Abstract
Mitochondria exist as dynamic interconnected networks that are maintained through a balance of fusion and fission. Equal distribution of mitochondria to daughter cells during mitosis requires fission. 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism*
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Adenosine Triphosphate / metabolism
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Aurora Kinases
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CDC2 Protein Kinase / genetics
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CDC2 Protein Kinase / metabolism
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Cell Line
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Cell Proliferation
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Cyclin B / genetics
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Cyclin B / metabolism
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Dynamins
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / metabolism
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GTPase-Activating Proteins / genetics
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GTPase-Activating Proteins / metabolism*
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HeLa Cells
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Humans
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Immunoblotting
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Microscopy, Confocal
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Microscopy, Fluorescence
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Mitochondria / metabolism*
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mitosis*
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Models, Biological
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Phosphorylation
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism
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RNA Interference
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Serine / metabolism
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ral GTP-Binding Proteins / genetics
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ral GTP-Binding Proteins / metabolism*
Substances
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ATP-Binding Cassette Transporters
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Cyclin B
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GTPase-Activating Proteins
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Luminescent Proteins
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Microtubule-Associated Proteins
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Mitochondrial Proteins
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RALBP1 protein, human
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Serine
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Adenosine Triphosphate
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Aurora Kinases
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Protein Serine-Threonine Kinases
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CDC2 Protein Kinase
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GTP Phosphohydrolases
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RALA protein, human
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ral GTP-Binding Proteins
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DNM1L protein, human
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Dynamins