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Identification of new OPA1 cleavage site reveals that short isoforms regulate mitochondrial fusion

Wang, Ruohan and Mishra, Prashant and Garbis, Spiros D. and Moradian, Annie and Sweredoski, Michael J. and Chan, David C. (2021) Identification of new OPA1 cleavage site reveals that short isoforms regulate mitochondrial fusion. Molecular Biology of the Cell, 32 (2). pp. 157-168. ISSN 1059-1524. PMCID PMC8120690. doi:10.1091/mbc.e20-09-0605. https://resolver.caltech.edu/CaltechAUTHORS:20201202-104543824

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Abstract

OPA1, a large GTPase of the dynamin superfamily, mediates fusion of the mitochondrial inner membranes, regulates cristae morphology, and maintains respiratory chain function. Inner membrane–anchored long forms of OPA1 (l-OPA1) are proteolytically processed by the OMA1 or YME1L proteases, acting at cleavage sites S1 and S2, respectively, to produce short forms (s-OPA1). In both mice and humans, half of the mRNA splice forms of Opa1 are constitutively processed to yield exclusively s-OPA1. However, the function of s-OPA1 in mitochondrial fusion has been debated, because in some stress conditions, s-OPA1 is dispensable for fusion. By constructing cells in which the Opa1 locus no longer produces transcripts with S2 cleavage sites, we generated a simplified system to identify the new YME1L-dependent site S3 that mediates constitutive and complete cleavage of OPA1. We show that mitochondrial morphology is highly sensitive to the ratio of l-OPA1 to s-OPA1, indicating that s-OPA1 regulates mitochondrial fusion.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1091/mbc.e20-09-0605DOIArticle
https://www.molbiolcell.org/doi/suppl/10.1091/mbc.E20-09-0605PublisherSupplemental Material
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120690PubMed CentralArticle
ORCID:
AuthorORCID
Wang, Ruohan0000-0001-8361-4005
Garbis, Spiros D.0000-0002-1050-0805
Moradian, Annie0000-0002-0407-2031
Sweredoski, Michael J.0000-0003-0878-3831
Chan, David C.0000-0002-0191-2154
Alternate Title:Novel s-OPA1 regulates mitochondrial fusion
Additional Information:© 2021 Wang et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). Received: Sep 22, 2020; Revised: Nov 9, 2020; Accepted: Nov 16, 2020. We thank Thomas Langer (Max-Planck-Institute for Biology of Ageing) for the Oma1-null, Yme1l-null, and Oma1/Yme1l-null cells. We thank Carlos López Otin (Universidad de Oviedo) for the Oma1 knockout mice. This work was supported by a grant to D.C.C. from the National Institute of General Medical Sciences (R35GM127147). The authors declare they have no conflicts of interest with the contents of this article. Author contributions: R.W. and D.C.C. conceptualized the project, analyzed the data, and wrote the manuscript. R.W. carried out the experimental analysis. P.M. performed the PA-GFP fusion assays. A.M. performed the LC-MS experiments. The data were analyzed by S.D.G. and M.J.S.
Funders:
Funding AgencyGrant Number
NIHR35GM127147
Subject Keywords:OPA1, mitochondrial dynamics, mitochondrial fusion, dynamin, GTP hydrolyzing enzyme, membrane fusion
Issue or Number:2
PubMed Central ID:PMC8120690
DOI:10.1091/mbc.e20-09-0605
Record Number:CaltechAUTHORS:20201202-104543824
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201202-104543824
Official Citation:Identification of new OPA1 cleavage site reveals that short isoforms regulate mitochondrial fusion Ruohan Wang, Prashant Mishra, Spiros D. Garbis, Annie Moradian, Michael J. Sweredoski, and David C. Chan Molecular Biology of the Cell 2021 32:2, 157-168
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:106876
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:02 Dec 2020 19:30
Last Modified:17 May 2021 18:10

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