural role and influences conformational stability and activity of the Oma1 high-mass complex. Finally, in line with these findings, engineered Oma1 substrate is shown to engage with the protease in a redox-sensitive manner. Innovation: This study provides new insights into the function of the Oma1 protease, a central controller of mitochondrial membrane homeostasis and dynamics, and reveals the novel conserved mechanism of the redox-dependent regulation of Oma1. Conclusion: Disulfide bonds formed by IMS-exposed residues Cys272 and Cys332 play an important evolutionarily conserved role in the regulation of Oma1 function. We propose that the redox status of these cysteines may act as a redox-tunable switch to optimize Oma1 proteolytic function for specific cellular conditions or homeostatic challenges.

Original languageEnglish (US)
Pages (from-to)429-443
Number of pages15
JournalAntioxidants and Redox Signaling
Volume31
Issue number6
DOIs
StatePublished - Aug 20 2019

Keywords

  • Oma1
  • mitochondria
  • mitochondrial quality control
  • proteases
  • redox regulation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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