Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells
Open accessAbstract
The mammalian mitochondrial inner membrane fusion protein OPA1 is controlled by complex patterns of alternative splicing and proteolysis. A subset of OPA1 isoforms is constitutively cleaved by YME1L. Other isoforms are not cleaved by YME1L, but they are cleaved when mitochondria lose membrane potential or adenosine triphosphate. In this study, we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1. We find that OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function. We also find that OMA1 is normally cleaved from 60 to 40 kD by another as of yet unidentified protease. Loss of membrane potential causes 60-kD protein to accumulate, suggesting that OMA1 is attenuated by proteolytic degradation. We conclude that a proteolytic cascade controls OPA1. Inducible cleavage provides a mechanism for quality control because proteolytic inactivation of OPA1 promotes selective removal of defective mitochondrial fragments by preventing their fusion with the mitochondrial network.
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OPA1L is cleaved in exon 5 (site S1) by OMA1 in a process dependent on mitochondrial membrane potential.
“OPA1L is anchored to the IMM by a transmembrane domain at the N-terminus and can be further cleaved in exon 5 (site S1) by OMA1, a process which depends on the mitochondrial membrane potential [75].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [75]
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Cites
Fission and selective fusion govern mitochondrial segregation and elimination by autophagy
Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., et al. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601963 · Cited by 3,082 · see citing works
The Role of Dynamin-Related Protein 1, a Mediator of Mitochondrial Fission, in Apoptosis
Frank, S., Gaume, B., Bergmann-Leitner, E. S., Leitner, W. W., Robert, E. G., Catez, F., Smith, C. L., & Youle, R. J. (2001) · Developmental Cell · doi:10.1016/s1534-5807(01)00055-7 · Cited by 1,755 · see citing works
Cassidy-Stone, A., Chipuk, J. E., Ingerman, E., Song, C., Yoo, C., Kuwana, T., Kurth, M. J., Shaw, J. T., Hinshaw, J. E., Green, D. R., et al. (2008) · Developmental Cell · doi:10.1016/j.devcel.2007.11.019 · Cited by 1,200 · see citing works
Olichon, A., Baricault, L., Gas, N., Guillou, E., Valette, A., Belenguer, P., & Lenaers, G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c200677200 · Cited by 1,168 · see citing works
Regulation of mitochondrial morphology through proteolytic cleavage of OPA1
Ishihara, N., Fujita, Y., Oka, T., & Mihara, K. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601184 · Cited by 899 · see citing works
Song, Z., Chen, H., Fiket, M., Alexander, C., & Chan, D. C. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200704110 · Cited by 818 · see citing works
The Machines that Divide and Fuse Mitochondria
Hoppins, S., Lackner, L., & Nunnari, J. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.071905.090048 · Cited by 790 · see citing works
Gandre-Babbe, S., & van der Bliek, A. M. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-12-1287 · Cited by 769 · see citing works
Self-citationCipolat, S., Rudka, T., Hartmann, D., Costa, V., Serneels, L., Craessaerts, K., Metzger, K., Frezza, C., Annaert, W. G., D'adamio, L., et al. (2006) · Cell · doi:10.1016/j.cell.2006.06.021 · Cited by 735 · see citing works
Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery
Yang, Y., Ouyang, Y., Yang, L., Beal, M. F., McQuibban, G. A., Vogel, H. S., & Lu, B. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711845105 · Cited by 536 · see citing works
Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage
Griparić, L., Kanazawa, T., & van der Bliek, A. M. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200704112 · Cited by 467 · see citing works
Duvezin‐Caubet, S., Jagasia, R., Wagener, J., Hofmann, S., Trifunović, A., Hansson, A., Chomyn, A., Bauer, M. F., Attardi, G. M., Larsson, N., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606059200 · Cited by 431 · see citing works
Coassembly of Mgm1 isoforms requires cardiolipin and mediates mitochondrial inner membrane fusion
DeVay, R. M., Domínguez‐Ramírez, L., Lackner, L. L., Hoppins, S. C., Stahlberg, H., & Nunnari, J. M. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200906098 · Cited by 276 · see citing works
Wong, E. D., Wagner, J. A., Scott, S. V., Okreglak, V., Holewinske, T. J., Cassidy-Stone, A., & Nunnari, J. M. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200209015 · Cited by 255 · see citing works
Metalloprotease‐mediated OPA1 processing is modulated by the mitochondrial membrane potential
Guillery, O., Malka, F., Landes, T., Guillou, E., Blackstone, C. D., Lombès, A., Belenguer, P., Arnoult, D., & Rojo, M. (2008) · Biology of the Cell · doi:10.1042/bc20070110 · Cited by 189 · see citing works
Käser, M., Kambacheld, M., Kisters–Woike, B., & Langer, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305584200 · Cited by 155 · see citing works
Membrane Potential-Driven Protein Import into Mitochondria
Geissler, A., Krimmer, T., Bömer, U., Guiard, B., Rassow, J., & Pfanner, N. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.11.3977 · Cited by 144 · see citing works
OPA1 cleavage depends on decreased mitochondrial ATP level and bivalent metals
