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RALA and RALBP1 regulate mitochondrial fission at mitosis

Nature Cell Biology volume 13, pages 1108–1115 (2011)Cite this article

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Abstract

Mitochondria exist as dynamic interconnected networks that are maintained through a balance of fusion and fission1. Equal distribution of mitochondria to daughter cells during mitosis requires fission2. Mitotic mitochondrial fission depends on both the relocalization of the large GTPase DRP1 to the outer mitochondrial membrane and phosphorylation of Ser 616 on DRP1 by the mitotic kinase cyclin B–CDK1 (ref. 2). We now report that these processes are mediated by the small Ras-like GTPase RALA and its effector RALBP1 (also known as RLIP76, RLIP1 or RIP1; refs 3, 4). Specifically, the mitotic kinase Aurora A phosphorylates Ser 194 of RALA, relocalizing it to the mitochondria, where it concentrates RALBP1 and DRP1. Furthermore, RALBP1 is associated with cyclin B–CDK1 kinase activity that leads to phosphorylation of DRP1 on Ser 616. Disrupting either RALA or RALBP1 leads to a loss of mitochondrial fission at mitosis, improper segregation of mitochondria during cytokinesis and a decrease in ATP levels and cell number. Thus, the two mitotic kinases Aurora A and cyclin B–CDK1 converge on RALA and RALBP1 to promote mitochondrial fission, the appropriate distribution of mitochondria to daughter cells and ultimately proper mitochondrial function.

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Figure 1: Aurora A promotes RALA mitochondrial localization and fission.
Figure 2: RALBP1 promotes mitochondrial fragmentation.
Figure 3: RALA and RALBP1 promote mitochondrial localization of DRP1.
Figure 4: RALBP1 promotes phosphorylation of DRP1.
Figure 5: Knockdown of RALA or RALBP1 prevents mitosis-induced mitochondrial fission.

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Acknowledgements

We thank S. Kornbluth (Duke University, USA) for DRP1 plasmids, C. Freel, S. Johnson, Y. Gao and K. Norris for technical support, S. Issaq (Duke University, USA) for the RALBP1–RALA fusion protein and S. Kornbluth, J. Rathmell, T-P. Yao, C. Der, J. Kashatus and S. Horn for discussions and/or review of the manuscript. This work was supported by NIH grant CA94184 (C.M.C.). D.F.K. is a Leukemia and Lymphoma Society Fellow.

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Author notes

  1. Kian-Huat Lim

    Present address: Present address: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA,

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA

    David F. Kashatus, Kian-Huat Lim, Donita C. Brady, Nicole L. K. Pershing & Christopher M. Counter

  2. Department of Pharmacology and Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    Donita C. Brady & Adrienne D. Cox

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Contributions

Initial pilot experiments were carried out by K-H.L. and expanded on by D.F.K., D.C.B. and N.L.K.P. All authors contributed to the study design. The manuscript was written by D.F.K. and C.M.C. with contributions by K-H.L., D.C.B., N.L.K.P. and A.D.C.

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Correspondence to Christopher M. Counter.

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Kashatus, D., Lim, KH., Brady, D. et al. RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat Cell Biol 13, 1108–1115 (2011). https://doi.org/10.1038/ncb2310

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