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PreprintCited by 2Mitochondrial Function and PathologyAutophagy in Disease and TherapyCell death mechanisms and regulation

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OMA1-mediated cleavage of AIFM1 upon mitochondrial stress and suppression of cell growth through the control of OXPHOS activity

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Nishigori, Mitsuhiro, Hirata, Serina, Kosako, Hidetaka, Nolte, Hendrik, Riemer, Jan, Langer, Thomas, Koshiba, Takumi·2025·The EMBO Journal
DOI 10.1101/2025.05.19.654756

Preprint — published as 10.1038/s44318-026-00734-y

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Abstract

Mitochondrial proteases regulate the dynamic properties of organelle morphology and ensure functional plasticity at the cellular level. The metalloprotease OMA1 mediates constitutive and stress-inducible processing of its mitochondrial substrates, but the number of functionally characterized targets remains limited. Using multiproteomic and biochemical approaches, we demonstrated that the membrane-anchored inner membrane space (IMS) protein AIFM1 serves as a mitochondrial stress-responsive substrate of OMA1. OMA1 cleaves AIFM1 in the IMS under stress conditions with a kinetically slower reaction than that of its conventional substrate, dynamin-like GTPase OPA1. Membrane dislocation of cleaved AIFM1 in mitochondria reduces its binding to subunits of the oxidative phosphorylation machinery, leading to decreased respiratory activity and ultimately impaired cell growth. Mechanistically, we revealed that AIFM1 broadly safeguards the mitochondrial proteome under steady-state conditions by mediating the import of proteins, particularly respiratory complex I subunits, via the TIM23 complex. These findings reveal a previously unrecognized role for OMA1 in integrating mitochondrial stress sensing and cellular energetics by altering the AIFM1 topology.

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Metadata

Authors
Nishigori, M., Hirata, S., Kosako, H., Nolte, H., Riemer, J., Langer, T., & Koshiba, T.
Affiliations
  • Fukuoka University (JP)
  • Institute of Advanced Medical Sciences, Tokushima University (JP)
  • Max Planck Institute for Biology of Ageing (DE)
  • University of Cologne (DE)
Corresponding author
Koshiba, Takumi
ORCID
Venue
The EMBO Journal
Publisher
openRxiv
Published
2025-05-21
Volume
45
Issue
11
Pages
3655-3698
ISSN
0261-4189 (ISSN-L)
DOI
10.1101/2025.05.19.654756
OpenAlex
W7140192728
Cited by
2
References
1
Citations by year
2026: 2
FWCI
4.13
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
JSPS KAKENHI (25K14949, 21K19389, 23K26789, 25H02336)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
OMA1, apoptosis-inducing factor, mitochondrial stress, oxidative phosphorylation, cell growth, mitochondrial proteome, TIM23 complex, mitochondrial complex I, OPA1, viral infection, mitochondrial protein import, respiratory activity
MeSH terms
Animals, Humans, Metalloendopeptidases, Mitochondria, Oxidative Phosphorylation, Stress, Physiological, GTP Phosphohydrolases, Mitochondrial Proteins, Metalloproteases, Cell Proliferation, Apoptosis Inducing Factor, Mitochondrial Membranes, Mice, Proteolysis

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