Baricault, L., Ségui, B., Guégand, L., Olichon, A., Valette, A., Larminat, F., & Lenaers, G. (2007) · Experimental Cell Research · doi:10.1016/j.yexcr.2007.08.008 · Cited by 103 · see citing works
Bao, Y.-C. (2003) · DNA Research · doi:10.1093/dnares/10.3.123 · Cited by 5 · see citing works
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Youle, R. J., & van der Bliek, A. M. (2012) · Science · doi:10.1126/science.1219855 · Cited by 3,674 · see citing works
Mitochondria: In Sickness and in Health
Nunnari, J., & Suomalainen, A. (2012) · Cell · doi:10.1016/j.cell.2012.02.035 · Cited by 3,479 · see citing works
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Larsson, L., Degens, H., Li, M., Salviati, L., Lee, Y. I., Thompson, W., Kirkland, J. L., & Sandri, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00061.2017 · Cited by 1,797 · see citing works
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Friedman, J. R., & Nunnari, J. (2014) · Nature · doi:10.1038/nature12985 · Cited by 1,803 · see citing works
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Giacomello, M., Pyakurel, A., Glytsou, C., & Scorrano, L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0210-7 · Cited by 1,550 · see citing works
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Jin, S. M., Lazarou, M., Wang, C., Kane, L. A., Narendra, D. P., & Youle, R. J. (2010) · Journal of Cell Biology · doi:10.1083/jcb.201008084 · Cited by 1,375 · see citing works
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Suen, D.-F., Norris, K. L., & Youle, R. J. (2008) · Genes & Development · doi:10.1101/gad.1658508 · Cited by 1,270 · see citing works
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Chan, D. C. (2012) · Annual Review of Genetics · doi:10.1146/annurev-genet-110410-132529 · Cited by 1,196 · see citing works
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Ding, W.-X., & Yin, X.-M. (2012) · bchm · doi:10.1515/hsz-2012-0119 · Cited by 1,032 · see citing works
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Anand, R., Wai, T., Baker, M. J., Kladt, N., Schauss, A. C., Rugarli, E., & Langer, T. (2014) · Journal of Cell Biology · doi:10.1083/jcb.201308006 · Cited by 812 · see citing works
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Eisner, V., Picard, M., & Hajnóczky, G. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0133-0 · Cited by 622 · see citing works
The mitochondrial pathways of apoptosis
Estaquier, J., Vallette, F., Vayssiere, J.-L., & Mignotte, B. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-94-007-2869-1_7 · Cited by 637 · see citing works
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Wai, T., García-Prieto, J., Baker, M. J., Merkwirth, C., Benit, P., Rustin, P., Rupérez, F. J., Barbas, C., Ibañez, B., & Langer, T. (2015) · Science · doi:10.1126/science.aad0116 · Cited by 551 · see citing works
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Romanello, V., & Sandri, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03662-0 · Cited by 197 · see citing works
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Lee, H., & Yoon, Y. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160129 · Cited by 183 · see citing works
Constriction of the mitochondrial inner compartment is a priming event for mitochondrial division
Cho, B., Cho, H. M., Jo, Y., Kim, H. D., Song, M., Moon, C., Kim, H., Kim, K., Sesaki, H., Rhyu, I. J., et al. (2017) · Nature Communications · doi:10.1038/ncomms15754 · Cited by 179 · see citing works
Hartmann, B., Wai, T., Hu, H., MacVicar, T., Musante, L., Fischer-Zirnsak, B., Stenzel, W., Gräf, R., van den Heuvel, L., Ropers, H.-H., et al. (2016) · eLife · doi:10.7554/elife.16078 · Cited by 124 · see citing works
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Kang, S., Louboutin, J.-P., Datta, P., Landel, C. P., Martinez, D., Zervos, A. S., Strayer, D. S., Fernandes-Alnemri, T., & Alnemri, E. S. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2012.117 · Cited by 84 · see citing works
Neubauer, M., Zhu, Z., Penka, M., Helmschrott, C., Wagener, N., & Wagener, J. (2015) · Molecular Microbiology · doi:10.1111/mmi.13167 · Cited by 76 · see citing works
- Authors
- Head, B., Griparic, L., Amiri, M., Gandre-Babbe, S., & van der Bliek, A. M.
- Affiliations
- University of California, Los Angeles (US)
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095
- ORCID
- Head, Brian
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2009-12-28
- Volume
- 187
- Issue
- 7
- Pages
- 959-966
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2806274
- OpenAlex
- W2111626525
- Cited by
- 515
- References
- 19
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 30 · 2023: 31 · 2022: 39 · 2021: 44 · 2020: 34 · 2019: 41 · 2018: 34 · 2017: 32 · 2016: 33 · 2015: 33 · 2014: 29 · 2013: 26 · 2012: 40
- FWCI
- 8.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM051866, GM-051866)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- OPA1, OMA1, proteolytic inactivation, zinc metalloprotease, YME1L, alternative splicing, mitochondrial membrane potential, ATP depletion, apoptosis, proteolytic cascade, mitochondrial quality control, mitochondrial fragmentation
- MeSH terms
- Carbonyl Cyanide m-Chlorophenyl Hydrazone, HeLa Cells, Humans, Membrane Potentials, Metalloendopeptidases, Mitochondria, Peptide Hydrolases, Apoptosis, Protein Isoforms, GTP Phosphohydrolases, Mitochondrial Proteins, RNA Interference
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