Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria
Abstract
Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.
Additional Information
© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 13 January 2021; Accepted 04 February 2022; Published 24 March 2022. We thank H.J. Bellen, A. Whitworth, and R.J. Youle for reagents, A.M. van der Bliek for comments on the manuscript, Y. Sun and P. Zheng for technical advice, and F.A. Laski, L. Dreier, E. Videlock, the BRI/UCLA EM Core Facility and the BSCRC/MCDB Microscopy Core Facility at UCLA for equipment. This work was supported by the China Scholarship Council Fellowship and UCLA Dissertation Year Fellowship to H.Y., the Wellcome Trust-NIH Ph.D. Studentship (WT088328AIA) to C.S., C.B., and R.J.H., the Intramural Research Program of the NINDS to C.B., and the R01 from the National Institute on Aging, Glenn Foundation for Medical Research, Kenneth Glenn Family Foundation, the Louis B. Mayer Foundation, the B. Freeman and R. Spogoli Fund for Aging and Neurodegeneration, the UCLA Laurie and Steven Gordon Commitment to Cure Parkinson's Disease, the Renee and Meyer Luskin Family Fund to M.G. Data availability: All data are available within the Article, Supplementary Information, or Source Data file. Source data for Fig. 3a, b, and Supplementary Table 1 have been provided as Supplementary Table 2. All other source data are provided in the Source Data file with this paper. The knockout cell lines and transgenic flies generated in this work are available from the corresponding author upon request. Source data are provided with this paper. Contributions: H.Y. designed, performed, and analyzed experiments and wrote the paper. C.S., R.L., J.Y., C.B., and R.J.H. designed, performed, and analyzed experiments. B.A.H. designed and analyzed experiments and wrote the paper. D.C.C. designed and analyzed experiments. M.G. designed and supervised the experiments, analyzed the results, provided the funding, and wrote the paper. The authors declare no competing interests. Peer review information: Nature Communications thanks Dorothy Lerit and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.Attached Files
Published - s41467-022-29071-4.pdf
Supplemental Material - 41467_2022_29071_MOESM1_ESM.pdf
Supplemental Material - 41467_2022_29071_MOESM2_ESM.pdf
Supplemental Material - 41467_2022_29071_MOESM3_ESM.pdf
Supplemental Material - 41467_2022_29071_MOESM4_ESM.xlsx
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Additional details
- Eprint ID
- 114100
- Resolver ID
- CaltechAUTHORS:20220328-640822600
- China Scholarship Council
- UCLA
- WT088328AIA
- Wellcome Trust
- NIH
- Glenn Foundation for Medical Research
- Kenneth Glenn Family Foundation
- Louis B. Mayer Foundation
- B. Freeman and R. Spogoli Fund for Aging and Neurodegeneration
- Renee and Meyer Luskin Family Fund
- Created
-
2022-03-28Created from EPrint's datestamp field
- Updated
-
2022-03-28Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering, Division of Biology and Biological Engineering