Proteolytic Cleavage of Opa1 Stimulates Mitochondrial Inner Membrane Fusion and Couples Fusion to Oxidative Phosphorylation
Open accessAbstract
Mitochondrial fusion is essential for maintenance of mitochondrial function. The mitofusin GTPases control mitochondrial outer membrane fusion, whereas the dynamin-related GTPase Opa1 mediates inner membrane fusion. We show that mitochondrial inner membrane fusion is tuned by the level of oxidative phosphorylation (OXPHOS), whereas outer membrane fusion is insensitive. Consequently, cells from patients with pathogenic mtDNA mutations show a selective defect in mitochondrial inner membrane fusion. In elucidating the molecular mechanism of OXPHOS-stimulated fusion, we uncover that real-time proteolytic processing of Opa1 stimulates mitochondrial inner membrane fusion. OXPHOS-stimulated mitochondrial fusion operates through Yme1L, which cleaves Opa1 more efficiently under high OXPHOS conditions. Engineered cleavage of Opa1 is sufficient to mediate inner membrane fusion, regardless of respiratory state. Proteolytic cleavage therefore stimulates the membrane fusion activity of Opa1, and this feature is exploited to dynamically couple mitochondrial fusion to cellular metabolism.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
YME1L1 cuts site S2 in exon 5b of OPA1L splicing variants 4, 6, 7, and 8 under high OXPHOS conditions.
“YME1L1 cuts the site S2 in exon 5b of a subset of OPA1L belonging to the splicing variants 4, 6, 7, and 8 [76] under high OXPHOS conditions [77].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [77]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Mitochondrial Fission, Fusion, and Stress
Youle, R. J., & van der Bliek, A. M. (2012) · Science · doi:10.1126/science.1219855 · Cited by 3,674 · see citing works
Chen, H., Detmer, S. A., Ewald, A. J., Griffin, E. E., Fraser, S. E., & Chan, D. C. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200211046 · Cited by 2,601 · see citing works
Self-citationMitochondrial fusion and fission in cell life and death
Westermann, B. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3013 · Cited by 2,002 · cited 1× · see citing works
“Within a cell, the mitochondria exist as a population of dynamic organelles that continually interact through fusion and fission (Chan, 2012; Westermann, 2010; Youle and van der Bliek, 2012).”
BackgroundMitochondrial Respiratory-Chain Diseases
DiMauro, S., & Schon, E. A. (2003) · New England Journal of Medicine · doi:10.1056/nejmra022567 · Cited by 1,650 · see citing works
Fusion and fission: interlinked processes critical for mitochondrial health
Chan, D. C. (2012) · Annual Review of Genetics · doi:10.1146/annurev-genet-110410-132529 · Cited by 1,196 · see citing works
Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria
Cereghetti, G. M., Stangherlin, A., de Brito, O. M., Chang, C. R., Blackstone, C., Bernardi, P., & Scorrano, L. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808249105 · Cited by 1,129 · see citing works
RESPIRATORY ENZYMES IN OXIDATIVE PHOSPHORYLATION
Chance, B., & Williams, G. R. (1955) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)57191-5 · Cited by 1,125 · see citing works
Cribbs, J. T., & Strack, S. (2007) · EMBO Reports · doi:10.1038/sj.embor.7401062 · Cited by 1,024 · 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
Respiratory Enzymes in Oxidative Phosphorylation
Chance, B., & Baltscheffsky, H. (1958) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)64738-6 · Cited by 893 · see citing works
Energy Substrate Modulates Mitochondrial Structure and Oxidative Capacity in Cancer Cells
Rossignol, R., Gilkerson, R., Aggeler, R., Yamagata, K., Remington, S., & Capaldi, R. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-1101 · Cited by 865 · 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
Self-citationLegros, F., Lombès, A., Frachon, P., & Rojo, M. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-06-0330 · Cited by 676 · see citing works
Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion
Song, Z., Ghochani, M., McCaffery, J. M., Frey, T. G., & Chan, D. C. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-03-0252 · Cited by 623 · see citing works
Mitochondrial Fusion in Yeast Requires the Transmembrane GTPase Fzo1p
Hermann, G. J., Thatcher, J., Mills, J. P., Hales, K. G., Fuller, M., Nunnari, J., & Shaw, J. (1998) · Journal of Cell Biology · doi:10.1083/jcb.143.2.359 · Cited by 572 · see citing works
Regulation of OPA1 processing and mitochondrial fusion by m -AAA protease isoenzymes and OMA1
Ehses, S., Lauria, I., Mancuso, G., Bernacchia, A., Geimer, S., Tondera, D., Martinou, J., Westermann, B., Rugarli, E. I., & Langer, T. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200906084 · Cited by 570 · see citing works
Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells
Head, B., Griparic, L., Amiri, M., Gandre-Babbe, S., & van der Bliek, A. M. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200906083 · Cited by 515 · see citing works
Rogers, G. W., Brand, M. D., Petrosyan, S., Ashok, D., Elorza, Á. A., Ferrick, D. A., & Murphy, A. N. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021746 · Cited by 474 · see citing works
Mitochondrial Inner-Membrane Fusion and Crista Maintenance Requires the Dynamin-Related GTPase Mgm1
Meeusen, S., DeVay, R. M., Block, J., Cassidy-Stone, A., Wayson, S. M., McCaffery, J. M., & Nunnari, J. M. (2006) · Cell · doi:10.1016/j.cell.2006.09.021 · Cited by 474 · 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
Mitochondrial Fusion Intermediates Revealed in Vitro
Meeusen, S. L., McCaffery, J., & Nunnari, J. (2004) · Science · doi:10.1126/science.1100612 · Cited by 466 · see citing works
Karbowski, M., Arnoult, D., Chen, H., Chan, D. C., Smith, C. L., & Youle, R. J. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200309082 · Cited by 433 · see citing works
Self-citationDuvezin‐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
Mutation spectrum and splicing variants in the OPA1 gene
Delettre, C., Griffoin, J., Kaplan, J., Dollfus, H., Lorenz, B., Faivre, L. O., Lenaers, G., Belenguer, P., & Hamel, C. (2001) · Human Genetics · doi:10.1007/s00439-001-0633-y · Cited by 398 · see citing works
Herlan, M., Vogel, F., Bornhövd, C., Neupert, W., & Reichert, A. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211311200 · Cited by 378 · 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
Quirós, P. M., Ramsay, A. J., Sala, D., Fernández‐Vizarra, E., Rodríguez, F., Peinado, J. R., Fernández‐García, M. S., Vega, J. A., Enríquez, J. A., Zorzano, A., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.70 · Cited by 269 · see citing works
The Soluble Form of Bax Regulates Mitochondrial Fusion via MFN2 Homotypic Complexes
Hoppins, S. C., Edlich, F., Harwig, M. C., Banerjee, S., McCaffery, J. M., Youle, R. J., & Nunnari, J. M. (2011) · Molecular Cell · doi:10.1016/j.molcel.2010.11.030 · Cited by 243 · see citing works
Separate fusion of outer and inner mitochondrial membranes
Malka, F., Guillery, O., Cifuentes-Díaz, C., Guillou, E., Belenguer, P., Lombès, A., & Rojo, M. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400488 · Cited by 233 · see citing works
Structure and function of the bacterial AAA protease FtsH
Schäkermann, S., Baumann, U., & Narberhaus, F. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.08.015 · Cited by 219 · see citing works
Koopman, W. J. H., Visch, H.-J., Verkaart, S., van den Heuvel, L. P., Smeitink, J. A. M., & Willems, P. H. G. M. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00104.2005 · Cited by 192 · 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
Stibůrek, L., Cesnekova, J., Kostková, O., Fornůsková, D., Vinšová, K., Wenchich, L., Houštěk, J., & Zeman, J. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-08-0674 · Cited by 180 · see citing works
Baracca, A., Solaini, G., Sgarbi, G., Lenaz, G., Baruzzi, A., Schapira, A. H. V., Martinuzzi, A., & Carelli, V. (2005) · Archives of Neurology · doi:10.1001/archneur.62.5.730 · Cited by 163 · see citing works
Self-citationKäser, M., Kambacheld, M., Kisters–Woike, B., & Langer, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305584200 · Cited by 155 · see citing works
The mitochondrial respiratory chain is a modulator of apoptosis
Kwong, J. Q., Henning, M. S., Starkov, A. A., & Manfredi, G. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200704059 · Cited by 145 · see citing works
Self-citationEnergetic requirements and bioenergetic modulation of mitochondrial morphology and dynamics
Sauvanet, C., Duvezin‐Caubet, S., di Rago, J., & Rojo, M. (2009) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2009.12.006 · Cited by 114 · see citing works
OPA1 promotes pH flashes that spread between contiguous mitochondria without matrix protein exchange
Domingo, J. S., Giacomello, M., Poburko, D., Scorrano, L., & Demaurex, N. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.124 · Cited by 100 · see citing works
Modulation of mitochondrial morphology by bioenergetics defects in primary human fibroblasts
Guillery, O., Malka, F., Frachon, P., Miléa, D., Rojo, M., & Lombès, A. (2008) · Neuromuscular Disorders · doi:10.1016/j.nmd.2007.12.008 · Cited by 90 · see citing works
Schauss, A. C., Huang, H., Choi, S., Xu, L., Soubeyrand, S., Bilodeau, P. S., Zunino, R., Rippstein, P. U., Frohman, M. A., & McBride, H. M. (2010) · BMC Biology · doi:10.1186/1741-7007-8-100 · Cited by 47 · see citing works
Huckriede, A. L. W., Heikema, A. P., Agsteribbe, E., et al. (1995) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/bf00196521 · Cited by 37 · see citing works
