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Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
2003 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 8, 6495-6502 p.Article in journal (Refereed) Published
Abstract [en]

The human genomic sequencing effort has revealed the presence of a large number of Rho GTPases encoded by the human genome. Here we report the characterization of a new family of Rho GTPases with atypical features. These proteins, which were called Miro-1 and Miro-2 (for mitochondrial Rho), have tandem GTP-binding domains separated by a linker region containing putative calcium-binding EF hand motifs. Genes encoding Miro-like proteins were found in several eukaryotic organisms from Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster to mammals, indicating that these genes evolved early during evolution. Immunolocalization experiments, in which transfected NIH3T3 and COS 7 cells were stained for ectopically expressed Miro as well as for the endogenous Miro-1 protein, showed that Miro was present in mitochondria. Interestingly, overexpression of a constitutively active mutant of Miro-1 (Miro-1/Val-13) induced an aggregation of the mitochondrial network and resulted in an increased apoptotic rate of the cells expressing activated Miro-1. These data indicate a novel role for Rho-like GTPases in mitochondrial homeostasis and apoptosis.

Place, publisher, year, edition, pages
2003. Vol. 278, no 8, 6495-6502 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96848DOI: 10.1074/jbc.M208609200PubMedID: 12482879OAI: oai:DiVA.org:uu-96848DiVA: diva2:171563
Available from: 2008-03-20 Created: 2008-03-20 Last updated: 2013-10-30Bibliographically approved
In thesis
1. Cell signaling by Rho and Miro GTPases: Studies of Rho GTPases in Cytoskeletal Reorganizations and of Miro GTPases in Mitochondrial Dynamics
Open this publication in new window or tab >>Cell signaling by Rho and Miro GTPases: Studies of Rho GTPases in Cytoskeletal Reorganizations and of Miro GTPases in Mitochondrial Dynamics
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Ras superfamily of GTPases embraces six major branches of proteins: the Ras, Rab, Ran, Arf, Rho and Miro subfamilies. The majority of GTPases function as binary switches that cycle between active GTP-bound and inactive GDP-bound states. This thesis will focus primarily on the biological functions of the Rho and Miro proteins. The Rho GTPases control the organization of the actin cytoskeleton and other associated activities, whereas the Miro GTPases are regulators of mitochondrial movement and morphology.

A diverse array of cellular phenomena, including cell movement and intracellular membrane trafficking events, are dependent on cytoskeletal rearrangements mediated by Rho GTPases. Although human Rho GTPases are encoded by 20 distinct genes, most studies involving Rho GTPases have focused on the three representatives RhoA, Rac1 and Cdc42, which each regulate specific actin-dependent cellular processes. In an effort to compare the effects of all Rho GTPase members in the same cell system, we transfected constitutively active Rho GTPases in porcine aortic endothelial (PAE) cells and examined their effects on the organization of the actin cytoskeleton. We identified a number of previously undetected roles of the different members of the Rho GTPases. Moreover, we demonstrated that the downstream effectors of Rho GTPases have a broader specificity than previously thought.

In a screen for novel Ras-like GTPases, we identified the Miro GTPases (Mitochondrial Rho). In our characterization of Miro, we established that these proteins influence mitochondrial morphology and serve functions in the transport of mitochondria along the microtubule system. Additionally, we provided evidence that Miro can be under control of calcium signaling pathways. Mitochondria are highly dynamic organelles that undergo continuous change in shape and distribution. Defects in mitochondrial dynamics are associated with several neurodegenerative diseases. In conclusion, our findings have contributed to a deeper understanding of the biological roles of Rho and Miro GTPases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 320
Keyword
Ras superfamily, Rho GTPases, cytoskeleton, Miro GTPases, mitochondrial dynamics
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-8514 (URN)978-91-554-7122-4 (ISBN)
Public defence
2008-04-10, B42, Uppsala Biomedical Center, BMC, Husarg. 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-03-20 Created: 2008-03-20Bibliographically approved

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