Mitochondrial DNA Mutations Provoke Dominant Inhibition of Mitochondrial Inner Membrane Fusion
Sauvanet, C., Duvezin‐Caubet, S., Salin, B., David, C., Massoni‐Laporte, A., di Rago, J., & Rojo, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049639 · Cited by 24 · see citing works
Handran, S. D., Werth, J. L., DeVivo, D. C., et al. (1997) · Neurobiology of Disease · doi:10.1006/nbdi.1996.0125 · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial Dynamics and Its Involvement in Disease
Chan, D. C. (2020) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012419-032711 · Cited by 1,416 · see citing works
Self-citationMitochondrial dynamics in health and disease: mechanisms and potential targets
Chen, W., Zhao, H., & Li, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01547-9 · Cited by 1,306 · see citing works
AMP-activated protein kinase mediates mitochondrial fission in response to energy stress
Toyama, E. Q., Herzig, S., Courchet, J., Lewis, T. L., Losón, O. C., Hellberg, K., Young, N. P., Chen, H., Polleux, F., Chan, D. C., et al. (2016) · Science · doi:10.1126/science.aab4138 · Cited by 1,085 · see citing works
Self-citationMitochondrial dynamics in adaptive and maladaptive cellular stress responses
Eisner, V., Picard, M., & Hajnóczky, G. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0133-0 · Cited by 622 · see citing works
Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice
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
Exercise Promotes Healthy Aging of Skeletal Muscle
Cartee, G. D., Hepple, R. T., Bamman, M. M., & Zierath, J. R. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.007 · Cited by 483 · see citing works
Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin
Ban, T., Ishihara, T., Kohno, H., Saita, S., Ichimura, A., Maenaka, K., Oka, T., Mihara, K., & Ishihara, N. (2017) · Nature Cell Biology · doi:10.1038/ncb3560 · Cited by 410 · see citing works
Cloonan, S. M., & Choi, A. M. K. (2016) · Journal of Clinical Investigation · doi:10.1172/jci81113 · Cited by 322 · see citing works
How mitochondrial dynamism orchestrates mitophagy
Shirihai, O. S., Song, M., & Dorn, G. W. (2015) · Circulation Research · doi:10.1161/circresaha.116.306374 · Cited by 311 · see citing works
Mishra, P., Varuzhanyan, G., Pham, A. H., & Chan, D. C. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.09.027 · Cited by 290 · see citing works
Self-citationHou, J., Zhang, J., Cui, P., Zhou, Y., Liu, C., Wu, X., Ji, Y., Wang, S., Cheng, B., Ye, H., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci135197 · Cited by 239 · see citing works
Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system
Yang, S., Qin, C., Hu, Z.-W., Zhou, L.-Q., Yu, H.-H., Chen, M., Bosco, D. B., Wang, W., Wu, L.-J., & Tian, D.-S. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105290 · Cited by 232 · see citing works
Romanello, V., & Sandri, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03662-0 · Cited by 197 · see citing works
Mitochondrial fission and fusion
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
Dysregulated mitophagy and mitochondrial organization in optic atrophy due to <i>OPA1</i> mutations
Liao, C., Ashley, N., Diot, A., Morten, K., Phadwal, K., Williams, A., Fearnley, I., Rosser, L., Lowndes, J., Fratter, C., et al. (2017) · Neurology · doi:10.1212/wnl.0000000000003491 · Cited by 97 · see citing works
Mitochondrial Proteolysis and Metabolic Control
Ahola, S., Langer, T., & MacVicar, T. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a033936 · Cited by 37 · see citing works
- Authors
- Mishra, P., Carelli, V., Manfredi, G., & Chan, D. C.
- Affiliations
- California Institute of Technology (US)
- Cornell University (US)
- Corresponding author
- Chan, David C.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 19
- Issue
- 4
- Pages
- 630-641
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4018240
- OpenAlex
- W2117931978
- Cited by
- 473
- References
- 43
- Citations by year
- 2026: 20 · 2025: 39 · 2024: 50 · 2023: 39 · 2022: 50 · 2021: 46 · 2020: 53 · 2019: 38 · 2018: 29 · 2017: 38 · 2016: 38 · 2015: 25 · 2014: 8
- FWCI
- 14.89
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-05-06)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (R01GM062967, GM062967)
- 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 › ATP Synthase and ATPases Research
- Keywords
- OPA1, oxidative phosphorylation, proteolytic cleavage, YME1L, dynamin-related GTPase, mitochondrial fusion, mitochondrial DNA mutations
- MeSH terms
- Animals, Membrane Fusion, Oxidative Phosphorylation, Mitochondrial Encephalomyopathies, GTP Phosphohydrolases, RNA Interference, RNA, Small Interfering, Mitochondrial Membranes, Mice, Mitochondrial Size, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
